Type 2 diabetes mellitus (T2DM) is increasing in incidence around the world, making it one of the greatest current health risks. T2DM is invariably associated with insulin resistance, one of the components of the Metabolic Syndrome, also comprised of obesity, non-alcoholic fatty liver disease (NAFLD) and hypertension. Insulin resistance is associated with many complications of the Metabolic Syndrome, specifically the atherogenic lipid abnormalities called diabetic dyslipidemia. However, the mechanism of how insulin resistance causes the development of dyslipidemia is unknown. The protein kinase, Akt2/PKB-beta is a major mediator of insulin's normal metabolic actions, and mice lacking Akt2 are glucose intolerant due to defects in insulin signaling, but have not been studied with regards to lipid metabolism. I have determined that when crossed onto a leptin-deficient ob/ob background, Akt2 deficient mice have dramatically decreased hepatic but increased serum triglycerides compared with ob/ob mice. This observation suggests that Akt2 is required for normal lipid homeostasis, and the goal of this proposal is to address the role of Akt2 in insulin-dependent lipid metabolism. The first portion of these studies will investigate how loss of Akt2 leads to a dysregulation of normal hepatic lipid flux. It will include physiological experiments aimed at determining the states of lipogenesis, VLDL export, fatty acid esterification and beta-oxidation in the Akt2 null mouse when crossed with models of obesity and NAFLD. In addition, the signaling pathways through which Akt2 exerts its effects on lipid metabolism will be studied. The second portion of these studies will test the hypothesis that these defects in lipid metabolism are due to a loss of Akt2 specifically in the hepatocytes. Two different mouse models lacking Akt2 in the liver will be used to elucidate whether loss of hepatic Akt2 expression disrupts normal lipid metabolism. Additionally, this aim will determine whether Akt2 in the liver alone can reverse the lack of hepatic triglyceride accumulation observed in the ob/ob Akt2 null animals. Ultimately, these studies will provide further insight into insulin's control of normal lipid metabolism, and advance the knowledge of how these processes are dysregulated in disease. Diabetes is one of the greatest dangers to public health due to the increasing numbers of patients with this condition. Diabetes is strongly associated with heart disease, and this connection appears to be related to the body's use of fat. The research described in this proposal aims to investigate how fat is normally used in the body, and how these processes are disrupted in the presence of diabetes, potentially leading to heart disease.
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