Abstract
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may be related to alterations in fat metabolism. Fatless mice have been created using dominant-negative protein (A-ZIP/F-1) targeted gene expression in the adipocyte and shown to develop diabetes. To understand the mechanism responsible for the insulin resistance in these mice, we conducted hyperinsulinemic-euglycemic clamps in awake fatless and wild type littermates before the development of diabetes and examined insulin action and signaling in muscle and liver. We found the fatless mice to be severely insulin-resistant, which could be attributed to defects in insulin action in muscle and liver. Both of these abnormalities were associated with defects in insulin activation of insulin receptor substrate-1 and -2-associated phosphatidylinositol 3-kinase activity and a 2-fold increase in muscle and liver triglyceride content. We also show that upon transplantation of fat tissue into these mice, triglyceride content in muscle and liver returned to normal as does insulin signaling and action. In conclusion, these results suggest that the development of insulin resistance in type 2 diabetes may be due to alterations in the partitioning of fat between the adipocyte and muscle/liver leading to accumulation of triglyceride in the latter tissues with subsequent impairment of insulin signaling and action.
Highlights
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may be related to alterations in fat metabolism
Insulin action on glucose transport and metabolism was examined during a 2-h hyperinsulinemic-euglycemic clamp in awake wild type and fatless littermates at 3 weeks of age before the onset of hyperglycemia [7]
We examined insulin action and signaling in individual tissues of fatless mice, prior to the development of diabetes, and found that these mice are severely insulin resistant because of defects in insulin action in liver and muscle
Summary
Male fatless (A-ZIP/F-1; n ϭ 19) and wild type (n ϭ 25) littermates were studied at 3 weeks of age (9 –13 g of body weight) at least 7 days after arrival. Two studies were conducted, starting at 1000 h, after an overnight fast (mice were removed from their mothers at 1700 h on the day before the experiment). Blood samples (20 l) were collected at 30-min intervals for the immediate measurement of plasma glucose concentration, and 20% glucose was infused at variable rates to maintain plasma glucose at ϳ6.3 mM. Insulin-stimulated whole body glucose flux was estimated using a prime continuous infusion of high pressure liquid chromatography-purified [3-3H]glucose (10-Ci bolus, 0.1 Ci/min; NEN Life Science Products) throughout the clamps. Blood samples (20 l) were taken at 77, 80, 85, 90, 100, 110, and 120 min after the start of clamps for the determination of plasma [3H]glucose, 2-[14C]DG, and 3H2O concentrations. Additional blood samples (10 l) were collected before the start and at the end of clamps for measurement of plasma insulin concentrations. The basal rates of glucose turnover were meas-
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