title: Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation?
abstract: It has long been known that excesses of glucose and branched chain amino acids, such as leucine, lead to insulin resistance in skeletal muscle. A recent study in incubated rat muscle suggests that both molecules may do so by virtue of their ability to downregulate the fuel sensing and signaling enzyme AMP-activated protein kinase (AMPK) and activate mTOR/p70S6 kinase (p70S6K) signaling. The results also demonstrated that inhibition of mTOR/p70S6K with rapamycin prevented the development of insulin resistance but had no effect on AMPK activity (Thr172 phosphorylation of its catalytic subunit). In contrast, activation of AMPK by both AICAR and α-lipoic acid led to the phosphorylation of specific molecules that diminished both mTOR/p70S6K signaling and insulin resistance. These findings suggest that downregulation of AMPK precedes mTOR/p70S6K activation in mediating glucose and leucine-induced insulin resistance, although the mechanism by which it does so remains to be determined. Also requiring study is how an excess of the two nutrients leads to AMPK downregulation.
authors: Diabetes Research Unit, Section of Endocrinology, Department of Medicine, Boston University Medical Center, Boston, MA, USA. aksaha@bu.edu
authors: Asish K
authors: AK
authors: Saha
authors: X Julia
authors: XJ
authors: Xu
authors: Thomas W
authors: TW
authors: Balon
authors: Amanda
authors: A
authors: Brandon
authors: Edward W
authors: EW
authors: Kraegen
authors: Neil B
authors: NB
authors: Ruderman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000597:Amino Acids, Branched-Chain; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases; D005947:Glucose