Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Am J Physiol Regul Integr Comp Physiol. 2015 Oct 15;309(8):R855-63. doi: 10.1152/ajpregu.00285.2015. Epub 2015 Aug 12.

Abstract

The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m(-2)·min(-1))-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P < 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P < 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/min) were lower (P < 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P < 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P < 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals.

Keywords: glucocorticoid; insulin resistance; mTOR; signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Humans
  • Insulin / pharmacology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DDIT4 protein, human
  • Insulin
  • Multiprotein Complexes
  • Transcription Factors
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases