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Published online May 1, 2007
Diabetes Care 30:2001-2002, 2007
DOI: 10.2337/dc06-2480
© 2007 by the American Diabetes Association
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Clinical Care/Education/Nutrition/Psychosocial Research
Original Article

Effects of Blood Glucose Rate of Changes on Perceived Mood and Cognitive Symptoms in Insulin-Treated Type 2 Diabetes

Daniel J. Cox, PHD1, Anthony McCall, MD, PHD1, Boris Kovatchev, PHD1, Samiha Sarwat, MS2, Liza L. Ilag, MD2 and Meng H. Tan, MD2

1 University of Virginia Health Sciences Center, Charlottesville, Virginia
2 Eli Lilly and Company, Indianapolis, Indiana

Address correspondence and reprint requests to Dr. Daniel J. Cox, Psychiatry and Neurobehavioral Sciences, University of Virginia Health Sciences Center, Charlottesville, VA. E-mail: djc4f{at}virginia.edu

Abbreviations: BDI-II, Beck Depression Inventory II • BGRATE, blood glucose rate of change


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Studies indicate that diabetes affects mood, cognitive function, and motor performance (1–5). As cognitive dysfunction and depressive mood symptoms have been reported with hyperglycemia (5–7), we hypothesized that the impact of insulin on blood glucose parameters would affect mood and cognitive symptoms. Consistent with our past post hoc findings (7), we specifically hypothesized that rapid pre- to postmeal blood glucose rate of change (BGRATE) correlates with negative mood and cognitive postmeal symptoms but not with energy or positive mood. We report the results of correlation analyses of BGRATE with symptoms from a pilot investigation designed to evaluate whether improvements in glycemic control seen with basal plus prandial insulin analog regimens compared with basal insulin analog in patients with type 2 diabetes (8–10) would lead to measurable mood and cognitive differences.


   RESEARCH DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
A single-center, open-label, crossover, randomized, controlled clinical trial enrolled 60 adults with type 2 diabetes, A1C 7–10%, and prestudy use of metformin (with or without oral antihyperglycemic medications or once daily insulin). Pregnant or breast-feeding women and patients with a previous diagnosis of depression or treated with centrally acting medications (e.g., antidepressants or anxiolytics) were excluded.

Patients were randomly assigned to treatment with Humalog Mix 75/25 (insulin lispro mixture [75% lispro protamine suspension/25% lispro injection], Eli Lilly), twice daily subcutaneous injection (before breakfast and before dinner) for 12 weeks, followed by Lantus (insulin glargine; Sanofi-Aventis Pharmaceuticals), once daily subcutaneous injection (bedtime) for 12 weeks or the reverse sequence. Patients discontinued all prestudy diabetes therapy except metformin, which was continued along with the study insulins. Insulin was individually adjusted to target preprandial blood glucose levels <6.7 mmol/l (121 mg/dl) and 2-h postprandial blood glucose levels <8.0 mmol/l (144 mg/dl) after the morning and evening meals without increasing hypoglycemia. Hypoglycemia was defined as any time a patient experienced a sign or symptom associated with hypoglycemia or had a blood glucose level <3.5 mmol/l (<63 mg/dl).

The Beck Depression Inventory II (BDI-II) was administered at baseline and at the end of each crossover treatment (11). During the last 4 weeks of the two 12-week treatment periods, before breakfast and dinner and 1 h later, patients entered their blood glucose measurements and rated 13 perceived mood and cognitive symptoms (symptoms listed in Table 1) on a 0 ("Not at all") to 6 ("Extremely") scale using a handheld computer (Handspring Visor). This method is similar to those described in a previous study (7). The before and after breakfast and dinner blood glucose levels entered into the handheld computer were used to calculate BGRATE at breakfast and at dinner. BGRATE is a metric of speed of blood glucose (BG) change in milligrams per minute, i.e., (BGtime2 – BGtime1)/(Time 2 – Time 1), for measurements of average blood glucose changes over a defined period of time (12). Symptom ratings after meals were clustered into Depressive, Anxious, Cognitive, and Energetic scores and then were correlated with respective mealtime BGRATE values. A t test was used for within-treatment comparison, and Koch's model was used for between-treatment comparisons. Pearson correlation analysis was performed to evaluate the correlation between BGRATE at breakfast and dinner with mood and cognitive symptoms after a meal.


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  		Table 1— Blood glucose parameters (combined periods by treatment) and correlation of symptoms with BGRATE

 

   RESULTS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Of 60 patients screened, 45 were randomly assigned (mean ± SD age 52.6 ± 11.9 years, BMI 35.08 ± 8.4 kg/m2, and duration of diabetes 11.9 ± 7.5 years). There were 33 completers (lispro mixture/glargine, n = 17; glargine/lispro mixture group, n = 16).

Postdinner blood glucose levels (millimoles per liter) were lower with lispro mixture treatment than with glargine (Table 1), but no significant between-treatment differences were noted in breakfast or dinner BGRATE (range 2.2 ± 0.7–3.1 ± 1.3 mmol/l). This finding was consistent with trends noted in patients’ self-monitored blood glucose levels, which showed lower prelunch, 2-h postdinner, and bedtime levels with the lispro mixture than with glargine treatment (data on file). There were no severe hypoglycemic episodes, and no differences were noted in hypoglycemia incidence at the end point.

Consistent with our hypothesis, postmeal negative mood (depressive and anxious) and cognitive symptoms significantly correlated with BGRATE (a reflection of the rapid increase in blood glucose levels from pre- to postmeal) at both breakfast and dinner for both the lispro mixture and glargine. Further, consistent with our hypothesis, positive mood (energetic) did not correlate with BGRATE (Table 1). BDI-II scores decreased with both therapies from baseline (8.2 ± 6.0) to the end point (lispro mixture 5.5 ± 3.8; glargine 6.8 ± 5.9), with a significant decrease only with lispro mixture treatment (P = 0.018) but no end point difference between treatments (P = 0.115).


   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
This pilot study investigating the potential effects of specific insulin regimens for type 2 diabetes showed that negative mood and cognitive symptoms reported 1 h after breakfast and supper significantly correlated with a rapid rise in pre- to postmeal blood glucose levels in insulin-treated patients, confirming earlier post hoc observations (7). No significant differences were seen for mood or cognitive symptoms between insulin regimens. A significant baseline-to-end point improvement occurred in BDI-II score in lispro mixture–treated patients.

In light of epidemiological evidence indicating an association between chronic effects of dysglycemia and brain function (13), studies with larger and more diverse samples are warranted to further evaluate the effects of insulin on mood or cognition and the impact of different insulin treatments on diabetes-related mood and cognitive changes.


   Acknowledgments
 
Funding was received from the National Institutes of Health (grant DKR01-28288), the University of Virginia Health Sciences Center, and Eli Lilly and Company (Study F3Z-MC-I00C).

We thank Shirley Fleishman and Ruth Warner, study coordinators, and Margaret Campbell, technical writer.

Parts of this study were presented in abstract form at the 67th annual meeting of the American Diabetes Association, Chicago, Illinois, 22–26 June 2007.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 1 May 2007. DOI: 10.2337/dc06-2480. Clinical Trial reg. no. NCT00191178, clinicaltrials.gov.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication December 6, 2006. Accepted for publication April 25, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Van der Does FEE, De Neeling JND, Snoek FJ, Kostense PJ, Grootenhuis PA, Bouter LM, Heine RJ: Symptoms and well-being in relation to glycemic control in type II diabetes. Diabetes Care 19:204–210, 1996[Abstract]
  2. Ryan CM, Geckle MO: Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care 23:1486–1493, 2000[Abstract]
  3. Biessels GJ, Ter Braak EWMT, Erkelens DW, Hijman R: Cognitive function in patients with type 2 diabetes mellitus. Neurosci Res Commun 28:11–22, 2001
  4. Cox D, Gonder-Frederick L, McCall A, Kovatchev B, Clarke W: The effects of glucose fluctuation on cognitive function and QOL: the functional costs of hypoglycaemia and hyperglycaemia among adults with type 1 or type 2 diabetes. Int J Clin Pract Suppl 129:20–26, 2002[Medline]
  5. Sommerfield AJ, Deary IJ, Frier BM: Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care 27:2335–2340, 2004[Abstract/Free Full Text]
  6. Cox DJ, Kovatchev BP, Gonder-Frederick LA, Summers KH, McCall A, Grimm KJ, Clarke WL: Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care 28:71–77, 2005[Abstract/Free Full Text]
  7. Korvatchev B, Cox DJ, Summers KH, Goner-Frederick L, Clarke WL: Postprandial glucose dynamics and associated symptoms in type 2 diabetes mellitus. J Appl Res 4:1–10, 2003
  8. Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH, Lispro Mixture-Glargine Study Group: Combined therapy with insulin lispro mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther 25:2034–2044, 2004; erratum in Clin Ther27:1112, 2005
  9. Malone JK, Bai S, Campaigne BN, Reviriego J, Augendre-Ferrante B: Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with type 2 diabetes. Diabet Med 22:374–381, 2005[Medline]
  10. Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA, Hu P, Bode B, Garber A: Initiating insulin therapy in type 2 diabetes. Diabetes Care 28:260–265, 2005[Abstract/Free Full Text]
  11. Beck AT, Steer RA, Ball R, Ranieri WF: Comparison of Beck Depression Inventories-IA and -II in psychiatric outpatients. J Pers Assess 67:588–597, 1996[Medline]
  12. Kovatchev BP, Cox DJ, Gonder-Frederick LA, Clarke WL: Methods for quantifying self-monitoring blood glucose profiles exemplified by an examination of blood glucose patterns in patients with type 1 and type 2 diabetes. Diabetes Technol Ther 4:295–303, 2002[Medline]
  13. Yaffe K, Blackwell T, Kanaya AM, Davidowitz BA, Barrett-Connor E, Krueger K: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 63:658–663, 2004[Abstract/Free Full Text]

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