Impaired muscle glycogen synthase in type 2 diabetes is associated with diminished phosphatidylinositol 3-kinase activation.
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.
Nikoulina
S E
SE
Veterans Affairs San Diego Healthcare System, San Diego, California 92161, USA.
Ciaraldi
T P
TP
Carter
L
L
Mudaliar
S
S
Park
K S
KS
Henry
R R
RR
D000328:Adult; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005981:Glutathione Synthase / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases; D005981:Glutathione Synthase