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Unraveling the Temporal Pattern of Diet-Induced Insulin Resistance in Individual Organs and Cardiac Dysfunction in C57BL/6 Mice

¹ Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
² Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
³ Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
⁴ Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, Connecticut
⁵ Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, New Haven, Connecticut

Type 2 diabetes is a heterogeneous disease characterized by insulin resistance and altered glucose and lipid metabolism in multiple organs. To understand the complex series of events that occur during the development of obesity-associated diabetes, we examined the temporal pattern of changes in insulin action and glucose metabolism in individual organs during chronic high-fat feeding in C57BL/6 mice. Insulin-stimulated cardiac glucose metabolism was significantly reduced after 1.5 weeks of high-fat feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling and GLUT4 levels. Insulin resistance in skeletal muscle, adipose tissue, and liver developed in parallel after 3 weeks of high-fat feeding. Diet-induced whole-body insulin resistance was associated with increased circulating levels of resistin and leptin but unaltered adiponectin levels. High-fat feeding caused insulin resistance in skeletal muscle that was associated with significantly elevated intramuscular fat content. In contrast, diet-induced hepatic insulin resistance developed before a marked increase in intrahepatic triglyceride levels. Cardiac function gradually declined over the course of high-fat feeding, and after 20 weeks of high-fat diet, cardiac dysfunction was associated with mild hyperglycemia, hyperleptinemia, and reduced circulating adiponectin levels. Our findings demonstrate that cardiac insulin resistance is an early adaptive event in response to obesity and develops before changes in whole-body glucose homeostasis. This suggests that obesity-associated defects in cardiac function may not be due to insulin resistance per se but may be attributable to chronic alteration in cardiac glucose and lipid metabolism and circulating adipokines.

Abbreviations: 2-[¹⁴C]DG, 2-deoxy-D-[1-¹⁴C]glucose; AMPK, AMP-activated protein kinase; CVD, cardiovascular disease; GSK-3ß, glycogen synthase kinase-3ß; HGP, hepatic glucose production; ¹H-MRS, ¹H-magnetic resonance spectroscopy

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