To describe retinal microvascular geometric parameters in young patients with type 1 diabetes.

Patients with type 1 diabetes (aged 12-20 years) had clinical assessment and retinal photography following standardized protocol at a tertiary care hospital in Sydney. Retinal microvascular geometry, including arteriolar and venular tortuosity, branching angles, optimality deviation, and length to diameter ratio (LDR), were measured from digitized photographs. Associations of these geometric characteristics with diabetes duration, HbA1c level, systolic blood pressure (SBP), and other risk factors were assessed.

Of the 1159 patients enrolled, 944 (81.4%) had gradable photographs and 170 (14.7%) had retinopathy. Older age was associated with decreased arteriolar (p=0.024) and venular (p=0.002) tortuosity, and females had larger arteriolar branching angle than males (p=0.03). After adjusting for age and gender, longer diabetes duration was associated with larger arteriolar branching angle (p=<0.001) and increased arteriolar optimality deviation (p=0.018); higher HbA1c was associated with increased arteriolar tortuosity (>8.5% vs ≤8.5%, p=0.008); higher SBP was associated with decreased arteriolar LDR (p=0.002); and higher total cholesterol levels was associated with increased arteriolar LDR (p=0.044) and decreased venular optimality deviation (p=0.044). These associations remained after controlling for HbA1c, retinal vessel caliber and retinopathy status, and were seen in subjects without retinopathy.

Key diabetes-related factors affect retinal microvascular geometry in young type 1 diabetes, even in those without evidence of retinopathy. These early retinal alterations may be markers of diabetes microvascular complications.

To evaluate whether use of oral hypoglycaemic agents is associated with an altered breast cancer risk in women.

Using the UK-based General Practice Research Database (GPRD), we conducted a nested case-control analysis among 22,621 female users of oral antidiabetic drugs with type 2 diabetes mellitus. We evaluated whether they had an altered risk of breast cancer in relation to use of various types of oral hypoglycaemic agents. Cases and controls with a recorded diagnosis of diabetes mellitus type 2, were matched on age, calendar time, and general practice, and the multivariate conditional logistic regression analyses were further adjusted for use of oral antidiabetic drugs, insulin, estrogens, smoking, body mass index (BMI), diabetes duration, and HbA1c.

We identified 305 cases with a recorded incident diagnosis of breast cancer. The mean age was 67.5 (±std 10.5) years at the time of the cancer diagnosis. Long-term use of 40+ prescriptions (>5 years) of metformin, based on 17 exposed cases and 120 exposed controls, was associated with an adjusted OR of 0.44 (95% CI 0.24-0.82) for developing breast cancer, as compared to no use of metformin. Neither short-term metformin use, nor use of sulfonylureas or other antidiabetic drugs were associated with a materially altered risk for breast cancer.

A decreased risk of breast cancer was observed in female patients with type 2 diabetes mellitus using metformin on a long-term basis.

We hypothesized that people with type 2 diabetes in an on-line diabetes self-management program, compared to usual-care controls, would demonstrate 1) reduced A1c at 6 and 18 months, 2) have fewer symptoms, 3) increased exercise and 4) improved self-efficacy and patient activation. In addition, participants randomized to listserve reinforcement would have better 18-month outcomes than participants receiving no reinforcement.

761 participants were randomized to 1) the program, 2) program with email reinforcement, or 3) usual-care controls (no treatment). This sample included 110 American Indians/Alaska Natives (AI/AN). Analyses of covariance models were used at 6 and 18-month follow-up to compare groups.

At six months A1c, patient activation and self efficacy were improved for program participants compared to usual care controls (p<.05). There were no changes in other health or behavioral indicators. The AI/AN program participants demonstrated improvements in health distress and activity limitation compared to usual-care controls The subgroup with initial A1c above 7 demonstrated stronger improvement in A1c (p=.01). At 18 months, self-efficacy and patient activation were improved for program participants. A1c was not measured. Reinforcement showed no improvement.

An on-line diabetes self-management program is acceptable for people with type 2 diabetes. Although the results were mixed they suggest 1) that the program may have beneficial effects in reducing A1c, 2) AI/AN populations can be engaged in and benefit from on-line interventions, and 3) our follow-up reinforcement appeared to have no value.

To derive a 5-year cardiovascular (CVD) risk equation from usual care data that is appropriate for people with type 2 diabetes from a wide range of ethnic groups, variable glycaemic control and high rates of albuminuria in New Zealand.

This prospective open cohort study used primary care data from 36,127 people with type 2 diabetes without previous cardiovascular disease to derive a CVD equation using Cox proportional hazards regression models. Data from 12,626 people from a geographically different area were used for validation. Outcome measure was time to first fatal or non-fatal cardiovascular event, derived from national hospitalisation and mortality records. Risk factors were age at diagnosis, diabetes duration, sex, systolic blood pressure, smoking status, total cholesterol:HDL ratio, ethnicity, glycated haemoglobin and urine albumin:creatinine ratio.

Baseline median age was 59 years, 51% were women, 55% of non-European ethnicity and 33% had micro- or macro-albuminuria. Median follow-up was 3.9 years (141,169 person-years) including 10,030 individuals followed for at least 5 years. 6,479 first cardiovascular events occurred during follow-up. The 5-year observed risk was 20.8% (95%CI: 20.3%,21.3%). Risk increased with each 1% HbA1c (adjusted hazard ratio 1.06 (1.05,1.08)), when macroalbuminuria was present (2.04, (1.89,2.21)), and in Indo-Asians (1.29 (1.14,1.46)) and Maori (1.23 (1.14,1.32)) compared with Europeans. The derived risk equations performed well on the validation cohort compared with other risk equations.

Renal function, ethnicity and glycaemic control contribute significantly to cardiovascular risk prediction. Population-appropriate risk equations can be derived from routinely collected data.

Any combination of metabolic abnormalities may constitute the "metabolic syndrome" (MetS), conferring coronary artery disease (CAD) risk, but the independent effect of different combinations on CAD onset remains unknown.

Healthy adult siblings (N=987) of premature CAD (<60 years) cases were followed for 9.8 ± 3.8 years. Baseline MetS variables (insulin sensitivity index, waist circumference, systolic blood pressure, HDLC, and triglycerides) were recombined into 5 principal components (PC1-5) and risk-factor adjusted proportional hazards for CAD onset of median-dichotomized PCs estimated.

The significant hazard ratios were, for PC1 (all abnormalities except blood pressure) 1.66 (p=0.036), PC2 (high blood pressure levels, high HDLC) 1.71 (p=0.016), and PC4 (low HDLC, high insulin sensitivity, low triglycerides) 2.0 (p=0.001). Traditionally defined MetS had a HR of 1.32 (p=0.18).

Independent MetS variants identified by PC analysis may explain metabolic mechanisms that increase CAD risk better than the presence of traditional MetS.

Type 2 diabetes is associated with a moderate degree of cerebral atrophy and a higher white matter hyperintensity (WMH) volume. How these brain imaging abnormalities evolve over time is unknown. The present study aims to quantify cerebral atrophy and WMH progression over 4 years in type 2 diabetes.

55 patients with type 2 diabetes and 28 age, sex and IQ matched controls had two 1.5T MRI scans with a 4 year interval. Volumetric measurements of total brain, peripheral cerebrospinal fluid (CSF), lateral ventricles and WMH were performed with k-Nearest Neighbor-based probabilistic segmentation. All volumes were expressed as percentage of intra-cranial volume. Linear regression analyses, adjusted for age and sex, were performed to compare brain volumes between the groups and to identify determinants of volumetric change within the type 2 diabetes group.

At baseline patients with type 2 diabetes had a significantly smaller total brain volume and larger peripheral CSF volume than controls. In both groups all volumes showed a significant change over time. Patients with type 2 diabetes had a greater increase in lateral ventricular volume than controls (mean adjusted between group difference in change over time (95% confidence interval): 0.11% in 4 years (0.00 to 0.22), p=0.047).

The greater increase in lateral ventricular volume over time in patients with type 2 diabetes as compared with controls shows that type 2 diabetes is associated with a slow increase of cerebral atrophy over the course of years.

Acute, short-term hyperglycemia enhances high shear-stress-induced platelet activation in type-2-diabetes-mellitus (T2DM). Several observations suggest that platelets in T2DM are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide-donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in T2DM.

In a double-blind, placebo-controlled, randomized trial, 40 T2DM patients were allocated to aspirin 100mg, o.i.d., NCX 4016 800 mg, b.i.d., both of them, or placebo, for 15 days. On day 15, one hour after the morning dose, a four-hour hyperglycemic clamp (plasma glucose 13.9mmol/l) was performed and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies.

Acute hyperglycemia enhanced shear stress-induced platelet activation in placebo-treated patients (basal closure time 63±7.1sec, after hyperglycemia 49.5±1.4sec, –13.5±6.3sec, P<0.048); pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (–12.7±6.9sec, P=NS vs placebo); on the contrary, pretreatment with the NO-donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016:+10.5±8.3sec; NCX 4016 plus aspirin:+12.0±10.7sec, P<0.05 vs placebo for both). Other parameters of shear-dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1.

Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with T2DM.

To investigate if long-acting insulin analogs decrease the risk of diabetic ketoacidosis (DKA) in young individuals with type 1 diabetes.

Of 48,110 type 1 diabetes patients prospectively studied between 2001 and 2008, the incidence of DKA requiring hospitalization was analyzed in 10,682 individuals aged ≤20 years with a diabetes duration of ≥2 years.

The overall rate of DKA was 5.1 (SE ± 0.2)/100 patient-years. Patients using insulin glargine or detemir (n = 5317) had a higher DKA incidence than individuals using NPH insulin (n = 5365, 6.6 ± 0.4 vs. 3.6 ± 0.3, p < 0.001). The risk for DKA remained significantly different after adjustment for age at diabetes onset, diabetes duration, A1C, insulin dose, sex and migration background (p = 0.015, odds ratio 1.357 [1.062-1.734]).

Despite their long-acting pharmacokinetics, the use of insulin glargine or detemir is not associated with a lower incidence of DKA compared to NPH insulin.

To assess whether TCF7L2 polymorphism has a role in the deterioration of glycemic control.

Metabolic variables were evaluated at baseline and after 6-year follow-up in 1,480 Caucasian subjects from a population-based cohort.

At baseline, T allele carriers showed significantly lower BMI and Homeostasis-Model-Assessment-for-β-cell-function (HOMA-B) values and higher fasting glycemia and diabetes prevalence. At follow-up, fasting glucose and HOMA-B index were increased and reduced, respectively, in carriers of the T allele. Incident impaired fasting glucose (IFG) and incident diabetes were 5.7%, 10.7%, 16.9% and 1.6%, 1.7%, 3.0%, in the CC, CT, TT genotypes, respectively. In a multiple logistic regression model, the association between incident IFG and the T allele was significant (OR=2.08; 95%CI 1.35-3.20 and OR=3.56; 95%CI 2.11-5.98, in CT and TT genotypes, respectively).

The T allele of TCF7L2 rs7903146 polymorphism was independently associated with increasing fasting glucose values toward hyperglycemia in the follow-up.

We used confirmatory factor analysis to test whether a single factor might explain the clustering of the metabolic syndrome (MS) components in children.

We studied 1020 children aged 10-13 years from 20 schools in Cuenca, Spain. The single-factor model included: waist circumference (WC), fasting insulin, triglycerides to HDL-cholesterol ratio (Triglyl/HDL-c), and mean arterial pressure (MAP). The standardized scores of the four variables in the model were used to develop a continuous MS index.

Factor loadings were 0.67 for WC, 0.68 for fasting insulin, 0.57 for Triglyl/HDL-c, and 0.37 for MAP. The single-factor model also showed a good fit to the data. As compared with the ATP III criteria, the MS index showed a good validity in the diagnosis of MS (area under the ROC curve=0.98; 95% confidence interval 0.96-0.99).

A single underlying factor has acceptable validity to represent MS in children.

Diabetes and heart failure commonly co-exist and prior studies suggested better outcomes with metformin than other antidiabetic agents. We designed this study to determine whether this association reflects a beneficial effect of metformin or a harmful effect of other agents.

Case control study nested within the United Kingdom General Practice Research Database cohort in which diagnoses are assigned by each patient's primary care physician. Cases were patients 35 years or older newly diagnosed with both heart failure and diabetes after January 1988 and who died prior to October 2007. Controls were matched to cases based on age, sex, clinic site, calendar year, and duration of follow-up and analyses were adjusted for comorbidities, A1C, renal function, and body mass index.

The duration of concurrent diabetes and heart failure was 2.8 years (SD 2.6) in our 1633 cases and 1633 controls (mean age 78 years, 53% male). Compared to patients who were not exposed to antidiabetic drugs, current use of metformin monotherapy (adjusted OR 0.65 [0.48 to 0.87]) or metformin with/without other agents (adjusted OR 0.72 [0.59 to 0.90]) was associated with lower mortality; however, use of other antidiabetic drugs or insulin was not associated with all-cause mortality. Conversely, use of ACE inhibitors/ARBs (adjusted OR 0.55 [0.45 to 0.68]) and beta-blockers (adjusted OR 0.76 [0.61 to 0.95]) were associated with reduced mortality.

Our results confirm the benefits of trial-proven anti-failure therapies in patients with diabetes and support the use of metformin-based strategies to lower glucose.

Sulfonylureas have historically been analyzed as a medication class, which may be inappropriate given the differences in properties inherent to the individual sulfonylureas: hypoglycemic risk, sulfonylurea receptor selectivity and effects on myocardial ischemic preconditioning. The purpose of this study was to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes.

A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 11,141 patients with type 2 diabetes (4,279 initiators of monotherapy with glyburide, 4,325 initiators of monotherapy with glipizide, and 2,537 initiators of monotherapy with glimepiride), ≥ 18 years of age, with and without a history of coronary artery disease (CAD), and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models were used to compare cohorts.

No statistically significant difference in the risk of overall mortality was observed among these agents in the entire cohort, but we did find evidence of a trend towards an increased overall mortality risk with glyburide vs. glimepiride (HR 1.36; CI 0.96-1.91) and glipizide vs. glimepiride (HR 1.39; 95% CI 0.99-1.96), in those with documented CAD.

Our results did not identify an increased mortality risk among the individual sulfonylureas but did suggest that glimepiride may be the preferred sulfonylurea in those with underlying CAD.

Intensive therapy targeting normal blood glucose increased mortality compared to standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes(T2DM) at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the ACCORD participants.

CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-sec resting electrocardiograms in 8,135 ACCORD participants with valid measurements, mean age 63.0 years, 40 % females. Prespecified CAN definitions included a composite of lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history and multiple prespecified baseline covariates.

During a mean 3.5 years follow-up there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55-2.14 times as likely to die as participants without CAN, depending on the CAN definition used (p<0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (P for interaction>0.7).

Whereas CAN was associated with increased mortality in this high-risk T2DM cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

To determine how childhood overweight, in conjunction with other life course weight characteristics, relates to the development of type 2 diabetes in adulthood.

Among 109,172 women in the Nurses' Health Study II, body fatness at ages 5, 10, and 20 years was assessed by recall using 9-level pictorial diagrams (somatotypes) representing extreme thinness (category "1") to obesity (category "9"). Recalled weight at age 18 years and adulthood were used to derive BMI. Self-reported type 2 diabetes cases were confirmed by supplementary questionnaire.

Somatotypes at ages 5 and 10 years were positively associated with diabetes risk (p-trends <0.0001). The adjusted relative risks (RR) of women with somatotype ≥"6" (versus "2") at age 5 years was 2.19 (95% CI: 1.79-2.67) and at age 10 years was 2.57 (2.20-3.01). Increases in size by somatotype or by weight gain since age 18 were associated with increased risk. Compared to women who were never overweight at any age, women who were overweight as an adult (BMI >25) but not previously had an adjusted RR of 8.23 (7.41-9.15). The adjusted RR was 15.10 (13.21-17.26) for women who were also overweight at age 10 (somatotype ≥"5") and 18 (BMI >25). Increased childhood size was not associated with risk among women who did not continue to be overweight in adulthood.

Increased body size starting from childhood is associated with a greater risk of diabetes in adulthood. However, women who become lean in adulthood do not have an increased risk.

To study trough levels of metformin in serum and its intra individual variation in patients using a newly developed assay.

Trough serum levels of metformin was measured once using Liquid Chromatography Tandem Mass Spectrometry (LcMSMS) in 137 type 2 diabetes patients with varying renal function (99 men) and followed repeatedly during two months in 20 patients (16 men) with estimated GFR (eGFR) below 60 ml/min/1.73 m² body surface.

Patients with eGFR >60, 30-60, and <30 ml/min/1.73 m² had a median trough metformin concentration of 4.5 µmol/l (range 0.1-20.7, n=107), 7.71 µmol/l (0.12-15.15, n=21), and 8.88 µmol/l (5.99-18.60, n=9), respectively. The median intraindividual overall coefficient of variation (CV) was 29.4 % (range 9,8-74,2).

Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values over 20 µmol/L. Metformin measurement is less suitable for dose titration.

Adolescent offspring of women with history of gestational diabetes (GD) was evaluated for their cardiometabolic risks at a mean age of 15 years.

129 adolescents who were assessed for their cardiometabolic risks at 8 years of age were reassessed at 15 years of age.

Adolescent offspring of mothers with GD had similar blood pressure, plasma lipid profile and rate of abnormal glucose tolerance as controls. In utero hyperinsulinemia was associated with 17-fold increase in metabolic syndrome and 10-fold increase in overweight at adolescence, independent of birth weight, Tanner stage, maternal GD status and mother's BMI.

In utero environment of hyperinsulinemia, irrespective of the degree of maternal GD, was associated with increased risk of overweight and metabolic syndrome during early adolescence in the offspring.

Diabetes during pregnancy is a strong risk factor for obesity in the offspring but the age at which this association becomes apparent is unknown. The purpose of this study was to examine the relation of glycaemia during pregnancy with anthropometry in offspring of non-diabetic pregnant women from the Belfast UK center of the multi-national Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO).

Women from the HAPO study were invited to participate in follow up of their offspring aged 2 years. Measurements included height, weight and thickness of triceps, subscapular and suprailiac skin folds.

1165 offspring (72%) of eligible children (598 boys, 567 girls) were seen from ages 22-30 completed months. The only association that reached statistical significance was between categories of maternal 1-hour glucose and BMI z-score ≥85^th percentile at 2 years (p=0.017). Overall the correlations between maternal glucose during pregnancy and BMI z-score at age 2 years were weak (fasting glucose r=0.05, p=0.08, 1h-glucose r=0.04, p=0.22, 2h-glucose r=0.03, p=0.36, and area under the curve for glucose (r=0.04, p=0.18).

This study found little association between maternal glucose during pregnancy and obesity in the offspring at this young age. These findings are not unexpected given that studies of young offspring whose mothers had diabetes during pregnancy were indistinguishable from normal at this age. It will be interesting to see if, as these children age, maternal glucose during pregnancy in the ranges included in the HAPO study will be associated with obesity in their children.

To examine cross-sectional associations of serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration with insulin resistance (IR) and beta (β)-cell dysfunction in 712 subjects at risk for type 2 diabetes.

Serum 25(OH)D was determined using a chemiluminescence immunoassay. Insulin sensitivity/resistance were measured using the Matsuda index (IS_OGTT) and HOMA-IR. Beta-cell function was determined using both the insulinogenic index divided by HOMA-IR (IGI/IR) and the Insulin Secretion Sensitivity Index-2 (ISSI-2).

Linear regression analyses indicated independent associations of 25(OH)D with IS_OGTT andHOMA-IR (β=0.004, p=0.0003 and β=-0.003, p=0.0072 respectively), and with IGI/IR and ISSI-2 (β=0.004, p=0.0286 and β=0.003, p=0.0011 respectively), after adjusting for sociodemographics, physical activity, supplement use, parathyroid hormone and BMI.

Vitamin D may play a role in the pathogenesis of type 2 diabetes, as 25(OH)D concentration was independently associated with both insulin sensitivity and β-cell function among individuals at risk of type 2 diabetes.

Oral leukoplakia is an oral lesion with a premalignant character. Besides smoking and alcohol, diabetes could be a risk factor. The aim is to search for such an association.

Subjects with leukoplakia (N=123) from the population-based Study of Health in Pomerania (SHIP) were matched 1:2 for age and gender with unaffected controls. Behavioral and lifestyle factors were assessed by a questionnaire. Lipoprotein concentrations, glycemia and inflammation parameters were determined.

Subjects with oral leukoplakia showed higher levels of diabetes-related metabolites, LDL/HDL-cholesterol ratio (p=0.004) and HbA_1c (p=0.002) and they were more frequently smokers (p<0.001). Assessed by conditional logistic regression, the probability of leukoplakia increases with current smoking (OR=2.20, 95%C.I. 1.16-4.17) and higher levels of HbA_1c (OR=1.51, 1.08-2.12) revealing interaction between both factors (p=0.012).

Diabetes is associated with the risk of oral leukoplakia which is exaggerated by smoking. The risk is positively correlated with HbA_1c concentrations.

To evaluate day-to-day variations of insulin needs in Type 2 diabetic patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD).

We developed a 24-hour euglycemic clamp in patients receiving an average 2200 calories in a standardized 3-meal and 2-snack regimen per day adjusted to body size and sex. Intravenous insulin was adjusted every 30 minutes to achieve 5.5±1.1mmol/l glycemia over 24 hours pre-HD, during HD session, and 24 hours post-HD in 10 type 2 diabetic patients aged 55.7±8.7 years with 11.9±4.5 years diabetes duration, undergoing maintenance HD since 2.3±2.3 years. Insulin requirements were derived from the dose of insulin administered to maintain euglycemia per period of time, and day-to-day comparisons performed.

Mean capillary glycemia was 5.5±0.3mmol/l pre-HD and 5.3±0.2mmol/l post-HD (p=0.39). Pre- and post-HD area under the glucose curve were comparable. This was achieved by infusing 23.6±7.7IU/24h pre-HD vs. 19.9±4.9IU/24h post-HD, indicating 15.3%-decrease post HD (p=0.09). Basal insulin needs decreased from 0.4±0.1/hour pre-HD to 0.3±0.1/hour post-HD (p=0.01). Total boluses were decreased by 2.2±3.1IU (p=0.15). Changes in blood urea did not correlate with changes in insulin needs (r=0.1, p=0.79).

The present study has demonstrated a significant 25% reduction in basal insulin requirements the day after dialysis compared to the day before. No significant change in boluses was observed, and overall the reduction of total insulin requirements was –15% equivalent to –4IU/day post HD of marginal statistical significance.

Data relating vitamin D status with indices of glucose homeostasis as manifested by A1c in the U.S. adult population are few.

We examined the association between serum 25-OH vitamin D and A1c levels in 9773 adults (age ≥ 18 years old) participating in the 2003-2006 National Health and Nutrition Examination Survey. Multivariate linear regression analyzed the association after accounting for potential confounders.

Serum 25-OH vitamin D levels were inversely associated with A1c levels in subjects age 35 to 74 years (p=0.0045) and those who did not report a history of diabetes mellitus (p=0.0282).

These findings support a mechanistic link between serum vitamin D concentrations, glucose homeostasis, and the evolution of diabetes in a large segment of the U.S. adult population. Screening people with elevated A1c levels for vitamin D insufficiency should be considered.

To characterize glucose levels during daily living using continuous glucose monitors (CGM) in non-diabetic individuals.

Seventy-four healthy, non-obese children, adolescents, and adults aged 9-65 years with normal glucose tolerance used a blinded CGM device for 3 to 7 days.

Sensor glucose concentrations were 71-120 mg/dL for 91% of the day. Sensor values were ≤60 or >140 for only 0.2% and 0.4% of the day, respectively. Sensor glucose concentrations were slightly higher in children than adults (P=0.009) and were slightly lower during the night than day (95 mg/dL versus 99 mg/dL, P<0.001).

Glucose values ≤60 mg/dL and >140 mg/dL, measured with CGM, are uncommon in healthy, non-diabetic individuals. CGM may be useful to evaluate glucose tolerance in non-diabetic individuals over time. Furthermore, these data provide a basis for comparison for studies that use CGM to assess glucose control in subjects with diabetes.

Risks of diabetes and cardiovascular disease are elevated worldwide in Indian Asians. However, risks of other diabetes-related complications, i.e. foot ulceration and amputation, also with a vascular basis, are substantially lower in Asians than White Europeans in the UK, possibly due to less neuropathy. We therefore compared signs, symptoms and objective quantitative measures of diabetic neuropathy, and their risk factors, in Indian Asians and Europeans.

This was a cross-sectional study of a population-based sample of age- and sex-matched adults with type 2 diabetes of European (95 male: 85 female) and Asian (96 male: 84 female) descent in the UK. Patients were assessed for neuropathic symptoms, signs, nerve conduction, autonomic function and quantitative sensory testing. Peripheral vascular function and other potential risk factors for neuropathy were measured.

Mean nerve conduction velocity Z-scores were better in Asians (0·07±0·62; mean±SD) than Europeans (–0·11±0·60; p=0·007) and were explained by the shorter height, fewer pack-years smoked and higher transcutaneous oxygen levels (TCpO₂) in Indian Asians (p value for ethnic comparison attenuated to 0·2). Small fibre neuropathy was less prevalent in Indian Asians compared to Europeans (odds ratio 0.58 (95% CI 0·37-0·93) p=0.02) and was primarily accounted for by better TCpO₂ (0.70 (0·40-1·21) p=0.2).

Asians with diabetes have substantially less large and small fibre neuropathy than Europeans, despite comparable traditional risk factors. Independent from smoking, the lower risk of neuropathy in Asians is due to better skin microvascularisation and may help explain the substantially reduced Asian foot ulcer risk.

To evaluate an algorithm guiding responses of Continuous Subcutaneous Insulin Infusion (CSII) treated Type 1 diabetes (T1D) patients using real time-continuous glucose monitoring (RT-CGM).

Sixty CSII-treated T1D participants (13-70Y, including adult and adolescent subgroups, HbA_1c≤9.5%) randomised in age, gender and HbA_1c matched pairs. Phase 1: Open 16 week multi-center randomised controlled trial. Group A: CSII/RT-CGM with algorithm. Group B: CSII/RT-CGM without algorithm. Primary outcome: Difference in time in target (4-10mmol/L) glucose range on six-day masked-CGM. Secondary outcomes: Differences in HbA_1c, low (≤3.9mmol/L) glucose CGM time and glycemic variability. Phase 2: Week 16-32 follow-up: Group A: Returned to usual care. Group B: Provided algorithm. Glycemia parameters as above. Comparisons were made between baseline and 16 and 32 weeks.

Phase 1: Withdrawals left 29/30 (Group A) and 28/30 (Group B) subjects. Change in target glucose time did not differ between groups. HbA_1c (mean[95%CI]) fell (7.9[7.7-8.2]% to 7.6[7.2-8.0]%; p<0.03) in Group A but not Group B (7.8[7.5-8.1]% to 7.7[7.3-8.0]% p=NS) with no difference between groups. More of Group A achieved HbA1c≤7% than Group B (2/29 to 14/29 vs. 4/28 to 7/28; p=0.015). Phase 2: One participant was lost from each group. Group A HbA_1c returned to baseline with RT-CGM discontinuation, but did not change in Group B who continued RT-CGM with algorithm addition.

Early but not late algorithm provision to T1D patients using CSII/RT-CGM did not increase target glucose time but increased HbA_1c ≤7% achievement. Upon RT-CGM cessation HbA_1c returned to baseline.

The primary aim of the study was to investigate the relationship among executive functioning, diabetes treatment adherence, and glycemic control.

Two hundred and thirty-five children with type 1 diabetes and their primary caregivers were administered the Diabetes Self-Management Profile (DSMP) to assess treatment adherence. Executive functioning was measured using the Behavior Rating Inventory of Executive Functioning (BRIEF) and glycemic control was based on hemoglobin A1c.

Structural equation modeling indicated that a model in which treatment adherence mediated the relationship between executive functioning and glycemic control best fit the data. All paths were significant at p<.01.

These results indicate that executive functioning skills (e.g. planning, problem-solving, organization, and working memory) were related to adherence, which was related to diabetes control. Executive functioning may be helpful to assess in ongoing clinical management of type 1 diabetes.

While single assessments of cardiorespiratory fitness have been shown to predict lower incidence of type 2 diabetes mellitus, there are no data on long-term trends in fitness and risk. We investigated the relationship between long-term trends in fitness and the incidence of type 2 diabetes.

A cohort of 4187 Japanese men free of diabetes completed annual health check-ups and fitness tests for estimated maximal oxygen uptake at least four times over seven years (1979-1985). We modeled the trend in fitness over seven years for each man using simple linear regression. Men were then divided into quartiles based on the regression coefficient (slope) from the model. During the follow-up period 1985-1999, 274 men developed diabetes. Hazard ratios and 95% CI for the incidence of diabetes were obtained using Cox proportional hazards model.

Men in the lowest quartile of the distribution decreased in fitness over the seven years (median slope, -1.25 ml/kg/min), while men in the highest quartile increased in fitness (median slope, 1.33 ml/kg/min). Adjusting for age, initial fitness level, body mass index (BMI), systolic blood pressure, cigarette smoking, alcohol intake, and a family history of diabetes, and using the lowest quartile, the hazard ratios and 95% CI for the 2nd through 4th quartiles were 0.64 (0.46-0.89), 0.40 (0.27-0.58), and 0.33 (0.21-0.50), respectively (P < 0.001 for trend).

These results indicate that the long-term trend in fitness is a strong predictor of the incidence of type 2 diabetes in Japanese men.

In the DURATION-1 study, the safety and efficacy of 30 weeks of treatment with the GLP-1 receptor agonist exenatide once weekly (exenatide QW; 2mg) was compared to exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in a) patients who continued treatment for an additional 22 weeks (52 weeks total), and b) patients who switched from exenatide BID to exenatide QW after 30 weeks.

In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n=128 QW-only; n=130 BID->QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.

Patients continuing exenatide QW maintained A1C improvements through 52 weeks (–2.0% [–2.1 to –1.8%]; LS mean [95% CI]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71% and 54% of all patients achieved an A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dL and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.

Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment; patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

ClinicalTrials.gov identifier: NCT00308139

To determine the prevalence of subnormal testosterone concentrations in patients with obesity and with type 2 diabetes in a primary care clinic population.

FT concentrations of 1849 men(1451 non-diabetic and 398 diabetic) in the Hypogonadism In Males(HIM) study were analyzed. HIM study was a US based cross-sectional study designed to define the prevalence of hypogonadism in men older than 45 years. FT was measured by equilibrium dialysis.

Prevalence of subnormal FT concentrations in lean, overweight and obese non-diabetic men was 26%(n=275), 29%(n=687) and 40%(n=489) respectively(p<0.001 for trend); and 44% (n=36), 44%(n=135) and 50%(n=227) respectively in diabetic men (p=0.46 for trend within group, p<0.05 compared to non-diabetic men). Mean FT concentration of diabetic men was significantly lower than that of non-diabetic men. FT concentrations were negatively and significantly (p<0.001) related to age(r=–0.37), BMI(r=–0.18) and SHBG(r=–0.11) in multiple regression analysis. The average decline of FT concentrations was 7.8 pg/ml/decade in non diabetic and 8.4 pg/ml/decade in diabetic men.

40% of obese non-diabetic and 50% of obese diabetic men above the age of 45 years have subnormal FT concentrations. In view of its high prevalence, obesity is probably the condition most frequently associated with subnormal FT concentration in males. The concomitant presence of diabetes is associated with an additional increase in prevalence of subnormal FT concentration.

Diabetic patients have a high prevalence of coronary artery disease (CAD), but timely diagnosis of CAD remains challenging. We assessed the ability of coronary CT angiography (CCTA) to detect CAD in diabetic patients and to predict subsequent cardiac events.

We analyzed 140 diabetic patients without known CAD undergoing CCTA. 1782 patients without diabetes were used as control group. Besides calcium scoring and the degree of the most severe stenosis, the atherosclerotic burden score counting the number of segments having either a nonstenotic plaque or a stenosis was recorded. The primary endpoint was a composite of hard cardiac events defined as all cause death, nonfatal myocardial infarction or unstable angina requiring hospitalization.

During a mean follow-up of 33 months, there were 7 events in the diabetes group and 24 events in the control group. The best predictor in diabetic patients was the atherosclerotic burden score: the annual event rate ranged from 0.5% for patients with less than 5 lesions to 9.6% for patients with more than 9 lesions resulting in a hazard ratio of 1.3 (95% CI 1.1 to 1.7) for each additional lesion (p=0.005). For comparison, in nondiabetic patients the annual event rate ranged from 0.3% to 2.2% respectively resulting in a hazard ratio of 1.2 (95%CI 1.1 to 1.3, p<0.001). The atherosclerotic burden score improved significantly the prognostic value of conventional risk factors (p<0.001)

In diabetic patients without known CAD, CCTA can identify a patient group at particularly high risk for subsequent hard cardiac events.

To determine whether glargine was non-inferior to detemir regarding the percentage of patients reaching HbA1c <7% without symptomatic hypoglycemia ≤3.1 mmol/l.

In this 24-week trial, 973 insulin-naive type 2 diabetic patients on stable OGLDs and HbA1c 7.0-10.5% were randomized to glargine once-daily or detemir twice-daily. Insulin doses were systematically titrated.

27.5 and 25.6% of patients reached the primary outcome with glargine and detemir, demonstrating non-inferiority of glargine. Improvements in HbA1c were –1.46±1.09% for glargine and –1.54±1.11% for detemir (P=0.149), with similar proportions of patients achieving HbA1c <7% (P=0.254), but more detemir-treated patients reaching HbA1c <6.5% (P=0.017). Hypoglycemia risk was similar. Weight gain was higher for glargine (difference: 0.77 kg, P<0.001). Glargine doses were lower than detemir doses: 43.5±29.0 versus 76.5±50.5 units/day (P<0.001).

In insulin-naive type 2 diabetic patients, glargine reached similar control as detemir, with more weight gain, but requiring significantly lower doses.

To measure relative and absolute educational disparities in mortality among US adults with diabetes and to compare their magnitude to disparities observed within the non-diabetic population.

85 867 individuals (5007 with diabetes) aged 35-84 years who participated in the National Health Interview Survey from 1986 to 1996 were followed for mortality through December 31, 2002. Relative and absolute educational disparities in all-cause, CVD and non-CVD mortality were measured.

In relative terms, the risk of all-cause mortality was 28% higher in diabetic adults with the lowest versus the highest position on the educational scale (Relative Index of Inequality, RII 1.28 [1.08-1.53]). This inverse relationship reflected marked disparities in CVD mortality and was found in all age, gender and race/ethnicity groups except Hispanics. Although substantial, this relative educational gradient in mortality among adults with diabetes was smaller than in the non-diabetic population. In absolute terms, diabetic adults with the lowest position on the educational scale suffered 503 excess deaths per 10 000 person-years of follow-up as compared to those with the highest position. These absolute disparities were stronger than in the non-diabetic population. The results were even more striking for CVD mortality.

The risk of mortality differs substantially according to educational level among persons with diabetes in the US. Although relative educational disparities in mortality are weaker in adults with versus without diabetes, their absolute impact is greater and translates into a major mortality burden.

We aimed to establish optimal definitions for abdominal obesity and metabolic syndrome (MetS) among Andean adults.

Among 1448 Andean adults, we assessed the relationship between waist circumference (WC) and: (1) Subclinical vascular disease assessed by carotid intima-media thickness (cIMT); (2) Manifest cardiovascular disease (M-CVD).

Optimal WC cutoffs to classify individuals with abnormal cIMT or M-CVD were >97 and >87 cm in men and women, respectively. With these cutoffs, there was substantial disagreement between the original American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) and the recently updated MetS definition, particularly among men (kappa=0.85). Subjects with MetS identified by the updated definition but not meeting original AHA/NHLBI MetS-criteria demonstrated significantly increased cIMT (p<0.001) compared to subjects who did not meet MetS-criteria by either definition.

Our findings support the use of ethnic-specific WC cutoffs and the updated MetS-definition in Andean adults.

We describe the long term outcomes of 510 diabetic patients with Critical Limb Ischemia(CLI), seen at the University Hospital of Rome Tor Vergata, a tertiary care clinic, and an active foot ulcer or gangrene.

These patients were seen between 11/02 and 11/07 (mean FU 20±13mo.1-66). The Texas Wound Classification(TWC) was used to grade these wounds that were either class C(ischemia) and D(ischemia+infection) and grade 2-3(deep-very deep).

This comprehensive treatment protocol includes rapid and extensive initial debridment, aggressive use of peripheral Percutaneous Angioplasty (PA), empiric IV antibiotic therapy and strict follow-up.

The protocol was totally applied in 456(89.4%)(PA+) and partially(without PA) in 54(10.6%) patients(PA–).

Outcomes for whole and PA+ve and PA–ve patients are respectively n(%): Healing: 310(60.8), 284(62.3), 26(48.1); Major amputation: 80(15.7), 67(14.7) 13(24.1); Death: 83(16.27), 68(14.9), 15(27.8); Nonhealing(NH): 37(7.25), 37(8.1), 0(0);(²<0.0009).

Predicting variables at multivariate analysis: Healing: ulcer dimension, infection and ischemic heart disease; Major amputation: ulcer dimension, number of minor amputations and age. Additional predicting variables for PA+ patients: Healing: TcPO2; Major amputation: Basal TcPO², basal HbA1c, TcPO² and PA technical failure.

The early diagnosis of CLI, the aggressive treatment of infection, extensive use of PA in ischemic affected ulcers offers improved outcome for many previously at risk limbs. Ulcer size>5cm² indicates reduced chance of healing and increased risk of major amputation.

It was felt that all ulcers warrant aggressive treatment including PA and that treatment should be considered even in the presence of small ischemic ulcers.

Restoration of insulin secretion is critical for the treatment of type 2 diabetes mellitus (T2DM). Exercise and diet can alter glucose-induced insulin responses but whether this is due to changes in β-cell function per se is not clear. The mechanisms by which lifestyle-intervention may modify insulin secretion in T2DM have also not been examined, but may involve the incretin axis.

Twenty-nine older, obese (age 65±1 y; BMI 33.6±1.0 kg/m²) subjects, including newly-diagnosed T2DM patients (Obese-T2DM) and normal glucose-tolerant (Obese-NGT) individuals, underwent three-months of nutritional counseling and exercise training. β-cell function (oral-glucose-induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) was examined.

Following exercise and diet-induced weight loss (–5.0±0.7 kg), oral-glucose-induced insulin secretion was increased in Obese-T2DMs, and decreased in Obese-NGT subjects (both P<0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the Obese-T2DM group (1.23±0.26 vs. 2.04±0.46 a.u.; P<0.01). Changes in insulin secretion were directly related to the GIP responses to oral-glucose (r=0.64, P=0.005), which were augmented in Obese-T2DMs and only moderately suppressed in Obese-NGTs.

Following lifestyle-induced weight-loss, improvements in oral-glucose-induced insulin secretion in older, obese, non-diabetics appear largely dependent on improved insulin sensitivity. However, in older obese diabetics, improved insulin secretion is a consequence of elevated β-cell function. We demonstrate for the first time, that changes in insulin secretion following lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells.

To characterize the amount of nocturnal hypoglycemia and evaluate factors associated with nocturnal hypoglycemia assessed with continuous glucose monitoring (CGM) in adults and children with type 1 diabetes who participated in the JDRF CGM Randomized Clinical Trial.

The analysis included 36,467 nights with ≥4 hours of CGM glucose readings between 12 midnight and 6 a.m. from 176 subjects assigned to the trial's CGM group. The percentage of nights in which hypoglycemia occurred (2 consecutive CGM readings ≤60mg/dL in 20 minutes) was computed for each subject. Associations with baseline characteristics and clinical factors were evaluated using a multivariate regression model.

Hypoglycemic events occurred during 8.5% of nights, with the median percentage of nights with hypoglycemia per subject being 7.4% (interquartile range 3.7% to 12.1%). The duration of hypoglycemia was ≥2 hours on 23% of hypoglycemic nights. In a multivariate model, a higher incidence of nocturnal hypoglycemia was associated with (1) lower baseline HbA1c levels (P<0.001) and (2) the occurrence of hypoglycemia on one or more nights during baseline blinded CGM (P<0.001). The hypoglycemia frequency was not associated with age or with insulin modality (pump versus multiple daily injections).

Nocturnal hypoglycemia is frequent and often prolonged in adults and children with type 1 diabetes. Patients with low HbA1c levels are at an increased risk for its occurrence. One week of blinded CGM can identify patients who are at greater risk for nocturnal hypoglycemia.

The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes (T1D).

40 subjects with T1D (age range # to #) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dL) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shut-off algorithms). During the subsequent 26 patient studies, pump shut-off occurred when either 3 of 5 (N=10) or 2 of 5 (N=16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator® (Abbott Diabetes Care).

The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. Using a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study there were 25 predictions of hypoglycemia due to some subjects having multiple hypoglycemia events during a night, and hypoglycemia was prevented for 84% of these events.

Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

Insulin resistance is a suspected causative factor in a wide variety of diseases. We aimed to determine whether insulin resistance, estimated by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), is associated with all-cause or disease-specific mortality amongst non-diabetic persons in the United States.

We determined the association between HOMA-IR and death certificate-based mortality among 5,511 non-diabetic, adult participants of the third US National Health and Nutrition Examination Survey (1988-1994) during up to 12 years of follow-up, after adjustment for potential confounders (age, gender, body mass index, waist-to-hip ratio, alcohol consumption, race/ethnicity, educational attainment, smoking status, physical activity, C-reactive protein, systolic and diastolic blood pressure, plasma total and HDL cholesterol and triglycerides).

HOMA-IR was significantly associated with all-cause mortality (adjusted hazard ratio [AHR] 1.16, 95% CI 1.01-1.3, comparing successive quartiles of HOMA-IR in a linear model and AHR 1.64, 95% CI 1.1-2.5, comparing the top [HOMA-IR >2.8] to the bottom quartile [HOMA-IR≤1.4]). HOMA-IR was significantly associated with all-cause mortality only in persons with BMI<25.2 kg/m² (the median value) but not in persons with BMI≥25.2 kg/m². Persons in the second, third and fourth quartile of HOMA-IR appeared to have higher cardiovascular mortality than persons in the lowest quartile of HOMA-IR. HOMA-IR was not associated with cancer-related mortality.

HOMA-IR is associated with all-cause mortality in the non-diabetic United States population but only among persons with normal BMI. HOMA-IR is a readily available measure that can be used in the future to predict mortality in clinical or epidemiological settings.

Endothelial dysfunction is frequently present in individuals with insulin resistance or type 2 diabetes and can be induced by high fat or high carbohydrate meals. Because exenatide reduces postprandial glucose and lipid excursions we hypothesized that it may also improve postprandial endothelial function (EF).

In a double-blinded, randomized cross-over design, postprandial EF was examined in 28 individuals with impaired glucose tolerance or recent onset type 2 diabetes after a single injection of exenatide or placebo given just prior to a high-fat meal. EF was determined with peripheral arterial tonometry pre- and postprandially.

Postprandial EF was higher after exenatide compared with placebo (p=0.0002). In the placebo phase, postprandial change in EF was inversely associated with mean postprandial concentrations of triglycerides (r=–0.62, p=0.0004). Changes in postprandial triglyceride concentrations explained 64% of exenatide's effect on postprandial EF.

Exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal.

In view of the previously described anti-inflammatory effects of insulin, we investigated the potential suppressive effect of insulin on plasma concentrations and expression of the chemokines, MCP-1 and RANTES and their receptors, CCR-2 and CCR-5 in mononuclear cells (MNC). We also investigated the effect of insulin on other chemokines.

10 obese type 2 diabetic (T2DM) patients were infused with insulin (2U/h with 100 ml of 5% dextrose/h) for 4h. Another 8 and 6 T2DM patients were infused with 100 ml of 5% dextrose/h or saline for 4h, respectively, and served as controls. Blood samples were obtained at 0h, 2h, 4h, and 6h.

Insulin infusion significantly suppressed the plasma concentrations of MCP-1, eotaxin and RANTES and the expression of RANTES, MIP-1, CCR-2 and CCR-5 in MNC at 2h and 4h. Dextrose and saline infusions did not alter these indices.

A low dose infusion of insulin suppresses the plasma concentration of key chemokines, MCP-1 and RANTES and the expression of their respective receptors, CCR-2 and CCR-5 in MNC. Insulin also suppresses the expression of RANTES and MIP-1 in MNC. These actions probably contribute to the comprehensive anti-inflammatory effect of insulin.

Age at onset of type 1 diabetes influences the risk of microvascular complications. However, the long-term risk of proliferative retinopathy within the wide spectrum of age at onset of type 1 diabetes is less well known.

A sample of 1117 consecutively recruited patients was drawn from the FinnDiane Study population (4800 patients). Type 1 diabetes was defined as age at onset ≤ 40 years, insulin treatment initiated within one year and C-peptide ≤ 0.3 nmol/l. Retinopathy status was graded based on ophthalmic records and/or fundus photographs. The risk of proliferative retinopathy was studied in age at onset groups 0-4, 5-14 and 15-40 years.

The mean durations to proliferative retinopathy were 24.3 (22.7-25.9) years in 0-4 group, 20.1 (19.2-21.1) years in 5-14 group and 21.6 (19.8-23.3) years in 15-40 group (P<0.001). In a Cox-regression model, with HbA_1c, blood pressure, sex and body mass index as covariates, the highest risk of proliferative retinopathy was observed in 5-14 group (HR 1.90 [95% CI 1.45-2.48], P<0.001). Diabetes onset 0-4 vs. 5-14 years had no difference in the long-term risk of proliferative retinopathy (P=0.2). When split into two groups, age at onset <15 years was associated with a higher long-term risk than age at onset ≥15 years (HR 1.82 [95% CI 1.40-2.36], P<0.001).

Age at onset significantly modifies the long-term risk of proliferative retinopathy. The highest risk is in age at onset group 5-14 whereas the lowest risk is in the age at onset group 15-40 years.

To investigate the effects of continuous intraperitoneal insulin infusion (CIPII) compared to subcutaneous insulin on health related quality of life (HRQOL) and treatment satisfaction, and to perform a cost analysis in type 1 diabetes.

Open-label, prospective, crossover, randomized, 16-month study (n=24). HRQOL and patient satisfaction were assessed with questionnaires (SF-36, WHO-5 and DTSQ, respectively). Direct costs of CIPII and continuous subcutaneous insulin infusion (CSII) were compared.

Questionnaires scores were higher with CIPII compared to subcutaneous therapy. Yearly direct pump- and procedures associated costs for CIPII were estimated at 10,910 compared to 4,810 for CSII.

Apart from improving glycemic control, CIPII improved HRQOL and treatment satisfaction as compared to subcutaneous insulin. Direct pump- and procedures associated costs are considerably higher, however.

Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation, and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor of progression to micro- and macroalbuminuria in type 1 diabetes.

From an inception cohort of 277 patients, u-LFABP, adjusted for u-creatinine, (ELISA, CMIC ®) was measured in 24 hour urine in 165 normoalbuminuric patients 9.6± 3.5 (mean ±SD) years after onset of type 1 diabetes. Outcome: Development of persistent micro- or macroalbuminuria or death.

Patients were followed for median (range): 18 (1-19) years and 39 progressed to microalbuminuria, and eight of those further to macroalbuminuria and 24 died. In a Cox regression model, baseline log u-LFABP levels predicted the development of microalbuminuria, adjusted for known risk factors (sex, age, Hba1c, systolic and diastolic blood pressure, albumin excretion rate, serum creatinine, smoking): hazard ratio (HR)(CI 95%): 2.3 (1.1-4.6) and log u-LFABP predicted mortality HR (95%CI): 3.0 (1.3-7.0) (adjusted). U-LFABP (above vs. below the median) predicted the development of macroalbuminuria HR (95% CI): 2.6 (1.2-5.4) (adjusted). As a continuous variable, u-LFABP tended to predict macroalbuminuria (HR 1.9, p=0.2), but numbers were small.

High levels of the tubular inflammation marker u-LFABP predict the initiation and progression to diabetic nephropathy and all cause mortality, independent of urinary albumin excretion rate and other established risk factors.

To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation in comparison to subcutaneously injected regular human insulin (RHI).

Ten male patients with type 2 diabetes (mean±SD, HbA1c 7.0±1.1%, BMI 28.3±2.7 kg/m²) received either 300 U insulin combined with 400 mg delivery agent orally or 15 U RHI subcutaneously under isoglycaemic clamp conditions.

Maximum insulin concentration was greater and onset of action was faster with OI (C_max 93±71 vs. 33±11 µU/mL; AUC_GIR(0-1h) 173±86 vs. 27±32 mg/kg, P < 0.05). Mean insulin concentration and glucose infusion rate (GIR) returned to baseline within three hours after OI administration. Relative bioavailability of OI was 7±4% (first two hours).

This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action, but also shows a rather high between-subject variability in absorption.

The role of oxidative damage in the pathogenesis of metabolic syndrome (MetS) is poorly understood.

A detailed cross-sectional study was performed to assess the relationship between lipid oxidation products, gamma glutamyltransferase (GGT), high-sensitivity C-reactive protein (hs-CRP) and phospholipase activities with respect to the metabolic status in a cohort of otherwise healthy individuals.

A total of 179 individuals (87 males and 92 females) of mean age 43 (standard deviation, 14 years) participated in this study. There were no differences in the levels of plasma F₂-isoprostanes, hydroxyeicosatetraenoic acids, cholesterol oxidation products and phospholipase activities in individuals with features of MetS. In multivariate analyses, serum hs-CRP was a consistent independent predictor of MetS.

Minimal changes were observed in multiple markers of oxidative damage in a well-characterized cohort of individuals with features of MetS.

To examine the relationship of diabetes and functional disability in older adults and the possible mediating roles of comorbidities and hemoglobin A1c (A1c).

We analyzed data from a nationally representative sample of 6097 participants aged ≥60 years in the National Health and Nutrition Examination Survey 1999-2006. Diabetes was defined by self-report. Disability was defined as difficulty performing a physical task. We evaluated disability by grouping 19 physical tasks into five functional groups: lower extremity mobility (LEM), general physical activities (GPA), activities of daily living (ADL), instrumental activities of daily living (IADL), leisure and social activities (LSA).

Older U.S. adults with diabetes had the greatest disability in GPA (prevalence 73.6%, 95% CI 70.2-76.9), followed by LEM (52.2%, 48.5-55.9), IADL (43.6%, 40.1-47.2), ADL (37.2%, 33.1-41.3), and LSA groups (33.8%, 30.8-36.9). Diabetes was associated with 2 – 3 times increased odds of disability across functional groups (all p<0.05). Comorbidities, mostly cardiovascular disease and obesity, and poor glycemic control (A1c ≥8%) together explained up to 85% of the excess odds of disability associated with diabetes, while poor glycemic control alone only ~10% of the excess odds. Adjustment for comorbidities, A1c and diabetes duration fully attenuated the associations of diabetes with disability in all functional groups (all p>0.05).

Older adults with diabetes have a high prevalence of disabilities with variable associations attributable to comorbidities and A1c. Aggressive management of cardiovascular risk factors and obesity may significantly reduce the burden of disability in this population.

Dipeptidyl peptidase IV (DPP-IV) is not only important in beta-cell function but also has pro-inflammatory actions. We aimed to investigate whether it could act as a link between low grade chronic inflammation and diabetes.

Using a case-cohort design, we followed 546 middle-aged individuals who developed diabetes and 538 who did not over ~9 years within the Atherosclerosis Risk in Communities Study.

In weighted analyses, correlation between DPP-IV levels and anthropometric, inflammatory or metabolic variables was minimal (Spearman correlations <0.11). Those who developed diabetes had mean DPP-IV values similar to those who did not (p=0.18). Individuals in the highest quartile of DPP-IV were not at greater risk of diabetes (HR=0.88; 95%CI 0.62–1.24) in Cox proportional hazards models adjusting for age, sex, race, study center and multiple additional diabetes risk factors.

Fasting DPP-IV levels do not appear to predict incident diabetes.

Ljungan virus (LjV) has been proposed as a potential environmental factor for type 1 diabetes. The objective was to test for any association of LjV with type 1 diabetes.

Design and Methods: A nested case-control design was employed to test for any association between the development of prediabetic autoimmunity and presence of LjV in stool samples (n=3803) in the MIDIA study. The children followed were 27 infants who developed prediabetic autoimmunity during or shortly after the sampling period, 54 matched controls and 94 other children.

No LjV RNA was detected.

The results indicate that LjV is rare in young children. LjV does not seem to be involved in the development of human type 1 diabetes.

Obstructive sleep apnea is common in patients with type 2 diabetes; cross-sectional studies have examined its association with insulin and insulin resistance. We evaluate risk factors for incident observed sleep apnea in a general population, not selected for sleep disturbances.

1780 men, 1785 women, aged 33 to 68 years, from the cohort: Data from an Epidemiologic Study on the Insulin Resistance syndrome (D.E.S.I.R.) responded to the question "has someone said to you that you stop breathing during your sleep" at baseline and 6 years. Anthropometric, clinic and biologic factors were recorded at both time-points.

At baseline, 14% of men and 7% of women reported to have observed sleep apnea (positive response to question); six-year incidences were 14% and 6% respectively. Age, anthropometric parameters, blood pressure and sleep characteristics were all associated with prevalent, observed apneas, in both genders. Baseline waist circumference was the strongest predictor of incident apnea: standardized odds ratio (OR) (95% Confidence Interval), adjusted for age and sex, 1.34(1.19-1.52). After adjusting for age, sex and waist circumference, the standardized ORs for incident observed apnea were: identical for fasting insulin and the HOmeostasis Model Assessment of insulin resistance: 1.31(1.13-1.51), 1.24(1.09-1.41) for triglycerides, 1.52(1.12-2.05) for smoking. Observed apnea at baseline was not associated with changes in anthropometric or biologic parameters over the 6-year follow-up.

The most important baseline risk factor for incident apnea was adiposity; after accounting for adiposity other risk factors were high insulin, insulin resistance, high triglycerides, and smoking, factors amenable to lifestyle intervention.

Nonalcoholic fatty liver disease is highly prevalent in obese and type 2 diabetic individuals and is strongly associated with dyslipidemia and inflammation. Weight loss and/or pharmacotherapy are commonly used to correct these abnormalities.

We carried out a 16-week intervention trial of a hypocaloric, low-fat diet plus 10mg/day ezetimibe (EZWL) (n=15) versus a hypocaloric, low-fat diet alone (WL) (n=10) on intrahepatic triglyceride (IHTG) content, plasma high sensitivity-C reactive protein (hsCRP), adipocytokines and fetuin-A concentrations and apolipoprotein (apo) B-100 kinetics in obese subjects. ApoB-100 metabolism was assessed using stable isotope tracer kinetics and compartmental modeling; liver and abdominal fat were determined by magnetic resonance techniques.

Both WL and EZWL significantly (all P<0.05) reduced body weight, visceral and subcutaneous adipose tissues, insulin resistance and plasma triglycerides, VLDL-apoB-100, apoC-III, fetuin-A, retinol-binding protein-4, and increased plasma adiponectin concentrations. Compared with WL alone, EZWL significantly (all P<0.05) decreased IHTG content (–18%), plasma hs-CRP (–53%), interleukin-6 (–24%), LDL-cholesterol (–18%), campesterol (–59%) and apoB-100 (–14%) levels, with a significant increase in plasma lathosterol concentrations (+43%). LDL-apoB-100 concentration also significantly fell with EZWL (–12%), chiefly owing to an increase in the corresponding fractional catabolic rate (+29%). VLDL-apoB-100 secretion rate fell with both interventions, with no significant independent effect of ezetimibe.

Addition of ezetimibe to a moderate weight loss diet in obese subjects can significantly improve hepatic steatosis, inflammation and LDL-apoB-100 metabolism.

Persons with diabetes are at higher risk for depression than the general population. Although depression can be treated with antidepressant medications, patients with diabetes and comorbid depression often go untreated. The goal of this study was to examine racial disparities in the treatment of depression with antidepressant medication in the southeastern United States.

Cross-sectional data were collected at baseline from 69,068 participants (71% African American, 60% female, 82% with incomes < $25,000) recruited from community health centers and enrolled in the Southern Cohort Community Study (SCCS). The SCCS is a prospective epidemiological cohort study designed to explore causes of health disparities in adults 40-79 years of age. Binary logistic regression was used to identify factors associated with antidepressant use among those with diabetes (n=14,279).

Individuals with diagnosed diabetes (14,279) were classified as not depressed (54.7%), mildly depressed (24.2%), moderately depressed (12.8%), or severely depressed (8.3%). After controlling for gender, age, insurance, income, education, body mass index, smoking status, alcohol consumption, and level of depression, African Americans with diabetes were much less likely to report taking antidepressant medication than Whites (AOR=0.32, 95% CI 0.29 – 0.35, p < 0.0001).

Antidepressant use is much less common among African Americans than Whites with diabetes. Reasons for racial disparities in treatment of depressive symptoms are unclear, but might include a combination of differential diagnosis and treatment by health professionals as well as cultural differences in seeking help for emotional distress.

Infection might be a type 2 diabetes mellitus risk factor. Periodontal disease is a chronic infection. We hypothesized that periodontal disease was related to hemoglobin A1C (HbA1C) progression in diabetes-free participants.

The Study of Health in Pomerania is a population-based cohort in Germany including 2,973 diabetes-free participants (53% women; aged 20-81 years). Participants were categorized into four groups according to increasing baseline periodontal disease levels (percent of sites per mouth with attachment loss≥5 mm, determined a priori); sample sizes for each respective category were 1,122, 488, 463 and 479 (241 were edentulous). Mean absolute changes (year five minus baseline) in HbA1C (HbA1C) were regressed across periodontal categories while adjusting for confounders (e.g., age, gender, smoking, obesity, physical activity, family history).

Across baseline periodontal disease categories, HbA1C(±SE) values were 0.023%±0.02%, 0.023%±0.02%, 0.065%±0.03% and 0.106%±0.03(p for trend=0.02), yielding an approximate 5-fold increase in the absolute difference of HbA1C when comparing dentate participants in the highest vs. lowest periodontal disease category; these results were markedly stronger among participants with hs-CRP≥1.0 mg/L (interaction p-value=0.01). When comparing individuals who had neither baseline periodontal disease nor deterioration in periodontal status at five years to individuals with both poor baseline periodontal health and longitudinal periodontal deterioration, mean HbA1C values were 0.005% vs. 0.143%(p=0.003).

Periodontal disease was associated with five-year HbA1C progression which was similar to that observed for a two standard deviation increase in either waist-to-hip ratio or age in this population.

Mean blood glucose (MBG) and MBG-independent factors both influence HbA1c levels. Race was related to HbA1c independent of MBG in adults. The goal of this study was to determine if racial disparity exists in HbA1c independent of MBG in children with diabetes.

Participants included 276 children with type 1 diabetes. HbA1c and MBG were obtained from multiple clinic visits and a hemoglobin glycation index (HGI, an assessment of HbA1c levels independent of MBG) was calculated. HbA1c and HGI were analyzed controlling for age, diabetes duration, and MBG.

African Americans had statistically significantly higher HbA1c (9.1±0.1) and HGI (0.64±0.11) compared to Caucasians (HbA1c = 8.3±0.1, HGI = –0.15±0.07) independent of covariates.

Due to racial disparity in HbA1c which is independent of MBG, we recommend that HbA1c and MBG be used together to make therapeutic decisions for children with diabetes.

To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFU)

Data were extrated from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFU managed from 1980. Finally, the results of all patients with acute Charcot foot and all controls managed between 1980 and 2007 were compared with normative mortality data for the UK population.

70 patients with presented with an acute Charcot foot (mean age 57.4±12.0; 48 (68.6%) male) between 2001 and 2007; there were 66 matched controls. By 1 October 2008, 13 (18.6%; 8 male) patients with a Charcot foot had died, after a median of 2.1 (IQR 1.1-3.3) years. 22 (33.3%; 20 male) controls had also died, after a median of 1.3 (IQR 0.6-2.5) years. There was no difference in survival between the two groups (log rank p>0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 (IQR 4.0-15.4) years and was not significantly different from the control NFU patients: 8.43 (IQR 3.4-15.8) years . When compared to normative UK population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively.

These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly high.

To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview (CIDI) to ascertain depression status.

Cross-sectional data collected from 1732 participants aged between 26 and 36 years. Insulin resistance (IR) was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method (HOMA). Those identified with mild, moderate or severe depression were classified as having depressive disorder.

The 12 month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean IR was 17.2%, (95% CI 0.7%–36.0%, P=0.04) higher in men and 11.4% (95% CI 1.5%–22.0%, P=0.02) higher in women with depressive disorder. Following adjustment for, behavioral and dietary factors, the increased level of IR associated with depressive disorder was 10.1% (95% CI –2.1%–23.9%, P=0.11) in men and 2.0% (95% CI –5.6%–10.0%, P=0.60) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance reducing the beta coefficient in the fully adjusted models in men by 38% and in women by 42%.

A positive association was found between depressive disorder and IR in this population-based sample of young adult men and women. The association appeared to be mediated partially by waist circumference.

Hypertensive patients are at increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure (PP) and the risk of new-onset diabetes in high-risk Japanese hypertensive patients.

The CASE-J trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between PP at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male, 1,471; mean age, 63.7 years; mean BMI, 24.8 kg/m²) as a subanalysis of the CASE-J trial.

During 3.3 ± 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, PP was an independent predictor for new-onset diabetes (hazard ratio per 1 SD increase 1.44, 95% CI 1.15-1.79), as were male sex, body mass index and additional use of diuretics, whereas age and heart rate were not. Plots of hazard ratios for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher PP with a lower DBP, indicating that the increased PP was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes.

PP is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.

To assess the prevalence and correlates of undertreatment for mental health problems among adults with diabetes and serious psychological distress (SPD).

We analyzed data of adults aged ≥18 years from the 2007 Behavioral Risk Factor Surveillance System. SPD was assessed with the K6 scale.

The prevalence of untreated SPD was estimated to be 2.1% (SE, 0.1), 3.4% (SE, 0.3), and 2.0% (SE, 0.1) in the total population, diabetic population, and non-diabetic population, respectively. Among people with SPD, those with diagnosed diabetes had a lower rate of undertreatment for mental health problems (45.0%) than those without diabetes (54.9%) (P=0.002). Non-white race/ethnicity, advanced age, lack of health insurance, and currently being employed were associated with increased likelihood of undertreatment for mental health problems (P<0.05).

People with diagnosed diabetes may be screened for SPD and treated for specific mental health problems in routine health care.

We developed a new method of estimating visceral fat area (VFA) using multi-frequency bioelectrical impedance (BI).

We considered abdominal composition as a parallel circuit model composed of VFA and subcutaneous fat area and calculated the impedance of VFA (IP_VFA) from this model. The methods were tested against measures of VFA by computer tomography (CT). Multiple regression analysis was performed on the 103 participants to estimate VFA. We cross-validated the regression equation against CT measured VFA in 30 additional participants.

The regression equation was:

VFA = 3.57 x sagittal abdominal diameter + 311.97 x waist-height ratio + 0.71 x age + 23.93 x sex + 1.57 x IP_VFA (250 kHz) – 174.35 (r = 0.904, p<0.01).

We observed a strong correlation by cross-validation (r = 0.905).

Our method using BI is a simple and convenient method for accurately estimating VFA.

To investigate relationships between baseline factors and treatment-associated efficacy changes in type 2 diabetes.

Multivariable analyses of treatment-response in 1,229 type 2 diabetes patients with hypercholesterolemia, who received ezetimibe/simvastatin or atorvastatin in a randomized, double-blind, 6-week study.

Increasing age was related to improvements in all lipid assessments. Men had greater triglyceride and non-HDL-C reductions than women, and Black/Hispanic patients had less favorable lipid-effects than other races/ethnicities. Increasing baseline LDL-C was associated with improvements in most lipids; higher baseline non-HDL-C with improved HDL-C and triglycerides; higher baseline HDL-C with greater non-HDL-C and hsCRP reductions; and higher baseline hsCRP with smaller LDL-C, non-HDL-C and apolipoproteinB reductions. Patients with high baseline non-HDL-C or triglycerides less frequently attained LDL-C targets. Obesity was inversely related to HDL-C and hsCRP changes, and higher baseline HbA1C to apolipoproteinB reductions. Metabolic syndrome was not a significant predictor.

Treatment-responses in type 2 diabetes patients were related to baseline factors, though treatment-effects (ezetimibe/simvastatin>atorvastatin) remained consistent. The presence of predictive factors should be considered in planning lipid-altering therapy.

To clarify previous findings that diabetes distress is related to glycemic control and self-management, whereas measures of depression are not, using both binary and continuous measures of depression.

463 type 2 patients completed measures of diabetes distress (DDS) and clinical depression (Patient Health Questionnaire 8-PHQ8). The PHQ8 was employed as either a binary (≥10) or continuous variable. Dependent variables were HbA1C, diet, physical activity (PA), and medication adherence (MA).

The inclusion of a binary or continuous PHQ8 score yielded no differences in any equation. DDS was significantly associated with HbA1C and PA, whereas PHQ8 was not; both DDS and PHQ8 were significantly and independently associated with diet and MA.

The lack of association between depression and glycemic control is not due to the use of a binary measure of depression. Findings further clarify the significant association between distress and HbA1C.

Current state-of-the-art artificial pancreas systems are either based on traditional linear control theory or rely on mathematical models of glucose-insulin dynamics. Blood glucose control using these methods is limited due to the complexity of the biological system. The aim of this study was to describe the principles and clinical performance of the novel MD-Logic Artificial Pancreas (MDLAP) system.

The MDLAP applies fuzzy logic theory to imitate lines of reasoning of diabetes caregivers. It uses a combination of control to range and control to target strategies to automatically regulate individual glucose levels. Feasibility clinical studies were conducted in 7 adults with type 1 diabetes (age, 19-30 yr; mean diabetes duration, 10±4 yr; mean HbA1C, 6.6±0.7%). All underwent 14 full closed-loop control sessions of 8 hours (fasting and meal-challenge conditions) and 24 hours.

The mean peak postprandial (overall sessions) glucose level was 224±22 mg/dl. Postprandial glucose levels returned to below 180 mg/dl within 2.6±0.6 hours and remained stable in the normal range for at least one hour. During 24-hour closed-loop control, 73% of the sensor values ranged between 70-180 mg/dl, 27% were >180 mg/dl, and none were <70 mg/dl. There were no events of symptomatic hypoglycemia during any of the trials.

The MDLAP system is a promising tool for individualized glucose control in patients with type 1 diabetes. It is designed to minimize high glucose peaks while preventing hypoglycemia. Further studies are planned in the broad population under daily life conditions.

Evaluate the effects of two low fat hypocaloric diets differing in carbohydrate:protein ratio, with and without resistance training (RT), on weight loss, body composition and cardiovascular disease (CVD) risk outcomes in overweight/obese patients with type 2 diabetes (T2D).

83 men/women with T2D (age:56.1±7.5yrs, BMI:35.4±4.6kg/m²) were randomly assigned to an isocaloric, energy restricted diet (females:6 MJ/day, males:7 MJ/day) of either standard carbohydrate (CON; carbohydrate:protein:fat, 53:19:26) or high protein (HP; 43:33:22), with or without supervised RT (3d/wk) for 16-wks. Body weight and composition, waist circumference (WC) and cardiometabolic risk markers were assessed.

59 participants completed the study. There was a significant group effect (P≤0.04) for body weight, fat mass and WC with greatest reductions in HP+RT; weight (CON:-8.6±4.6kg, HP:-9.0±4.8kg, CON+RT:-10.5±5.1kg, HP+RT:-13.8±6.0kg), fat mass (CON:-6.4±3.4kg, HP:-6.7±4.0kg, CON+RT:-7.9±3.7kg, HP+RT:-11.1±3.7kg), WC (CON:-8.2±4.6cm, HP:-8.9±3.9cm, CON+RT:-11.3±4.6cm, HP+RT:-13.7±4.6cm). There was an overall reduction (P<0.001) in fat-free mass:-2.0±2.3kg, blood pressure:-15/8±10/6mmHg, glucose:-2.1±2.2 mmol/L, insulin:-4.7±5.4mU/L, HbA1c:-1.25±0.94%, triglycerides:-0.47±0.81mmol/L, total cholesterol:-0.67±0.69 mmol/L and LDL-cholesterol:-0.37±0.53 mmol/L, with no difference between groups (P≥0.17).

An energy restricted HP diet combined with RT achieved greater weight loss and more favourable changes in body composition. All treatments had similar improvements in glycemic control and CVD risk markers.

Thiazolidinediones reduce hepatic steatosis and increase high-density lipoprotein (HDL)-cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride (TG) content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes mellitus.

We included 78 men with type 2 diabetes mellitus (age 56.5±0.6 years; HbA1c 7.1±0.1%) who were randomized to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebos, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL-cholesterol levels and CETP mass were measured and hepatic TG content was assessed by proton magnetic resonance spectroscopy.

Pioglitazone decreased hepatic TG content (5.9 (2.6-17.4) vs. 4.1 (1.9-12.3)%, P<0.05), decreased plasma CETP mass (2.33±0.10 vs. 2.06±0.10 µg/mL, P<0.05) and increased plasma HDL-cholesterol levels (1.22±0.05 vs. 1.34±0.05 mM, P<0.05). Metformin did not significantly change any of these parameters.

A decrease in hepatic TG content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL-cholesterol levels. These results in patients with type 2 diabetes mellitus fully confirm recent findings in mice.

Reduction of bone marrow-derived circulating progenitor cells has been proposed as a novel mechanism of CVD in type 2 diabetes (T2DM). The present study was designed to describe extent and potential mechanisms of progenitor cell reduction during the natural history of T2D.

We identified 425 individuals, divided into 7 categories according to carbohydrate metabolism status (NGT, IFG, IGT and newly diagnosed T2D) and diabetes duration (0-9; 10-19; ≥20 years). These categories were examined as ideally describing the natural history of T2D development and progression. We measured CD34+ and CD34+KDR+ progenitor cells by flow cytometry. We also evaluated progenitor cells in 20 coupled bone marrow and peripheral blood samples and examined progenitor cell apoptosis in 34 subjects.

In comparison to NGT, CD34+ cells were significantly reduced in IGT, had a first nadir in newly diagnosed T2D and a second nadir after 20 years of diabetes. Statistical adjustment for possible confounders confirmed that CD34+ cell count are deeply reduced at time of diagnosis, partially recover during the subsequent 0-19 years, and dip again after ≥20 years. A similar but less consistent trend was detected for CD34+KDR+ cells. Peripheral blood CD34+ cells were directly correlated with bone marrow CD34+ cells and inversely correlated with CD34+ cell apoptosis.

Circulating progenitor cell reduction marks the clinical onset of T2D. Both defective mobilization and increased apoptosis may account for this phenomenon. While a partial recovery occurs during subsequent years, bone marrow reserve seems exhausted in the long term.

To examine the association between the moisture status of the skin of the feet with foot ulceration (FU) in subjects with diabetes.

A total of 379 subjects with diabetes were examined. Assessment of peripheral neuropathy was based on neuropathy symptom score, neuropathy disability score, vibration perception threshold and the 10 g-monofilament perception. The moisture status of the skin of the feet was assessed using the visual test Neuropad.

Patients with FU had more severe peripheral neuropathy and more often an abnormal Neuropad response. Multivariate logistic regression analysis demonstrated that the odds of FU increased with measures of neuropathy but increased also with an abnormal Neuropad response.

An abnormal Neuropad response correlates with FU in subjects with diabetes. This finding, if confirmed prospectively, suggests that the Neuropad test may be included in the screening tests for the prediction of FU.

To evaluate the impact of former intensive- versus conventional insulin treatment on neuropathy in DCCT intensive and conventional treatment subjects with type 1 diabetes 13-14 years after DCCT closeout, during which time the two groups had achieved similar hemoglobin A1c (HbA1c) levels.

Clinical and nerve conduction studies (NCSs) performed during DCCT were repeated during EDIC by examiners masked to treatment status on 603 former intensive- and 583 former conventional-treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving ≥ 2 nerves among the median, peroneal, and sural nerves.

The prevalence of neuropathy increased 13-14 years after DCCT closeout from 9% to 25% in former intensive- and from 17% to 35% in former conventional treatment groups, but the difference between groups remained significant (P<0.001) and the incidence of neuropathy remained lower among former intensive- (22%) than former conventional treatment subjects (28%) (P=0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (OR=1.17; CI=0.84-1.63). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean HbA1c and measures of incident and prevalent neuropathy.

The benefits of former intensive insulin treatment persisted for 13-14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.

To determine the relationship between subclinical hypothyroidism (SCH) and the prevalence of diabetic retinopathy (DR) in type 2 diabetic (T2D) patients.

A total of 1170 T2D patients were screened for thyroid function. 127 T2D patients with SCH and 200 randomly selected euthyroid T2D patients were selected. Those with more severe than moderate non-proliferative DR were classified as having sight-threatening DR (STDR).

The trend for severe retinopathy was significantly higher in the SCH group than in the euthyroid group (²=20.43, P=0.000). SCH was associated with greater prevalence of DR, especially STDR [odds ratio (95% CI): 4.15 (2.17-7.96), P=0.000] after an adjustment for age, sex, duration of diabetes, HbA1c, body mass index, hypertension and LDL cholesterol. Even euthyroid patients with TSH levels between 2.0~<4.0µIU/ml had a higher rate of STDR then those between 0.4~<2.0µIU/ml (P=0.008).

T2D patients with SCH are associated with an increased risk of STDR.

To evaluate associations between psychosocial and social-environmental variables and diabetes self-management, and diabetes control.

Baseline data from a type 2 diabetes self-management randomized trial with 463 adults having elevated body mass index (BMI) (M = 34.8 kg/m²) were used to investigate relations among demographic, psychosocial, and social-environmental variables; dietary, exercise, and medication-taking behaviors; and biologic outcomes.

Self-efficacy, problem solving, and social-environmental support were independently associated with diet and exercise, increasing the variance accounted for by 23% and 19%, respectively. Only diet contributed to explained variance in BMI (β = –.17, p = .0003) and self-rated health status (β = .25, p < .0001); and only medication-taking contributed to lipid ratio (total/HDL) (β=–.20, p = .0001) and hemoglobin A1c (β = –.21, p < .0001).

Interventions should focus on enhancing self-efficacy, problem solving, and social-environmental support to improve self-management.

Gestational diabetes (GDM) may cause obesity in the offspring. The objective was to assess the effect of treatment for mild GDM on the body mass index (BMI) of 4-5-year-old children.

Participants were 199 mothers who participated in a randomized controlled trial of treatment of mild GDM during pregnancy and their children, among whom trained nurses measured their height and weight at pre-school visits in a state-wide surveillance program in the state of South Australia. The main outcome measure was age- and sex-specific BMI z-score based on standards of the International Obesity Task Force.

At birth, prevalence of macrosomia (birth weight ≥ 4000 g) was 5.3% among the 94 children whose mothers were in the intervention group, and 21.9% among the 105 in the routine care control group. At 4-5 years, mean (SD) BMI z-score was 0.49 (1.20) in intervention children and 0.41 (1.40) among controls. The difference between treatment groups was 0.08 (95% confidence interval –0.29, 0.44), an estimate minimally changed by adjustment for maternal race, parity, age, and socio-economic index (0.08 [95% CI –0.29, 0.45]). Evaluating BMI ≥ 85^th percentile rather than continuous BMI z-score gave similarly null results.

Although treatment of GDM substantially reduced macrosomia at birth, it did not result in a change in BMI at age 4-5 years.

To examine whether patterns in socioeconomic characteristics in Chicago over a thirty-year period are associated with neighborhood distribution of youth diabetes risk.

Incident cases of diabetes in youth ages 0-17 were identified from the Chicago Childhood Diabetes Registry (CCDR) between 1994- 2003. Those with a type 2-like clinical course or related indicators were classified as non-type 1 (nT1); the remaining cases were considered to have type 1 diabetes (T1).

Compared to stable diversity neighborhoods, significant associations for T1 were found for younger children residing in emerging low- income neighborhoods, relative risk (RR), 0.56 [95% CI 0.36, 0.90] and older children residing in emerging high- income neighborhoods, RR, 1.52 [1.17, 1.98]. For nT1, older youth residing in desertification neighborhoods were at increased risk [RR = 1.47, 1.09, 1.99].

Neighborhood socioeconomic characteristics in Chicago may be associated with the risk of diabetes in youth.

Clinicians who treat children with type 1 diabetes often try to minimize the number of daily injections to reduce treatment burden and improve compliance. Despite the manufacturer's cautions against mixing glargine with rapid-acting insulin analogs, clinical studies have failed to demonstrate deleterious effects of mixing on glucose excursions or A1c levels. However, no formal glucose clamp studies have been performed to determine whether mixing with glargine has an adverse effect on the early pharmacodynamic action of rapid-acting insulin in humans.

To examine this question, euglycemic glucose clamps were performed twice, in random order, in 11 youth with type 1 diabetes (age 15.1±3y, A1c 7.6±0.6%) with 0.2unit/kg lispro and 0.4unit/kg glargine, given either as separate or as a single mixed injection.

Mixing the two insulins shifted the time action curve to the right, with significantly lower GIR values after the mixed injections between 60 to 190 minutes and significantly higher values between 270 to 300 minutes, lowered the GIR_max (separate 7.1± 1 vs. mix 3 .9±1, p=0.03) and markedly delayed the time to reach GIR_max (separate 116±8 min vs. mix 209±15 min, p=0.004). The GIR area under the curve (AUC) was significantly lower after the mixed injections. Mixing had similar effects on plasma insulin pharmacokinetics.

These data demonstrate that mixing lispro with glargine markedly flattens the early pharmacodynamic peak of lispro and causes a shift to the right in the GIR curve changes that might lead to difficulties in controlling meal-related glucose excursions.

Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin.

In this 20-week, randomized, open-label, multicenter study, participants (mean age 56 ± 10 years, weight 93 ± 16 kg, A1C 7.8 ± 0.7%) continued their metformin regimen and received either EXE 10 µg twice daily (BID) (n = 45), ROSI 4 mg BID (n = 45), or EXE 10 µg BID + ROSI 4 mg BID (n = 47). 73 participants underwent clamp procedures to quantitate insulin secretion and insulin sensitivity.

A1C declined in all groups (P < 0.05), but decreased most with EXE+ROSI (EXE+ROSI –1.3 ± 0.1%; ROSI –1.0 ± 0.1%, EXE –0.9 ± 0.1%; EXE+ROSI vs. EXE or ROSI, P < 0.05). ROSI resulted in weight gain, while EXE and EXE+ROSI resulted in weight loss (EXE –2.8 ± 0.5 kg; EXE+ROSI –1.2 ± 0.5 kg; ROSI +1.5 ± 0.5 kg; P < 0.05 between and within all groups). At week 20, first and second phase insulin secretion was significantly higher in EXE and EXE+ROSI versus ROSI (both P < 0.05). Insulin sensitivity (M value) was significantly higher in EXE+ROSI versus EXE (P = 0.014).

Therapy with EXE plus ROSI offset the weight gain observed with ROSI, and elicited an additive effect on glycemic control, with significant improvements in beta-cell function and insulin sensitivity.

A trial was performed to establish whether our Group Care model for lifestyle intervention in type 2 diabetes can be exported to other clinics.

Four-year two-armed, multicentre controlled trial in 13 hospital-based diabetes clinics in Italy (Current Controlled Trials ISRCTN19509463). 815 non insulin-treated patients aged <80, with ≥1 year known diabetes duration were randomised to either group or individual care.

After 4 years, patients in Group Care had lower HbA1c, total cholesterol, LDL cholesterol, triglyceride, systolic and diastolic blood pressure, body mass index and serum creatinine, and higher HDL cholesterol (p<0.001, all) than controls receiving individual care, despite similar pharmacological prescriptions. Health behaviours, quality of life and knowledge of diabetes had become better in Group Care patients than controls (p<0.001, all).

The favourable clinical, cognitive and psychological outcomes of Group Care can be reproduced in different clinical settings.

Eliminating health disparities is a national priority, but progress has been difficult because of racial/ethnic differences in insurance coverage and access to healthcare. We investigated whether there were differences in diabetes care in the VA — where healthcare access should be relatively uniform.

A1c and plasma glucose were compared before/after diagnosis of diabetes.

Data were available for 1,456 black and 2,624 white veterans who met criteria for consistent primary care. Over 4-5 years before and after diagnosis, blacks had similar glucose and ~0.2% higher A1c levels compared to whites, and A1c differences could be attributed to glucose-independent associations between race and A1c. Blacks and whites also had comparable intervals between diagnostic-level hyperglycemia and diagnosis, and between diagnosis and drug initiation. However, A1c was higher in blacks at the time of diagnosis (7.8% vs. 7.1%), and at initiation of pharmacotherapy (8.5% vs. 7.8%), both p<0.001. Differences in A1c at diagnosis and drug initiation were too large to be explained by differences in age, gender, BMI, and glucose-independent associations between race and A1c.

In the VA, glucose levels are generally comparable in blacks and whites except at the times of diagnosis and initiation of pharmacotherapy, when glucose levels are higher in blacks. While understanding the basis for such residual disparities may be important to improve the health of racial/ethnic minorities in the U.S., a healthcare system with structure and organization similar to that in the VA may also contribute importantly to relieving disparities in health.

Little is known regarding recent changes in glitazone use.

Interrupted time-series analyses of nationally representative office-visit data using IMS Health's National Disease and Therapeutic Index^TM.

From 2003 through 2005, glitazone use increased steadily. From February 2005-January 2007, rosiglitazone use decreased by 16% (CI -20% to -11%) annually; pioglitazone use increased at an annual rate of 14% (CI 9% to 18%). During a period of FDA advisories, rosiglitazone use declined sharply from 0.42 million monthly treatment visits (February 2007) to 0.13 million monthly visits (May 2008). Pioglitazone use remained stable, accounting for approximately 5.8 million physician visits (77% of all glitazone use) where a treatment was used during the final 12 months of observation.

The combined effect of scientific publications, advisories, and media exposure was associated with a substantial decrease in rosiglitazone use. Despite a class-level FDA advisory, pioglitazone use was not similarly affected.

To determine if baseline subgroups in the ACCORD trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality.

Exploratory post-hoc intention-to-treat comparisons between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics.

There were few significant interactions between baseline characteristics and effects of intensive vs standard glycemia treatment on mortality: self-reported history of neuropathy (HR=1.95, 95% CI 1.41-2.69 versus no history of neuropathy (HR 0.99, 95% CI 0.79 – 1.26; p-value for interaction 0.0008), higher A1c (A1c > 8.5%: HR=1.64, 95% CI 1.22-2.22; A1c 7.5-8.4%, HR=1.00, 95% CI 0.75-1.34; A1c < 7.5%: HR=1.00, 95% CI 0.67-1.50; p-value for interaction 0.04), and aspirin use (HR = 1.45, 95% CI: 1.13–1.85, compared to HR=0.96 (0.72-1.27) in non-users; p-value for interaction 0.03).

We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, previous history of cardiovascular disease. The 3 baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from very intensive regimens for glycemia control. Further research is warranted.

To compare the sensitivity and specificity of luciferase immunoprecipitation (LIPS) with radioimmunoprecipitation (RIP) for the measurement of autoantibodies to the type 1 diabetes (T1D) autoantigens glutamic acid decarboxylase 65 (GAD65) and IA-2β.

Sera from 49 T1D patients and 100 non-diabetic controls from DASP-2007 were used to screen for autoantibodies to GAD65. An additional 200 T1D patients and 200 non-diabetic controls were used to validate the GAD65 results and screen for autoantibodies to IA-2β.

LIPS showed equal sensitivity and specificity to RIP for detecting autoantibodies to GAD65 and IA-2β. Receiver operating characteristic analysis revealed that the detection of autoantibodies to GAD65 and IA-2β by LIPS and RIP were not statistically different.

The LIPS assay does not require the use of radioisotopes or in vitro transcription/translation and is a practical alternative at the clinical level for the RIP assay.

To examine insulin's effect on the tissue glucose concentration at the site of subcutaneous insulin administration.

A CMA-60 microdialysis (MD) catheter and a 24-gauge microperfusion (MP) catheter were inserted into the subcutaneous adipose tissue of fasting, healthy subjects (n=5). Both catheters were perfused with regular human insulin (100 U/ml) over a 6-h period, and used for glucose sampling and simultaneous administration of insulin at sequential rates of 0.33, 0.66, and 1.00 U/h (each rate was used for 2h). Before and after the insulin delivery period, both catheters were perfused with an insulin-free solution (5%-mannitol) for 2h, and used for glucose sampling only. Blood plasma glucose was clamped at euglycemic levels during insulin delivery.

Start of insulin delivery with MD and MP catheters resulted in a decline of the tissue glucose concentration and the tissue-to-plasma glucose ratio for ~60 min (p<0.05). However, during the rest of the 6-h period of variable insulin delivery, tissue glucose concentration paralleled the plasma glucose concentration and the tissue-to-plasma glucose ratio for MD and MP catheters remained unchanged at 83.2 ± 3.1 and 77.1 ± 4.8 %, respectively. After subsequent switch to insulin-free perfusate, tissue glucose concentration and tissue-to-plasma glucose ratio increased slowly and re-attained pre-insulin-delivery levels by the end of the experiments.

The results show the attainment of a stable tissue-to-plasma glucose ratio at the site of insulin administration, thus indicating that insulin delivery and glucose sensing may be performed simultaneously at the same adipose tissue site.

Many studies have documented associations between inflammation and type 2 diabetes incidence; we assessed potential variability in this association in the major U.S. race/ethnic groups.

Incident type 2 diabetes was assessed among men and women aged 45-84 without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin 6 (IL-6), fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000-2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥ 126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HR) by quartiles of CRP, IL-6, and fibrinogen.

Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, 20.7% Hispanic) 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1000-person years). CRP, IL6 and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however quartile 4 (vs. quartile 1) of IL-6 (HR 1.5, 95%CI 1.1-2.2 ) and CRP (HR 1.7, 95%CI 1.3-2.4) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.

Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multi-ethnic American sample.

To determine whether evidence-based socio-culturally adapted collaborative depression care improves receipt depression care, receipt, and depression and diabetes outcomes in low-income Hispanics.

A randomized controlled trial of 387 diabetes patients (96.5% Hispanic) with clinically significant depression, recruited from two public safety net clinics August 2005 to July 2007 and followed over 18 months. Intervention (INT) included: Problem Solving Therapy and/or antidepressant medication based on a stepped care algorithm, first-line treatment choice, telephone treatment response/adherence/and relapse prevention follow-up over 12 months, plus systems navigation assistance. Enhanced usual care (EUC) included standard clinic care plus patient receipt of depression educational pamphlets and a community resource list.

Intervention patients had significantly greater depression improvement (≥50% reduction in SCL-20 depression score from baseline) (57%, 62%, 62% versus EUC 36%, 42%, 44% at 6, 12, 18 months, respectively; OR 2.46-2.57; P<.001). Mixed-effects linear regression models showed a significant study group by time interaction over 18 months in diabetes symptoms, anxiety, SF-12 emotional, physical and pain-related functioning, Sheehan disability, financial situation and number of social stressors (P=0.04 for disability and SF-12 physical, and P<.001 for all others), but no study group by time interaction in HbA_1c, diabetes complications, self-care management, or BMI.

Socioculturally adapted collaborative depression care improved depression, functional outcomes and receipt of depression treatment in predominantly Hispanic patients in safety net clinics.

This study assessed the effects of balance/strength training on falls risk and posture in older individuals with type 2 diabetes.

Sixteen individuals with type 2 diabetes and 21 age-matched controls (50-75 yrs) participated. Postural stability and falls risk was assessed before and after a 6-week exercise program.

Diabetes individuals had significantly higher falls risk score compared to controls. The diabetes group also exhibited evidence of mild-to-moderate neuropathy, slower reaction times and increased postural sway. Following exercise, the diabetes group showed significant improvements in leg strength, faster reaction times, decreased sway and consequently, reduced falls risk.

Older individuals with diabetes had impaired balance, slower reactions and consequently a higher falls risk than age-matched controls. However, all these variables improved after resistance/balance training. Together these results demonstrate that structured exercise has wide-spread positive effects on physiological function for older individuals with type 2 diabetes.

We examined potential mediators of the reported association between diabetes and hearing impairment.

Data come from 1508 participants aged 40-69 years who completed audiometric testing during 1999-2004 in the National Health and Nutrition Examination Survey (NHANES). We defined hearing impairment as the pure tone average >25 decibels hearing level of pure tone thresholds at low/mid- (500, 1000, and 2000 Hz) and high- (3000, 4000, 6000, and 8000 Hz) frequencies. Using logistic regression, we examined whether controlling for vascular or neuropathic conditions, cardiovascular risk factors, glycemia, or inflammation diminished the association between diabetes and hearing impairment.

Diabetes was associated with a 100% increased odds of low/mid-frequency hearing impairment [OR=2.03 (1.32, 3.10)] and a 67% increased odds of high-frequency hearing impairment [OR=1.67 (1.14, 2.44)] in preliminary models after controlling for age, sex, race/ethnicity, education, smoking, and occupational noise exposure. Adjusting for peripheral neuropathy attenuated the association with low/mid-frequency hearing impairment [OR=1.70 (1.02, 2.82)]. Adjusting for albuminuria and C-reactive protein attenuated the association with high-frequency hearing impairment [OR=1.54 (1.02, 2.32)] and [OR=1.50 (1.01, 2.23)], respectively. Diabetes was not associated with high-frequency hearing impairment after controlling for A1c [OR=1.09 (0.60, 1.99)], but remained associated with low frequency impairment. We found no evidence suggesting that our observed relationship between diabetes and hearing impairment is due to hypertension or dyslipidemia.

Mechanisms related to neuropathic or microvascular factors, inflammation, or hyperglycemia may be mediating the association of diabetes and hearing impairment.

People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.

Cross-sectional study of 1066 men and women aged 60-75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, non-verbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.

In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables and cardiovascular disease (p<0.05).

High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes.

Despite widespread dissemination of target values, achieving a blood pressure (BP) of <130/80 mmHg is challenging for many individuals with diabetes. The purpose of the present study was to examine temporal trends in BP control in hypertensive individuals with diabetes mellitus as well as the potential for race, sex, and geographic disparities.

We analyzed baseline data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal cohort study of 30,228 adults (58% European American and 42% African American), examining the causes of excess stroke mortality in the southeastern United States. We calculated mean BP and BP control rates (proportion with BP < 130/80 mmHg) for the 5,217 hypertensive diabetic participants by year of enrollment (2003-2007) using multivariable logistic regression models.

Only 43% and 30% of European American and African American diabetic hypertensive participants respectively demonstrated a target BP of <130/80 mmHg (p < 0.001). However, a temporal trend of improved control was evident; the odds of having a BP < 130/80 mmHg among diabetic hypertensive participants of both races enrolled in 2007 (as compared to those enrolled in 2003) were approximately 50% greater (p < 0.001) in multivariate models.

These data suggest temporal improvements in BP control in diabetes that may reflect broad dissemination of tighter BP control targets and improving medication access. However, control rates remain low and significant racial disparities persist among African Americans that may contribute to an increased risk for premature cardiovascular disease.

To examine the association between baseline elevated depressive symptoms and incident type 2 diabetes in a national sample of people aged 50 and over.

The sample consisted of 6,111 individuals free from self-reported doctor diagnosed diabetes at baseline in 2002-03. The 8-item Center for Epidemiological Studies – Depression (CES-D) scale was the measurement of depressive symptoms. Cox proportional hazards regression models were used to assess whether baseline elevated (≥ 4) depressive symptoms were associated with a higher risk of type 2 diabetes over 45.8 months of follow-up.

The hazard ratio (HR) for diabetes was 1.62 (95% CI 1.15-2.29) in a model adjusted for age, sex, marital status, education, total net household wealth, cardiovascular and psychiatric and other non-cardiovascular comorbidities, body mass index and health behaviors for participants with elevated CES-D symptoms compared with those without. Complementary analysis performed for a subsample (n=5,090) showed that additional adjustment of this model for use of antidepressants did not explain the association (HR 1.58, 95% CI 1.09-2.29).

Elevated depressive symptoms were associated with a higher risk of developing type 2 diabetes after accounting for sociodemographic, lifestyle and clinical factors in a national sample of people aged 50 and over.

Impaired lung function and innate immunity have both attracted growing interest as a potentially novel risk factor for glucose intolerance, insulin resistance, and type 2 diabetes. We aimed to evaluate whether surfactant protein D (SP-D), a lung-derived innate immune protein, was behind these associations.

Serum SP-D was evaluated in 4 different cohorts. The cross sectional associations between SP-D and metabolic and inflammatory parameters were evaluated in 2 cohorts; the cross sectional relationship with lung function in 1 cohort; and the longitudinal effects of weight loss on fasting and circadian rhythm of serum SP-D and cortisol concentrations in 1 prospective cohort.

In the cross sectional studies, serum SP-D concentration was significantly decreased in subjects with obesity and type 2 diabetes (p=0.005), and was negatively associated with fasting and post-load serum glucose. SP-D was also associated with HbA_1c, serum lipids, insulin sensitivity, inflammatory parameters, and plasma insulinase activity. Smoking subjects with normal glucose tolerance, but not smoking patients with type 2 diabetes, showed significantly higher serum SP-D concentration than non-smokers. Serum SP-D concentration correlated positively with end-tidal carbon dioxide tension (r=0.54, p=0.034). In the longitudinal study, fasting serum SPD concentration decreased significantly after weight loss (p=0.02). Moreover, the main components of cortisol and SP-D rhythms became synchronous after weight loss.

These findings suggest that lung innate immunity, as inferred from circulating SP-D concentrations, is at the cross-roads of inflammation, obesity and insulin resistance.

The study investigated the effect of angiotensin-receptor blockers (ARB) on glucose homeostasis and inflammatory parameters in patients with impaired glucose tolerance (IGT).

We prospectively studied the insulin sensitivity index (ISI) and homeostasis model of insulin resistance (HOMA-IR) in 13 obese males with IGT and in 13 matched controls with normal glucose tolerance (NGT) during hyperglycemic testing over 90 minutes. Adiponectin, retinol-binding protein 4 (RBP4), and high-sensitive C-reactive protein (hs-CRP) were analyzed. Measurements were performed at baseline and after a four-week treatment with valsartan 160 mg/day. The results of the IGT and NGT groups were compared.

At baseline, HOMA-IR (IGT 4.1±3 vs. NGT 2.3± 1.0, p<0.01), hsCRP (IGT 3.9±1.9 vs. NGT 1.8±1mg/l, p<0.05), and RBP4 (IGT 27.1±2.1 vs. NGT 24.0± 2.0 ng/ml, p<0.05) were significantly higher, whereas ISI (IGT 1.5±0.9 vs. NGT 1.8±1.2, p<0.05) and plasma adiponectin (IGT 3.2±0.9, NGT 5.2±2.4 µg/ml, p<0.05) were significantly lower in the IGT group compared to the NGT group.

Under ARB, there was an increase in both groups of adiponectin (IGT 4.1±1.9 µg/ml, NGT 6.3±2.9 µg/ml, p <0.05), and an increase in ISI (IGT 1.5±0.9 µg/ml to 2.3 ± 1, NGT 1.8±1 to 2.5±2, p <0.05). Homa-IR (4.1±3 to 2.6±2; p<0.01), hsCRP (3.9±1.9 to 1.8±1mg/l, p<0.05) and RBP4 (27.1±2.1 to 22.1±1.8 ng/ml, p<0.01) decreased significantly in the IGT group.

Insulin sensitivity and associated inflammatory factors improve under ARB in IGT patients. International Standard Randomized Controlled Trial Number07427212.

Reasons for failing to initiate prescribed insulin (primary non-adherence) are poorly understood. We investigated barriers to insulin initiation following a new prescription.

We surveyed insulin-naïve patients with poorly controlled type 2 diabetes, already treated with ≥2 oral agents who were recently prescribed insulin. We compared responses for respondents prescribed, but never initiating, insulin (n=69) to those dispensed insulin (n=100).

Subjects failing to initiate prescribed insulin commonly reported misconceptions regarding insulin risk (35% believed that insulin causes blindness, renal failure, amputations, heart attacks, strokes or early death); plans to instead work harder on behavioral goals; sense of personal failure; low self-efficacy, injection phobia; hypoglycemia concerns; negative impact on social life and job; inadequate health literacy; healthcare provider inadequately explaining risks/benefits; and limited insulin self-management training.

Primary adherence for insulin may be improved through better provider communication regarding risks, shared decision making, and insulin self-management training.

This trial was to test whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing beta cells in subjects with new onset type 1 diabetes (T1D).

A multicenter, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either: MMF-alone, MMF and DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2 hour mixed meal tolerance test.

One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF-alone, or MMF and DZB, versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly.

Neither MMF-alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new onset T1D. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.

Abnormal cellular cholesterol handling in islets may contribute to beta-cell dysfunction in type 2 diabetes. Beta-cell deficiency for the ATP Binding Cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol, leads to altered intracellular cholesterol homeostasis and impaired insulin secretion in mice. We aimed to assess the impact of ABCA1 dysfunction on glucose homeostasis in humans.

In heterozygous carriers of disruptive mutations in ABCA1 and family-based non-carriers of similar age, gender and body mass index we performed oral glucose tolerance tests (OGTT; N=15 vs. 14) and hyperglycemic clamps (N=8 vs. 8).

HDL-C levels in carriers were less than half those in non-carriers but low density lipoprotein cholesterol (LDL-C) levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after OGTT were mildly higher in carriers than in non-carriers. During hyperglycemic clamps, carriers demonstrated lower first phase insulin secretion than non-carriers but no difference in insulin sensitivity. Disposition index of the carriers – a measure of beta-cell function adjusted for insulin sensitivity – was significantly reduced in ABCA1 heterozygotes.

Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance. Our data provide evidence that ABCA1 is important for normal β cell function in humans.

To determine in Canadian children <18 years the: 1) incidence of type 2 diabetes, medication-induced diabetes and monogenic diabetes, 2) clinical features of type 2 diabetes and 3) co-existing morbidity associated with type 2 diabetes at diagnosis.

This Canadian prospective national surveillance study involved a network of pediatricians, pediatric endocrinologists, family physicians and adult endocrinologists. Incidence rates were calculated using Canadian Census population data. Descriptive statistics were used to illustrate demographic and clinical features.

345 cases of non-type 1 diabetes were reported from a population of 7.3 million children. The observed minimum incidence rates of type 2, medication-induced, and monogenic diabetes were 1.54, 0.4, and 0.2 cases/100,000 children <18 years of age/year, respectively. On average, children with type 2 diabetes were 13.7 years and 8% (19/227) presented before 10 years. Ethnic minorities were over-represented, but 25% (57/227) of children with type 2 diabetes were Caucasian. 95% (206/216) of children with type 2 diabetes were obese and 37% (43/115) had at least one co-morbidity at diagnosis.

This is the first prospective national surveillance study in Canada to report the incidence of type 2 diabetes in children and also the first in the world to report the incidence of medication-induced, and monogenic diabetes. Rates of type 2 diabetes were higher than expected with important regional variation. These results support recommendations that screening for co-morbidity should occur at diagnosis of type 2 diabetes.

Adiponectin, a hormone secreted by adipose tissue is of particular interest to metabolic syndrome (MetS), since it is inversely correlated with obesity and insulin sensitivity. However, it is unknown to what extent the genetics of plasma adiponectin and the genetics of obesity and insulin sensitivity are interrelated. We aimed to evaluate the heritability of plasma adiponectin and its genetic correlation with the MetS and MetS related traits and the association between these traits and ten ADIPOQ SNPs.

We made use of a family-based population, the Erasmus Rucphen family (ERF) study (1258 women and 967 men). Heritability analysis was performed using a polygenic model. Genetic correlations were estimated using bivariate heritability analyses. Genetic association analysis was performed using a mixed model.

Plasma adiponectin showed a heritability of 55.1%. Genetic correlation between plasma adiponectin HDL-C and plasma insulin ranged from 15% to 24% but were not significant for fasting glucose, TG, blood pressure, HOMA-IR and CRP. Significant association with plasma adiponectin was found for ADIPOQ variants rs17300539 and rs182052. Nominally significant association was found with plasma insulin and HOMA-IR and ADIPOQ variant rs17300539 after adjusting for plasma adiponectin.

The significant genetic correlation between plasma adiponectin and HDL-C, and plasma insulin should be taken into account in the interpretation of genome wide association studies. Association of ADIPOQ SNPs with plasma adiponectin was replicated and we showed association between one ADIPOQ SNP and plasma insulin and HOMA-IR.

To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy.

Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks.

For the primary endpoint, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400mg/day,P=0.12;600mg/day,P=0.18). Both doses were significantly more effective compared with placebo over the titration (P=0.03,P=0.006), maintenance (P=0.01,P=0.005), and entire treatment periods (P=0.03,P=0.02). Safety profiles between titration schemes were similar.

Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.

Iron deficiency has been reported to elevate hemoglobin A1c (HbA1c) levels apart from glycemia. We examined the influence of iron deficiency on HbA1c distribution among adults without diabetes.

Participants included adults without self-reported diabetes or chronic kidney disease in NHANES 1999-2006 who were aged ≥ 18 years of age and had complete blood counts, iron studies, and HbA1c levels. Iron deficiency was defined as at least 2 abnormalities including: free erythrocyte protoporphyrin > 70 ug/dl red blood cells, transferrin saturation < 16%, or serum ferritin ≤ 15 ug/L. Anemia was defined as hemoglobin < 13.5 g/dl in men and < 12.0 g/dl in women.

Among women (n=6,666), 13.7% had iron deficiency and 4.0% had iron deficiency anemia. While 316 women with iron deficiency had Hba1c >=5.5%, only 32 women with iron deficiency had Hba1c >=6.5%. Among men (n=3,869), only 13 had iron deficiency and an HbA1c >=5.5% and only 1 had iron deficiency and an HbA1c > 6.5%. Among women, iron deficiency was associated with a greater odds of HbA1c >= 5.5% (OR 1.39, 95% CI, 1.11, 1.73) after adjustment for age, race/ethnicity, and waist circumference, but not with a greater odds of HbA1c >= 6.5% (OR 0.79, 95% CI 0.33, 1.85).

Iron deficiency is common among women and is associated with shifts in HbA1c distribution from an HbA1c < 5.5% to > 5.5%. Further research is needed to examine whether iron deficiency is associated with shifts at higher HbA1c levels.

Arterial stiffness (AS) occurs early in the atherosclerotic process; however, few data are available concerning risk factors for AS in youth with diabetes. We identified factors associated with AS in youth with diabetes, and assessed the effects of these factors on the relationship between AS and diabetes type (type 1 vs. type 2).

A sub-set of SEARCH patients with type 1 (N=535) and type 2 diabetes (N=60), age 10-23 years (52% male, 82% non-Hispanic white, diabetes duration 65±49 months) had AS, anthropometrics, blood pressure, fasting lipids, and hemoglobin A1c measured. AS was measured by brachial distensibility (brachD), pulse wave velocity (PWV) and augmentation index adjusted to heart rate of 75 beats/minute (AI75).

Youth with type 2 diabetes had worse brachD (5.2±0.9 vs. 6.1±1.2 %/mmHg), PWV (6.4±1.3 vs. 5.3±0.8 m/sec), and AI75 (6.4±9.9 vs. 2.2±10.2 %) than those with type 1 diabetes (p<0.01 for each). These differences were largely mediated through increased central adiposity and higher blood pressure in youth with type 2 diabetes. We also found a pattern of association of AS measures with waist circumference and blood pressure, independent of diabetes type.

Youth with type 2 diabetes have worse arterial stiffness than similar youth with type 1 diabetes. Increased central adiposity and blood pressure are associated with measures of arterial stiffness, independent of diabetes type. Whether these findings indicate that youth with type 2 diabetes will be at higher risk for future complications requires longitudinal studies.

We have recently shown that a high fat high carbohydrate (HFHC) meal induces an increase in plasma concentrations of endotoxin (LPS), and the expression of toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in mononuclear cells (MNC) in addition to oxidative stress and cellular inflammation.

Saturated fat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and inflammation, also induce an increase in LPS, TLR-4 and SOCS3.

Fasting normal subjects were given 300 Calorie drinks of either glucose, saturated fat as cream, orange juice or only water to ingest. Blood samples were obtained at 0, 1, 3 and 5 hours for analysis.

Indices of inflammation including NFB binding, and the expression of SOCS3, TNF and IL-1β in MNC increased significantly following glucose and cream intake, but TLR-4 expression and plasma LPS concentrations increased only after cream intake. The intake of orange juice or water did not induce any change in any of the indices measured.

While both glucose and cream induce NFB binding and an increase in the expression of SOCS3, TNF and IL-1β in MNC, only cream caused an increase in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not induce a change in any of these indices. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance.

Individuals with Type 2 diabetes (T2DM) have a myriad of metabolic aberrations including increased inflammation that increase their cardiovascular risk. Toll-like receptors (TLRs) and their ligands play a key role in insulin resistance and atherosclerosis. However, there is a paucity of data examining the expression and activity of TLRs in T2DM. Thus, in the present study, we examined TLR2 and TLR4 mRNA and protein expression, their ligands, and signaling in monocytes of recently diagnosed T2DM patients.

TLR mRNA, protein expression, TLR ligands and TLR signaling were measured in freshly isolated monocytes from healthy human controls (n=23) and T2DM subjects (n=23) using real time RT PCR, Western blot, and Flow cytometric assays.

T2DM subjects had significantly increased TLR2, TLR4 mRNA and protein in monocytes compared to controls (P<0.05). Increased TLR2 and TLR4 expression correlated with BMI, HOMA-IR, glucose, HbA1c, CML, and FFA. Ligands of TLR2 and TLR4 namely, HSP60, HSP70, HMGB1, endotoxin, and hyaluronan levels were elevated in T2DM subjects and positively correlated with TLR2 and TLR4. T2DM subjects showed increased MyD88, phosphorylated IRAK-1, Trif, TICAM-1, IRF-3, and NF-B p65 expression in monocytes compared to controls. Furthermore, TLR-MyD88-NF-B signaling resulted in elevated levels of cytokines (P<0.05), but increased IL-1β, IFN-, and endotoxin were not significant when adjusted for BMI.

In this comprehensive study, we make the novel observation that TLR2 and TLR4 expression, their ligands, signaling, and functional activation are increased in recently diagnosed T2DM and contribute to the proinflammatory state.

To evaluate the impact of a preconception counseling (PC) program tailored for teens with type-1-diabetes on cognitive, psychosocial, and behavioral outcomes and to assess its cost-effectiveness.

Eighty-eight teens with type-1-diabetes from 2-sites were randomized into the "READY-Girls" (Reproductive-health Education and Awareness of Diabetes in Youth for Girls) intervention (IG) (n=43) or standard care (SC) (n=45) groups. During 3 diabetes clinic visits, IG subjects viewed a two-part CD-ROM, read a book, and met with a nurse. Program effectiveness was measured by knowledge, attitudes, intentions and behaviors regarding diabetes, pregnancy, sexuality, and PC. Assessments occurred at baseline, before and after viewing program materials, and at 9-months. Economic analyses included an assessment of resource utilization, direct medical costs, and a break-even cost analysis.

Age range was 13.2-19.7 years(mean=16.7±s.d 1.7 years); 6 (n=5) were African American and 24%(n=21) were sexually active. Compared to baseline and SC subjects, IG subjects demonstrated a significant group-by-time interaction for benefit and knowledge of PC and reproductive-health: increasing immediately after the first visit (p<0.001) and being sustained for 9-months (p<0.05 benefits; p<0.001 knowledge). For IG subjects, PC barriers decreased over time (p<0.001), and intention and initiation of PC and reproductive-health discussions increased (p<0.001). Costs of adverse reproductive outcomes are high. Direct medical costs of READY-Girls were low.

READY-Girls was beneficial and effects were sustained for at least 9-months. This low-cost self-instructional program can potentially empower young women with type-1-diabetes to make well informed reproductive-health choices, adding little time burden or cost to their diabetes management.

Measure ghrelin and energy intake (EI) in the laboratory after pioglitazone treatment.

Parallel 3-arm study with 51 obese diabetics randomized to either: 1) pioglitazone plus a portion-controlled diet (Pio+PC), 2) pioglitazone plus American Diabetes Association (ADA) dietary advice (Pio+ADA), or 3) metformin plus ADA advice (Met+ADA). EI and the suppressive response of a meal on ghrelin were measured at weeks 0 and 16. Mixed models tested if changes from week 0 to 16 differed by group.

The Pio+ADA group had a significantly larger increase (p<.05) in EI (adjusted mean±SEM; 207±53 kcal) compared to the Pio+PC (50±46 kcal) and Met+ADA (52±49 kcal) groups. Change in restraint and disinhibition (variables associated with eating behavior) mediated weight change. Ghrelin suppression increased in the Pio+ADA group, which gained weight.

A portion-controlled diet attenuated the increase in EI after pioglitazone. Ghrelin responded to weight change, not pioglitazone exposure.

To evaluate HbA_1c for screening and diagnosis of undiagnosed Type 2 diabetes defined by oral glucose tolerance testing in clinical and general populations.

HbA_1c cut-offs (≤5.5% to ‘rule-out’; ≥7.0% to ‘rule-in’ diabetes) were derived from a clinical group (MP: n= 2,494; undiagnosed diabetes 34.6%) and then evaluated in a population-based sample (AusDiab: n=6,015, undiagnosed diabetes 4.6%).

For diabetes in MP and AusDiab, HbA_1c at 5.5% gave sensitivities of 98.7% and 83.5%, while HbA_1c at 7.0% gave specificities of 98.2% and 100%, respectively. Many (61.9 – 69.3%) with impaired HbA_1c (IA_1c: 5.6 – 6.9%) in both populations had abnormal glucose status.

HbA_1c ≤5.5% and ≥7.0% predicts absence or presence of Type 2 diabetes while at HbA_1c 6.5–6.9%, diabetes is highly probable in clinical and population settings. A high proportion of people with IA_1c have abnormal glucose status requiring follow-up.

Patients with type 1 diabetes mellitus (T1DM) and microalbuminuria are at increased risk of cardiovascular disease (CVD). Abnormalities in vascular progenitor cells, which participate in vascular repair, may be implicated in this susceptibility.

We studied the number and function of vascular progenitor cells in 22 T1DM patients with history of microalbuminuria (MA+) and 22 T1DM patients without history of microalbuminuria (MA–), of similar age, diabetes duration, glycaemic control, renal function, and no history of CVD.

MA+ patients had lower circulating CD34⁺ and CD34⁺/CD133⁺ cells number compared to MA– (p<0.006). In in vitro functional assays, MA+ patients had significantly lower number of colony-forming units, and impaired VEGF-A mediated tube formation, when compared to MA– patients (p<0.01).

In T1DM with microalbuminuria, a marker of microvascular injury and a risk factor for CVD, circulating vascular progenitor cells number is reduced and function is impaired.

Most patients with ketosis-prone type 2 diabetes mellitus (KPDM) discontinue insulin therapy and remain in near-normoglycemic remission. This study aimed to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPDM.

Age- and BMI-matched obese African-Americans (AA) with history of KPDM (n=8), severe hyperglycemia but without ketosis (ketosis-resistant T2DM, n=7), and obese controls (n=13) underwent intravenous infusion of 10% dextrose at rate 200 mg/m²/min for 20 hours. β-cell function was assessed by changes in insulin and C-peptide concentration during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.

The mean time to discontinue insulin therapy was 7.1±1.7 weeks in KPDM and 9.6±2.3 weeks in ketosis-resistant T2DM, p=NS. During 20-hr dextrose infusion, changes in insulin, C-peptide and C-peptide/glucose ratio were similar among diabetic and control groups. During dextrose infusion ketosis-resistant T2DM had greater area under curve for blood glucose than KPDM and control subjects, p<0.05. The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among study groups.

Near-normoglycemia remission in obese AA patients with KPDM and ketosis-resistant T2DM is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, KPDM patients displayed a pattern of insulin secretion similar to ketosis-resistant T2DM and obese nondiabetic subjects.

To examine trends in the prevalence of diabetes among delivery hospitalizations in the United States and to describe the characteristics of these hospitalizations.

Hospital discharge data from 1994 through 2004 were obtained from the Nationwide Inpatient Sample (NIS). Diagnosis codes were selected for gestational diabetes mellitus (GDM), Type 1, Type 2, and unspecified diabetes. Rates of delivery hospitalization with diabetes were calculated per 100 deliveries.

Overall, an estimated 1,863,746 hospital delivery discharges contained a diabetes diagnosis, corresponding to a rate of 4.3/100 deliveries over the 11-year period. GDM accounted for the largest proportion of delivery hospitalizations with diabetes (84.7%), followed by Type 1 (7%), Type 2 (4.7%), and unspecified diabetes (3.6%). From 1994 to 2004, the rates for all-diabetes, GDM, Type 1 and Type 2 diabetes significantly increased overall and within each age group (15-24, 25-34, >=35 years) (p <0.05). The largest percent increase for all ages was among Type 2 diabetes (367%). By age group, the greatest percent increases for each diabetes type were among the two younger groups. Significant predictors of diabetes at delivery included age >=35 years vs. 15-24 years (OR=4.80, 95% CI 4.72-4.89), urban vs. rural location (OR=1.14, 95% CI 1.11-1.17), and Medicaid/Medicare vs. other payment sources (OR=1.29, 95% CI 1.26-1.32).

Given the increasing prevalence of diabetes among delivery hospitalizations particularly among younger women, it will be important to monitor trends in the pregnant population and target strategies to minimize risk for maternal/fetal complications.

To determine insulin resistance and response in PCOS patients with normal glucose tolerance (NGT) impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined glucose intolerance (CGI).

In this cross-sectional study, 143 PCOS patients (diagnosed based on NIH criteria) underwent oral glucose tolerance testing (OGTT) and 68 patients also had frequently sampled intravenous glucose tolerance tests. Changes in plasma glucose, insulin, cardiovascular risk factors and androgens were measured.

As compared to NGT, both IFG and CGI were significantly insulin resistant (HOMA: 3.3±0.2 vs. 6.1±0.9 and 6.4±0.5, p < 0.0001) and hyperinsulinemic (AUC_Insulin-120: 973±69 vs. 1,470±197 and 1,461±172 pmol/l, p <0.0001). Insulin response was delayed in CGI but not in IFG (2h OGTT-insulin: 1,001±40 vs. 583±45 pmol/l, p<0.0001). Compared to NGT, CGI group had lower disposition index (1,615±236 vs. 987±296, p<0.0234) and adiponectin (11.1±1.1 vs. 6.2±0.8 ng/ml, p <0.0096). Compared to the insulin resistant tertile of NGT, IFG had reduced insulinogenic index (421±130 vs. 268±68, p <0.05). Compared to insulin sensitive tertile of NGT, resistant tertile had higher triglyceride and hs-CRP and lower HDL-cholesterol and SHBG. In the entire population, insulin resistance correlated directly with triglyceride, hs-CRP and free androgen index, and inversely with SHBG.

PCOS patients develop IFG and CGI despite having significant hyperinsulinemia. The IFG and CGI exhibit similar insulin resistance but very different insulin response patterns. Increases in cardiac risk factors and free androgen level precede overt glucose intolerance.

To evaluate to what extent the association between family history of diabetes and risk of type 2 diabetes can be explained by excess adiposity and lifestyle risk factors.

We analyzed data from 73,227 women who participated in the Nurses' Health Study cohort. A family history of diabetes was defined as having at least one first degree family member with diabetes. Lifestyle factors, weight and height were assessed by using validated questionnaires, and body mass index (BMI) was calculated. The relative risk of type 2 diabetes was estimated using Cox proportional hazards analysis.

We documented 5101 cases of type 2 diabetes during 20 years of follow-up. The age-adjusted relative risk of type 2 diabetes in participants with a family history was 2.27 (95% CI 2.14-2.40) as compared with those without a family history of diabetes. Participants with a family history of diabetes had a higher BMI and were more likely to have a parental history of obesity. BMI explained 21.1% (95% CI 19.4-22.9) of the association between family history of diabetes and risk of type 2 diabetes. Intakes of red meat, alcohol and sugar-sweetened beverages explained 1.1% (95% CI 0.8-1.3), 4.8% (95% CI 4.3-5.3) and 2.8% (95% CI 2.4-3.2) of this association respectively.

These results suggest that excess adiposity and, to a lesser extent, specific dietary habits can explain a substantial part of the association between having a family history of diabetes and risk of type 2 diabetes.

To individuate a novel sex-specific index, based on Waist Circumference (WC), Body Mass Index (BMI), Triglycerides (TG) and HDL cholesterol (HDL), indirectly expressing visceral fat function.

Visceral Adiposity Index (VAI) was first modelled on 315 non-obese healthy subjects. Using two multiple logistic regression models, VAI was retrospectively validated in 1,498 primary care patients in comparison to classical cardio and cerebrovascular risk factors.

All components of metabolic syndrome increased significantly across VAI quintiles. VAI was independently associated with both cardiovascular (OR:2.45; 95%CI: 1.52-3.95; p<0.001) and cerebrovascular events (OR:1.63; 95%CI: 1.06-2.50; p=0.025). VAI also showed significant inverse correlation with insulin sensitivity during euglycemic-hyperinsulinemic clamp in a subgroup of patients (R_s= –0.721; p<0.001). By contrast, no correlations were found for WC and BMI.

Our study suggests VAI is a valuable indicator of "visceral adipose function" and insulin sensitivity, and its increase is strongly associated with cardiometabolic risk.

To examine variables associated with perceived diabetes control compared with an objective measure of glucose control (HbA1c).

Beliefs about diabetes were assessed among 334 individuals with diabetes living in a primarily low-income, minority, urban neighborhood. Regression analyses tested associations between disease beliefs and both participants' perceptions of control and actual control (HbA1c).

Poorer perceived diabetes control was associated with perceiving a greater impact of diabetes, greater depressive symptoms, not following a diabetic diet, HbA1c and a trend towards less exercise. Variables associated with better actual control (HbA1c) included higher BMI, older age and not using insulin.

Patients' perceptions of their diabetes control are informed by subjective diabetes cues (e.g., perceived impact of diabetes and adherence to a diabetic diet), which are not related to HbA1c. Clinicians should take into account what cues patients are using to assess their diabetes control.

To investigate the relation between serum concentration of 25-hydroxyvitamin D [25(OH)D] and insulin action and secretion.

In a cross-sectional study of 446 Pan-European subjects with the metabolic syndrome insulin action and secretion were assessed by homeostasis model assessment (HOMA) indices and intravenous glucose tolerance test to calculate acute insulin response, insulin sensitivity and disposition index. Serum 25(OH)D was measured by HPLC/MS.

The mean (SD) 25(OH)D₃ concentration was 57.1 (26.0) nmol/l, and only 20% of the subjects had 25(OH)D₃ levels ≥75 nmol/l. In multiple linear analyses, 25(OH)D₃ concentrations were not associated withparameters of insulin action or secretion after adjustment for BMI and other covariates.

In a large sample of subjects with the metabolic syndrome, serum concentrations of 25(OH)D₃ did not predict insulin action or secretion. Clear evidence that D-vitamin status directly influences insulin secretion or action is still lacking.

To determine if the dipeptidyl peptidase 4 inhibitor vildagliptin more effectively than the sulfonylurea glimepiride inhibits glucagon levels during meal.

Glucagon responses to a standard meal were measured at baseline and study endpoint (mean 1.8 years) in a trial evaluating add-on therapy to metformin with vildagliptin 50 mg bid compared to glimepiride up to 6 mg qd in type 2 diabetes (baseline HbA1c 7.3±0.6%).

HbA_1c and prandial glucose AUC_0-2h were reduced similarly in both groups, while prandial insulin AUC_0-2h increased to a greater extent by glimepiride. Prandial glucagon AUC_0-2h (baseline 66.6±2.3 pmol·h/l) decreased by 3.4±1.6 pmol·h/l by vildagliptin group (n=137) and increased by 3.8±1.7 pmolh/l by glimepiride group (n=121). The between-group difference was 7.3±2.1 pmol·h/l (p<0.001).

Vildagliptin therapy but not glimepiride improves post-prandial -cell function, which persists for at least 2 years.

To evaluate the prevalence of lower limb complications (LLCs) in a multi-racial cohort of patients with diabetes receiving dialysis.

A cross-sectional study of LLCs in dialysis-treated patients with diabetes in the UK and USA.

We studied 466 patients (UK 139; USA 327). The prevalence of LLCs was high (foot ulcers 12%, neuropathy 79%, peripheral arterial disease (PAD) 57%, history of foot ulceration 34% and prior amputation 18%), with no significant ethnic variation, except that foot ulcers were more common in Whites than in patients of African-descent (p=0.013). Ninety-five percent of patients were at-risk of LLCs. Prior amputation was related to foot ulcer history, PAD and hemodialysis modality in multivariable analysis. Prevalent ulceration showed independent associations with foot ulcer history and PAD, but not with ethnicity.

All patients with diabetes receiving dialysis are at high risk of LLCs independent of ethnic background.

We examined maximal graded exercise test (GXT) results in 5783 overweight/obese men and women, aged 45-76 years, with type 2 diabetes, entering the Look AHEAD Study, to determine the prevalence and correlates of exercise-induced cardiac abnormalities.

Participants underwent symptom-limited maximal GXTs. Questionnaires and physical examinations were used to determine demographic, anthropometric, metabolic, and health status predictors of abnormal GXTs, which were defined as an ST segment depression ≥1.0 mm, ventricular arrhythmia, angina pectoris, poor post-exercise heart rate recovery (< 22 beats per minute reduction two minutes after exercise), or maximal exercise capacity less than 5.0 METs. Systolic blood pressure response to exercise was examined as a continuous variable, without a threshold to define abnormality.

Exercise-induced abnormalities were present in 1303 (22.5%) participants, of which 693 (12.0%) consisted of impaired exercise capacity. ST segment depression occurred in 440 (7.6%), abnormal heart rate recovery in 206 (5.0%), angina in 63 (1.1%), and arrhythmia in 41 (0.71%). Of potential predictors, only greater age was associated with increased prevalence of all abnormalities. Other predictors were associated with some, but not all, abnormalities. Systolic blood pressure response decreased with greater age, duration of diabetes, and history of cardiovascular disease.

We found a high rate of abnormal GXTs despite careful screening for cardiovascular disease symptoms. In this cohort of overweight and obese people with type 2 diabetes, greater age most consistently predicted abnormal GXT. Long-term follow-up of these participants will show whether these abnormalities are clinically significant.(NCT00017953—Clinicaltrials.gov)

Genetic factors have been considered to contribute to the development and progression of diabetic nephropathy. The KCNQ1 gene (potassium voltage-gated channel, KQT-like subfamily, member 1) was originally identified as a strong susceptibility gene for type 2 diabetes in 2 Japanese genome-wide association studies. In this study, we examined the association of single nucleotide polymorphisms (SNPs) within KCNQ1 with diabetic nephropathy in Japanese subjects with type 2 diabetes.

We genotyped 33 SNPs in KCNQ1 using 754 type 2 diabetes patients with overt nephropathy and 558 controls (an initial study), and we further examined the association of a candidate SNP using 3 other independent Japanese populations (replications 1–3).

We found that 5 SNPs were nominally associated with diabetic nephropathy, and the association of rs2237897 was the strongest. We also found that the T allele frequencies of rs2237897 were consistently higher in the nephropathy groups than in the control groups for all study populations (initial study: 0.33 vs. 0.27; replication 1: 0.32 vs. 0.30; replication 2: 0.33 vs. 0.28; replication 3: 0.32 vs. 0.28), although the individual associations did not reach statistically significant levels. Combined analysis by a meta-analysis revealed that the T allele of rs2237897 was significantly associated with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes (OR = 1.22, 95% CI = 1.10–1.34, P = 3.1 x 10^–4, corrected P = 0.01).

These results suggest that KCNQ1 is a new candidate gene for conferring susceptibility to diabetic nephropathy.

Newer medications offer more options for glycemic control in type 2 diabetes. However, they come at considerable costs. We undertook a health economic analysis to better understand the value of adding two newer medications (exenatide and sitagliptin) as second-line therapy to glycemic control strategies for new-onset diabetic patients.

We performed a cost-effectiveness analysis for the U.S. population age 25 to 64. A lifetime analytic horizon and healthcare system perspective were used. Costs and quality-adjusted life years (QALYs) were discounted at 3% annually, and costs are presented in 2008 US$. We compared three glycemic control strategies: (1) glyburide as a second-line agent (2) exenatide as a second-line agent (3) sitagliptin as a second-line agent. Outcome measures included QALYs gained, incremental costs, and the incremental cost-effectiveness ratio associated with each strategy.

Exenatide and sitagliptin conferred 0.09 and 0.12 additional QALYs respectively, relative to glyburide as second-line therapy. In base case analysis, exenatide was dominated (cost more and provided fewer QALYs than the next most expensive option) and sitagliptin was associated with an incremental cost-effectiveness ratio of $169,572 per QALY saved. Results were sensitive to assumptions regarding medication costs, side-effect duration, and side effect-associated disutilities.

Exenatide and sitagliptin may confer substantial costs to healthcare systems. Demonstrated gains in quality and/or quantity of life are necessary for these agents to provide economic value to patients and healthcare systems.

To examine the association between parental BMI and offspring CVD risk factors.

The study comprised 940 children (9.5±0.4y) and 873 adolescents (15.5±0.5y). Parental weight and height were reported by the mother and the father, and BMI was calculated. CVD risk factors included total (sum of 5 skinfolds) and central (waist circumference) body fat, blood pressure, cardiorespiratory fitness, insulin sensitivity, total-cholesterol, HDL-cholesterol, triglycerides and fibrinogen.

Maternal and paternal BMI were positively associated with total and central fatness in offspring (P<0.001). Both parents BMI were significantly related to fibrinogen levels (P<0.02), but these associations disappeared when controlling for fatness. There was a positive relationship between maternal and paternal BMI and waist circumference in the offspring regardless of total adiposity and height (P<0.001). Maternal BMI was negatively associated with offspring cardiorespiratory fitness independently of fatness (P<0.02).. These relationships persisted when overweight descendants were excluded from the analysis. There were not significant associations between parental BMI and the other CVD risk factors.

Both maternal and paternal BMI increase CVD risk factors of the offspring characterized by total and central body fat, and higher mother BMI was associated with poorer cardiorespiratory fitness. Our findings give further support to the concept that adiposity in parents transmits susceptibility to CVD risk to descendant, which is detectable even in absence of overweight in offspring.

To compare the ages and sequence in which antibodies associated with type 1 diabetes and celiac disease appear and overt diseases develop in children with a HLA-conferred susceptibility to both diseases.

We observed 2,052 children carrying genetic risk for both type 1 diabetes and celiac disease from birth until the median age of 5.7 years and analyzed diabetes- and celiac disease-associated antibodies in serum samples collected at 3- to 12-month intervals. Diabetes was confirmed by WHO criteria and celiac disease by duodenal biopsies.

Altogether 342 children seroconverted to positivity for at least one diabetes-associated autoantibody and 88 to positivity for at least one celiac disease-associated antibody at the median ages of 3.0 and 1.5 years, respectively (P < 0.001). If only children with biochemically defined diabetes-associated autoantibodies against insulin, glutamic acid decarboxylase or IA-2A protein (n=146), and children with tissue transglutaminase autoantibodies were compared (n = 86), the median seroconversion ages were 2.5 and 3.0 years (P = 0.011). Fifty-one children progressed to overt diabetes at 4.5 years and 44 children to celiac disease at 4.3 years (P = 0.257). Of the 19 children who developed both diabetes- and celiac disease-associated antibodies, three progressed both to diabetes and celiac disease.

Children with HLA-conferred susceptibility to type 1 diabetes and celiac disease develop celiac disease-associated antibodies mostly at a younger or the same age than diabetes-associated autoantibodies. Clinical diabetes and celiac disease are commonly diagnosed at the same median age.

Little is known on the prevalence of beta-cells auto-antibodies in children with excess body weight.

The prevalence of type 1 diabetes auto-antibodies and its relation with hyperglycemia was analyzed in 686 overweight/obese children and adolescents. All children underwent OGTT and anti-GAD, anti-IA2 and anti-IAA auto-antibodies were measured. Auto-antibodies prevalence was evaluated in 107 normal weight children for comparison.

A single auto-antibody was present in 2.18% overweight/obese and in 1.86% normal weight subjects (p=NS). Post-load glycemia was significantly higher in antibody-positive children (133±69.9 vs. 105.4±17.7 mg/dl; p<0.0001) compared to auto-antibody-negative subjects. No difference in auto-antibodies distribution was seen when our cohort was stratified by age, sex, SDS-BMI, pubertal stage and HOMA-IR.

The 2.18% prevalence of type 1 diabetes auto-antibodies is very similar to that reported in non obese children. This study provided evidence that excess body weight and insulin-resistance do not influence auto-antibodies frequency.

To determine the effect of TPN-induced hyperglycemia on hospital outcome.

To determine whether blood glucose (BG) values prior to, within 24-hours, and during days 2-10 of TPN are predictive of hospital complications and mortality.

A total of 276 patients receiving TPN for a mean duration of 15±24 days (±SD). In multiple regression models adjusted for age, sex, and DM status, mortality was independently predicted by pre-TPN BG 121-150 mg/dl (OR 2.2, 95% CI 1.1-4.4, p=0.030), 151-180 mg/dl (OR 3.41, 95% CI 1.3-8.7, p: 0.01) and >180 mg/dl (OR 2.2, 95% CI 0.9-5.2, p=0.077), and by BG within 24h >180 mg/dl (OR 2.8, 95% CI 1.2-6.8, p=0.020). A BG within 24h >180 mg/dl was associated with increased risk of pneumonia (OR=3.1, 95% CI: 1.4-7.1) and acute renal failure (OR=2.3, 95% CI: 1.1-5.0).

Hyperglycemia is associated with increased hospital complications and mortality in patients receiving TPN.

To determine the longitudinal association of components of health related functioning (HRF) with incident impaired glucose metabolism and type 2 diabetes mellitus (DM).

The Australian Diabetes Obesity and Lifestyle study (AusDiab) is a national, longitudinal study of adults aged ≥25 years from 42 randomly selected areas of Australia. Diabetes status was defined using the World Health Organization criteria and HRF was assessed using the SF-36 questionnaire in 1999-2000 and 2004-2005.

Incident impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed type 2 diabetes mellitus (NDM) were associated with increased bodily pain (BP) at baseline compared to those with normal glucose tolerance (NGT) (IFG p=0.005, IGT p<0.004, NDM p=0.005), after adjustment. Additionally, those with incident IGT and NDM had significantly reduced physical functioning (PF), general health (GH), mental health and vitality (VT) at baseline compared to those with NGT. After controlling for factors associated with incident diabetes, those in the lowest quartile of the physical component summary scale at baseline had at least a 50% higher risk of progression to impaired glucose metabolism and diabetes 5 years later.

These findings show that incident IFG, IGT and NDM are associated with reduced HRF independent of CVD and that this is evident prior to the onset of these conditions. If future health promotion campaigns are to effectively target those at high risk of developing diabetes, an understanding of the process of declining health prior to the onset of the disease is essential.

Prospective evaluation of pregnancy outcomes in pre-gestational diabetes along the Atlantic seaboard 2006/2007.

The Atlantic Diabetes in Pregnancy group representing 5 antenatal centres in a wide geographical location was established in 2005. All women with diabetes for at > 6 months prior to the index pregnancy were included. Results were collected electronically via DIAMOND Diabetes Information System. Pregnancy outcome was compared with background rates.

There were 104 singleton pregnancies. The stillbirth rate (SBR) (25/1000) was 5 times, perinatal mortality rate (PMR) (25/1000) 3.5 times, and congenital malformation rate (CMR) (24/1000) twice that of the background population. 28% of women received pre pregnancy care (PPC), 43% pre pregnancy folic acid and 51% achieved an HbA1C <=7% at first antenatal visit.

Women are not well prepared for pregnancy and outcomes are suboptimal. A regional PPC programme and centralised glucose management are urgently needed.