Impaired muscle glycogen synthase in type 2 diabetes is associated with diminished phosphatidylinositol 3-kinase activation

• Published in: The journal of clinical endocrinology and metabolism 2001-09, Vol.86 (9), p.4307-4314
• Main Authors: NIKOULINA, Svetlana E, CIARALDI, Theodore P, CARTER, Leslie, MUDALIAR, Sunder, KYONG SOO PARK, HENRY, Robert R
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cells, Cultured; Diabetes Mellitus, Type 2 - enzymology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation - physiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glutathione Synthase - metabolism; Glycogen Synthase - metabolism; Humans; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Male; Medical sciences; Middle Aged; Mitogen-Activated Protein Kinases - metabolism; Muscle, Skeletal - cytology; Muscle, Skeletal - enzymology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Receptor, Insulin - metabolism
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.86.9.4307

Insulin signaling pathways potentially involved in regulation of skeletal muscle glycogen synthase were compared in differentiated human muscle cell cultures from nondiabetic and type 2 diabetic patients. Insulin stimulation of glycogen synthase activity as well as phosphorylation of MAPK, p70 S6 kinase, and protein kinase B (Akt) were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nM) and LY294002 (10 microM). In contrast to lean and obese nondiabetic subjects, where there were minimal effects (15-20% inhibition), insulin stimulation of glycogen synthase in muscle cultures from diabetic subjects was greatly diminished ( approximately 75%) by low concentrations of wortmannin (25 nM) or LY294002 (2 microM). This increased sensitivity of diabetic muscle to impairment of insulin-stimulated glycogen synthase activity occurs together with diminished insulin-stimulation (by 40%) of IRS-1-associated phosphatidylinositol 3-kinase activity in the same cells. Protein expression of IRS-1, p85, p110, Akt, p70 S6 kinase, and MAPK were normal in diabetic cells, as was insulin-stimulated phosphorylation of Akt, p70 S6 kinase, and MAPK. These studies indicate that, despite prolonged growth and differentiation of diabetic muscle under normal metabolic culture conditions, defects of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activity in diabetic muscle persist, consistent with intrinsic (rather than acquired) defects of insulin action.