Mechanisms of insulin resistance in non-oxidative glucose metabolism: the role of glycogen synthase.
Insulin-mediated non-oxidative glucose metabolism is more or less identical to glycogen synthesis in skeletal muscle and that is why this pathway is specifically discussed in this paper. All three major steps in non-oxidative glucose processing--glucose transport, phosphorylation and glycogen synthesis--are found to be reduced in response to insulin in insulin-resistant type 2 diabetic subjects compared with controls. The insulin-signalling cascade from the insulin receptor to PI-3-K was also found to be abnormal, resulting in a severely reduced phosphorylation degree of the IRS-1 (IRS-2?)-PI-3-K complex, which can explain both reduced glucose transport and glycogen synthesis. The most pronounced finding in our studies is reduced glycogen synthase activation by insulin which is found in prediabetic subjects with normal glucose tolerance as well as in type 2 diabetics, but more severely. This defect was not reversible after treatment (normalization of blood glucose) and is therefore a candidate for the primary defect which is likely to be of genetic origin, but also could be caused by genetic imprinting, intrauterine malnutrition and social inheritance (obesity). Most of the abnormalities in non-oxidative glucose metabolism may be of secondary origin due to hyperglycemia itself or obesity. Both events may stimulate production of glucosamine, malonyl CoA and intramuscular triglyceride accumulation. These metabolites can theoretically induce most of the defects in glucose processing and furthermore impair insulin signalling. Whether the primary defect in activation of glycogen synthase is due to an abnormality in the enzyme complex itself or in the insulin signalling cascade still has to be investigated.
Beck-Nielsen
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Odense University Hospital, Department of Endocrinology and Internal Medicine M, Denmark.
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000096:biosynthesis; D006006:Glycogen Synthase / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects* / Q000235:genetics; D006593:Hexokinase / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D014427:Twins
D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; D006003:Glycogen; D006006:Glycogen Synthase; D006593:Hexokinase; D005947:Glucose