The diabetes and obesity epidemics in the United States remain prominent public health issues. The two defining characteristics of diabete are postprandial and fasting hyperglycemia, the latter resulting from increased hepatic glucose production (HGP). Importantly, abnormal insulin action in the liver has major consequences for whole body physiology, seriously impacting lipid and glucose metabolism. In the last decade, significant progress has been made towards understanding the regulation of HGP by insulin and how this process is disrupted during insulin-resistant states. A consensus has emerged that the most important pathway involves insulin activation of Akt, which inhibits Foxo, suppressing Foxo1's transcriptional program. Surprisingly, recent experiments have shown that livers devoid of Akt and Foxo1 can still suppress HGP in response to both feeding and insulin, establishing that these proteins are not obligate intermediates in insulin signaling. Consequently, there must exist alternative, unknown mechanisms that mediate insulin action in the liver, and these may represent new therapeutic targets for the treatment of hyperglycemia. Moreover, these data are consistent with the increasing body of evidence that insulin may act cell-nonautonomously, signaling through non-hepatic tissues to regulate liver glucose and lipid metabolism in mice. Using primarily genetic loss- of-function approaches, this proposal aims to elucidate the non-canonical pathway by which insulin regulates hepatic glucose output and gluconeogenic gene expression. In doing so, I will 1) determine whether insulin is acting on an organ other than liver to regulat HGP in the absence of hepatic insulin action and 2) determine the Akt-independent pathway acting in hepatocytes. If insulin is still capable of regulating hepatic glucose metabolsm in the absence of hepatic insulin signaling, the insulin responsive tissue that is relaying the signal to suppress HGP will be identified~ likely candidates include brain and adipose tissue. Preliminary data suggest that Stat3 is activated in livers null for Akt and Foxo1. Targeed deletion of Stat3 in the liver will test the hypothesis that intact Stat3 signaling i required to suppress liver HGP independent of Akt and Foxo1. Ultimately, the new mechanisms identified by these studies will advance our knowledge of normal metabolism and will allow us to identify new therapeutic strategies for treatment of metabolic disorders such as diabetes.

Public Health Relevance

To maintain energy balance during periods of starvation and nutrient surfeit, the liver dynamically regulates the storage and production of glucose to meet the metabolic demands of the body. However in diabetic and obese individuals, insulin fails to properly suppress glucose production in the liver resulting in hyperglycemia. The study proposed here aims to identify novel mechanisms and sites of insulin action, thereby providing new therapeutic targets for insulin-resistant disorders such as type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-R (O1))
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Castle, Arthur
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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