Increased phosphorylation of skeletal muscle glycogen synthase at NH2-terminal sites during physiological hyperinsulinemia in type 2 diabetes.
In type 2 diabetes, insulin activation of muscle glycogen synthase (GS) is impaired. This defect plays a major role for the development of insulin resistance and hyperglycemia. In animal muscle, insulin activates GS by reducing phosphorylation at both NH(2)- and COOH-terminal sites, but the mechanism involved in human muscle and the defect in type 2 diabetes remain unclear. We studied the effect of insulin at physiological concentrations on glucose metabolism, insulin signaling and phosphorylation of GS in skeletal muscle from type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Analysis using phospho-specific antibodies revealed that insulin decreases phosphorylation of sites 3a + 3b in human muscle, and this was accompanied by activation of Akt and inhibition of glycogen synthase kinase-3alpha. In type 2 diabetic subjects these effects of insulin were fully intact. Despite that, insulin-mediated glucose disposal and storage were reduced and activation of GS was virtually absent in type 2 diabetic subjects. Insulin did not decrease phosphorylation of sites 2 + 2a in healthy human muscle, whereas in diabetic muscle insulin infusion in fact caused a marked increase in the phosphorylation of sites 2 + 2a. This phosphorylation abnormality likely caused the impaired GS activation and glucose storage, thereby contributing to skeletal muscle insulin resistance, and may therefore play a pathophysiological role in type 2 diabetes.
Højlund
Kurt
K
Diabetes Research Centre, University of Southern Denmark and Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, DK-5000 Odense C, Denmark.
Staehr
Peter
P
Hansen
Bo Falck
BF
Green
Kevin A
KA
Hardie
D Grahame
DG
Richter
Erik A
EA
Beck-Nielsen
Henning
H
Wojtaszewski
Jørgen F P
JF
D000273:Adipose Tissue / Q000033:anatomy & histology; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D006442:Glycated Hemoglobin / Q000032:analysis; D006006:Glycogen Synthase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012016:Reference Values
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D006006:Glycogen Synthase; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008055:Lipids; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; C526292:IRS1 protein, human