Nutrient Excess in AMPK Downregulation and Insulin Resistance

J Endocrinol Diabetes Obes. Jul-Sep 2013;1(1):1008.

Abstract

It is well established that chronic exposure to excess nutrients leads to insulin resistance (IR) in skeletal muscle. Since skeletal muscle is responsible for 70-80% of insulin-stimulated glucose uptake, skeletal muscle IR is a key pathological component of type 2 diabetes (T2D). Recent evidence suggests that inhibition of the nutrient-sensing enzyme AMP-activated protein kinase (AMPK) is an early event in the development of IR in response to high glucose, branched chain amino acids (BCAA), or fatty acids (FA). Whether the decrease in AMPK activity is causal to the events leading to insulin resistance (increased mTOR/p70S6K signaling) remains to be determined. Interestingly, pharmacological activation of AMPK can prevent activation of mTOR/p70S6K and insulin resistance, while inhibition of mTOR with rapamycin prevents insulin resistance, but not AMPK downregulation. AMPK can be inhibited by increased energy state (reduced AMP/ATP ratio), decreased phosphorylation of its activation site (αThr172) (by decreased upstream kinase activity or increased phosphatase activity), increased inhibitory phosphorylation at αSer485/491, changes in redox state or hormone levels, or other yet to be identified mechanisms. Excess nutrients also lead to an accumulation of the toxic lipid intermediates diacylglycerol (DAG) and ceramides, both of which can activate various protein kinase C (PKC) isoforms, and contribute to IR. The mechanism responsible for the initial downregulation of AMPK in response to excess nutrients, and whether glucose, BCAA, and FA act through similar or different pathways requires further study. Identification of this mechanism and the relative importance of other events would be beneficial for designing novel pharmacological interventions to prevent and/or reverse IR. This review will focus on the some of the mechanisms responsible for AMPK downregulation and the relative sequence and importance of these events.

Keywords: Branched Chain Amino Acids (BCAA); Fatty Acid (FA); Protein Kinase C (PKC); mTOR/p70S6K, Hyperglycemia.