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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Medical Center
United States
Zip Code
Weikel, Karen A; Ruderman, Neil B; Cacicedo, José M (2016) Unraveling the actions of AMP-activated protein kinase in metabolic diseases: Systemic to molecular insights. Metabolism 65:634-45
Weikel, Karen A; Cacicedo, José M; Ruderman, Neil B et al. (2016) Knockdown of GSK3? increases basal autophagy and AMPK signalling in nutrient-laden human aortic endothelial cells. Biosci Rep 36:
Coughlan, Kimberly A; Valentine, Rudy J; Sudit, Bella S et al. (2016) PKD1 Inhibits AMPK?2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells. J Biol Chem 291:5664-75
Brandon, Amanda E; Tid-Ang, Jennifer; Wright, Lauren E et al. (2015) Overexpression of SIRT1 in rat skeletal muscle does not alter glucose induced insulin resistance. PLoS One 10:e0121959
Coughlan, Kimberly A; Balon, Thomas W; Valentine, Rudy J et al. (2015) Nutrient Excess and AMPK Downregulation in Incubated Skeletal Muscle and Muscle of Glucose Infused Rats. PLoS One 10:e0127388
Doménech, Elena; Maestre, Carolina; Esteban-Martínez, Lorena et al. (2015) AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. Nat Cell Biol 17:1304-16
Martínez de Morentin, Pablo B; Lage, Ricardo; González-García, Ismael et al. (2015) Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats. Endocrinology 156:947-60
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

Showing the most recent 10 out of 36 publications