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.