Concomitant with the parallel obesity and diabetes epidemics, an increasing burden on our healthcare system is due to the complications of hyperglycemia (nephropathy, neuropathy, retinopathy and vascular disease) and hyperlipidemia (atherosclerosis and cardiovascular disease). Insulin resistance is a common contributor to the pathophysiology of obesity, diabetes and metabolic syndrome, and many of their associative complications. The liver is central to glucose and lipid metabolism and insulin plays a key regulatory role. Elevated hepatic glucose production contributes to hyperglycemia;whereas, increased very low-density lipoproteins (VLDL)- Triglyceride (TG) production contributes to atherogenic dyslipidemia (elevated TGs, small and dense low- density lipoproteins (LDL) and reduced high-density lipoproteins (HDL)). The resultant hyperglycemia and dyslipidemia are attributed to altered insulin action in the liver. "Selective" insulin resistance in liver is characterized by inability of insulin to suppress gluconeogenesis (impaired FOXO1 regulation) while continuing to stimulate de novo lipogenesis and VLDL-TG secretion (intact regulation of SREBP1c). Thus, selective insulin resistance is a potential mechanism by which hyperglycemia and hyperlipidemia can ensue;however, the molecular defect involved is not known. I hypothesize that "selective" insulin resistance is due to partial AKT activation that results from the uncoupling of Serine473 (S473) and Threonine308 (T308) phosphorylation sites on AKT;loss of S473 phosphorylation results in the failure of AKT to phosphorylate FOXO1 and suppress expression of key gluconeogenic enzymes, whereas partially activated AKT (only T308) is sufficient to phosphorylate and inhibit GSK3, leading to SREBP1c activation and hypertriglyceridemia. I will test this hypothesis by studying a mouse model in which the mTORC2 regulatory protein, rictor, has been genetically deleted in hepatocytes leading to impaired S473 phosphorylation with intact T308 phosphorylation. I will validate genetic loss of rictor in the liver, gene dosage specific effects of rictor gene expression and rictor/mTORC2 function (AKT phosphorylation). Euglycemic clamp and tracer dilution techniques will be employed to quantify the ability of insulin to suppress hepatic glucose production. Hypertriglyceridemia will be assessed by utilizing tyloxapol and radiolabeled lipid studies to quantify the rate of VLDL-TG production and clearance, and effects on the lipoprotein profile (VLDL, LDL, HDL and apoB). The possibility of hepatic steatosis will be assessed by liver lipid quantification.
Selective hepatic insulin resistance is hypothesized to contribute towards hyperglycemia and hyperlipidemia;metabolic risk factors for morbidity and mortality related to obesity, diabetes and metabolic syndrome. I hypothesize that a molecular mechanism for selective insulin resistance in the liver involves dysregulation at the level of the insulin signaling molecule, AKT. The studies herein are designed to improve our understanding of the pathogenesis of hyperglycemia and hyperlipidemia and may ultimately yield improved therapeutic and/or preventive approaches.