Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics.
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.
Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York; and davidwil@buffalo.edu.
David L
DL
Williamson
Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York; and.
Cory M
CM
Dungan
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.
Abeer M
AM
Mahmoud
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.
Jacob T
JT
Mey
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.
Brian K
BK
Blackburn
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.
Jacob M
JM
Haus
D000328:Adult; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C469991:DDIT4 protein, human; D007328:Insulin; D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
glucocorticoid; insulin resistance; mTOR; signaling