Associate Provost for Research Boston University Medical Campus
NIDDK - National Institute of Diabetes & Digestive & Kidney Diseases	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): 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 CoA fuel 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-NFB 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.

Thesaurus Terms:
enzyme activity, hyperglycemia, insulin sensitivity /resistance, malonyl coA, protein kinase
I kappa B beta, biological signal transduction, lipid metabolism, liver cell, nuclear factor kappa beta, oxidative stress, striated muscle
RNA interference, immunoelectron microscopy, laboratory rat, polymerase chain reaction, tissue /cell culture, western blotting

Institution:	BOSTON MEDICAL CENTER
	ONE BOSTON MEDICAL CENTER PLACE
	BOSTON, MA 02118
Fiscal Year:	2006
Department:
Project Start:	01-MAR-2006
Project End:	28-FEB-2011
ICD:	NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
IRG:	IPOD