Insulin receptor function and glycogen synthase activity in human skeletal muscle. Physiology and pathophysiology.
Insulin stimulates glucose uptake and non-oxidative glucose metabolism (predominantly glycogen synthesis) in skeletal muscle. Among other things, insulin resistance is characterized by a subnormal insulin-stimulated glucose disposal, and it appears to be associated with an increased risk for development of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present investigation has been to elucidate the mechanism of action of insulin on non-oxidative glucose metabolism both during conditions of insulin resistance and during physiological modification of glucose metabolism. To do so, the effect of insulin was investigated both with respect to its initial activation of the insulin receptor kinase and the terminal step of the signal pathway, namely stimulation of the glycogen synthase. From needle biopsies of human skeletal muscle (vastus lateralis) cellular membranes were solubilized and the insulin receptors were partially purified by affinity chromatography using wheat germ agglutinin. Subsequently insulin binding and the insulin-stimulated tyrosine kinase activity were characterized. The insulin receptor kinase activity did not change during physiological modification of the glucose metabolism (exercise training, acute exercise, growth hormone exposure or experimental hyperglycemia). No specific abnormalities of the insulin receptor kinase activity were revealed in insulin-dependent diabetes (IDDM) or in common NIDDM. In addition, insulin receptor kinase activity did not change during dietary or sulphonylurea treatment of NIDDM. Glucose deposition as glycogen in muscle is regulated by glycogen synthase (GS), which during insulin stimulation undergoes dephosphorylation and becomes more active at physiological concentrations of glucose-6-phosphate. Recently, insulin was shown to stimulate a cascade of phosphorylation-dependent kinases which ultimately activate a glycogen-bound subunit of a phosphatase (G-subunit of phosphatase-1) which promotes dephosphorylation GS by the catalytic subunit. The quantity of the GS enzyme (GStot) in muscle may be reduced in the diabetes disease. However, it may increase during physical training of insulin-dependent diabetic patients. GStot is not altered during acute exposure to insulin, hyperglycemia or muscle contraction. The insulin stimulation of GS is reduced in insulin resistant NIDDM patients. However, once the hyperglycemia and the insulin resistance is ameliorated during treatment with diet or sulphonylurea drugs the activation of GS improves. Growth hormone-induced transient insulin resistance in non-diabetic subjects, is accompanied by a reduced insulin stimulation of GS. Experimentally induced hyperglycemia in normal subjects has no influence on GS activation by insulin. After an acute exercise bout the GS in muscle becomes activated. The mechanism of this post-exercise GS activation is still unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
Bak
J F
JF
Department of Endocrinology and Metabolism, Aarhus Amtssygehus.
D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D009132:Muscles / Q000201:enzymology / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship
D006006:Glycogen Synthase; D011972:Receptor, Insulin