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Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes

¹ Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado
² Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, Colorado
³ Department of Pediatrics, University of Colorado Health Sciences Center, Aurora, Colorado
⁴ Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
⁵ Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio
⁶ Schwartz Center for Metabolism and Nutrition, MetroHealth Medical Center, Cleveland, Ohio
⁷ Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, Colorado

Address correspondence and reprint requests to Jacob E. Friedman, PhD, Departments of Pediatrics, Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, P.O. Box 6511, MS-F-8106, Aurora, CO 80045. E-mail: jed.friedman@uchsc.edu

Abbreviations: FFA, free fatty acid • GDM, gestational diabetes mellitus • hPGH, human placental growth hormone • hPL, human placental lactogen • IR, insulin receptor • IRS, insulin receptor substrate • PI, phosphatidylinositol • PPAR, peroxisome proliferator–activated receptor • TNF, tumor necrosis factor

The first 300 words of the full text of this article appear below.

	INTRODUCTION

 
The incidence of gestational diabetes mellitus (GDM) has doubled over the last 6–8 years and is paralleling the obesity epidemic. GDM carries long-term implications for the subsequent development of type 2 diabetes in the mother and increased risk for obesity and glucose intolerance in the offspring. Insulin resistance exists before pregnancy in women with a history of GDM but worsens during gestation. Insulin secretion is inadequate to compensate for the insulin resistance, leading to hyperglycemia that is detected by routine glucose screening in pregnancy. Thus, chronic insulin resistance is a central component of the pathophysiology of GDM.

Human pregnancy is characterized by a series of metabolic changes that promote adipose tissue accretion in early gestation, followed by insulin resistance and facilitated lipolysis in late pregnancy. In early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase (1,2). However, in late gestation, maternal adipose tissue depots decline, while postprandial free fatty acid (FFA) levels increase and insulin-mediated glucose disposal worsens by 40–60% compared with prepregnancy (2). The ability of insulin to suppress whole-body lipolysis is also reduced during late pregnancy (3), and this is further reduced in GDM subjects (4), contributing to greater postprandial increases in FFAs, increased hepatic glucose production, and severe insulin resistance (2,5–7). Although various placental hormones have been suggested to reprogram maternal physiology to meet fetal needs, the cellular mechanisms for this complex transition remain obscure (8). Further, the critical molecular mechanisms involved in increasing maternal lipid flux in obese women throughout pregnancy that may underlie skeletal muscle insulin resistance and increased fetal fuels are just beginning to be investigated.

	RECENT INSIGHTS RELATING PLACENTAL HORMONES AND ADIPOKINES IN THE INSULIN RESISTANCE OF PREGNANCY—

 
Skeletal muscle is the principal site of whole-body glucose disposal, and along with adipose . . . [Full Text of this Article]

	MECHANISMS UNDERLYING REDUCED GLUCOSE TRANSPORT IN SKELETAL MUSCLE FIBERS ISOLATED FROM OBESE PREGNANT WOMEN AND FURTHER REDUCTION IN GDM—

 

	IRS-1 IS DOWNREGULATED IN PREGNANCY AND MORE SO IN GDM—

 

	INCREASED IRS-1 SERINE PHOSPHORYLATION IS AN ADDITIVE FACTOR REDUCING INSULIN SIGNALING IN GDM—

 

	INCREASED p85 MONOMER OF PI 3-KINASE AND ITS ROLE IN THE INSULIN RESISTANCE OF NORMAL PREGNANCY—

 

	INSULIN RESISTANCE IN ADIPOSE TISSUE: IMPLICATIONS FOR EXCESS FUELS AND THE ORIGINS OF INSULIN RESISTANCE—

 

	SUMMARY—

 

	POSTPARTUM AND BEYOND

 

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