In patients with diabetes and experimental animals sustained hyperglycemia leads to insulin resistance in both liver and muscle. Data obtained by us in a number of models suggest that such glucose-induced insulin resistance is related to dysregulation of the AMP-activated protein kinase (AMPK)/malonyl CoAfuel sensing and signaling network (diminished AMPK activity and/or an increase in malonyl CoA concentration). The proposed studies will test this hypothesis in two of these models, cultured hepatocytes exposed to a high ambient glucose concentration (Aim 1) and glucose-infused rats (Aim 3), in both of which we have observed the aforementioned changes in AMPK and malonyl CoA, and, where studied, an impaired ability of insulin to activate Akt. In addition, we will attempt to develop a cell-based system for testing this hypothesis in muscle using C2C12 cells (Aim 2). We will determine in each of these models how changes in AMPK relate temporally to impaired insulin signaling (Akt, IRS-PY), alterations in lipid metabolites (malonyl CoA, DAG, LCCoA) and putative downstream pathogenetic events (e.g., PKC, IKKB-NF*B activation). In addition, using RNAi silencing, viral constructs and/or pharmacological agents as tools, we will determine whether the changes in AMPK and malonyl CoA play a causal role. Finally, we will explore possible mechanisms for the decrease in AMPK activity in the glucose-infused rats. These studies will provide a rigorous test of the hypothesis that dysregulation of the AMPK/malonyl CoA network can be both a cause of glucose-induced insulin resistance and a target for its therapy. They will also provide a potentially novel framework for understanding the pathogenesis and treatment of insulin resistance, a problem that antedates type 2 diabetes, premature coronary heart disease, NAFLD/NASH and other disorders associated with the metabolic syndrome. Thus, they could have an important impact on public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067509-04
Application #
7575756
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$251,897
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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Coughlan, Kimberly A; Valentine, Rudy J; Ruderman, Neil B et al. (2014) AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes 7:241-53
Valentine, Rudy J; Coughlan, Kimberly A; Ruderman, Neil B et al. (2014) Insulin inhibits AMPK activity and phosphorylates AMPK Ser???/??¹ through Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch Biochem Biophys 562:62-9
Coughlan, Kimberly A; Valentine, Rudy J; Ruderman, Neil B et al. (2013) Nutrient Excess in AMPK Downregulation and Insulin Resistance. J Endocrinol Diabetes Obes 1:1008

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