Unraveling the Temporal Pattern of Diet-Induced Insulin Resistance in Individual Organs and Cardiac Dysfunction in c57bl/6 Mice

Abstract

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 obesityassociated 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. Diabetes 54: 3530 -3540, 2005

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…This finding stimulated us to measure tissue-specific insulin action and we showed that liver and adipose tissue exhibit peak insulin resistance for glucose metabolism within 1 week on an HFD, while additional time is required for insulin action to deteriorate in muscle. Other rodent studies using HFDs with differing lipid content and composition have reported a similar temporal pattern of the development of tissue-specific insulin resistance [7,19,20], indicating that insulin-regulated glucose metabolism in liver and adipose tissue are particularly sensitive to the effects of dietary lipid overload. However, unlike these studies we provide novel evidence demonstrating that once tissue insulin resistance develops it reaches a plateau and is not exacerbated by extended periods of fat feeding.…”

“…Furthermore, consistent with our hypothesis, we show that an increase in lipid metabolites are associated with defects in tissue insulin action, suggesting that lipotoxicity is a generalised mechanism associated with the induction of insulin resistance in individual tissues of mice. Studies in rodents [7,[19][20][21]23], dogs [24] and humans [25][26][27], have shown that short-term exposure to HFD/overfeeding (3-28 days) results in the rapid development of insulin resistance and glucose intolerance. Often these changes occur with only modest increases in fat mass, highlighting that metabolic defects occur prior to the onset of obesity and do not require extensive periods of fat feeding.…”

“…Another critical issue is the timing of the HFD. Many groups feed animals for 12-16 weeks to elicit marked differences in body and fat mass, but as it has been reported that insulin resistance is induced rapidly (1-3 weeks) in different tissues on exposure to excess dietary fat [7,[19][20][21], the mechanisms/factors that have been proposed to underlie insulin resistance and glucose intolerance in long-term studies may be different from those occurring in short-term studies and a consequence of chronic obesity and/or hyperinsulinaemia.…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…2005). As in genetic models of type‐2 diabetes ( ob/ob and db/db mice), PPAR α activation and related changes in expression levels of PPAR α targets such as PDK4 or MCAD appear only after 5 weeks (Buchanan et al.…”

Lipid-induced cardiovascular diseases

“…Insulin signaling mediated by activation of eNOS in hearts such as increasing the carbohydrate oxidation during ischemia and direct activation of AKT have shown antiapoptotic function and cardiac protecting effect [69]. Insulin resistance is caused due to the improper metabolism of lipid in heart which leads to the improper management of insulin and decreases cardiac ef iciency in cardiomyocytes [30,[70][71][72][73].…”