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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 309; no. 8; pp. R855 - R863
• Main Authors: Williamson, David L., Dungan, Cory M., Mahmoud, Abeer M., Mey, Jacob T., Blackburn, Brian K., Haus, Jacob M.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.10.2015
• Subjects: Adult; Case-Control Studies; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Female; Glucose; Humans; Insulin; Insulin - pharmacology; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Obesity; Obesity, Diabetes and Energy Homeostasis; Phosphorylation; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; mTOR; glucocorticoid; signaling; insulin resistance
• ISSN: 0363-6119; 1522-1490; 1522-1490
• DOI: 10.1152/ajpregu.00285.2015

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.