Insulin Resistance in Skeletal Muscles in Patients ... - Diabetes Care

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Skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin; i.e., the effect of insulin on glucose disposal is ...
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skeletal muscles may be a primary genetic defect preceding the diabetic state. The cellular abnormality responsible for that may be a reduced covalent insulin activation of the enzyme glycogen synthase. Hyperinsulinemia, in the prediabetic state, and hyperglycemia, in the diabetic state may, through an increased G-6-P concentration inside the muscle cell, compensate allosterically for the reduced insulin effect on the glycogen synthase. The compensation results in nearnormalization of glycogen synthesis, but the price diabetic subjects must pay to obtain this is hyperglycemia.

Insulin Resistance in Skeletal Muscles in Patients With NIDDM HENNING BECK-NIELSEN, PHD ALLAN VAAG, MD PETER DAMSBO, MD AASE HANDBERG, MD OLE HOTHER NIELSEN, MD JAN ERIK HENRIKSEN, MD PETER THYE-RONN, MD

Skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin; i.e., the effect of insulin on glucose disposal is reduced compared with the effect in control subjects. This defect has been found to be localized to the nonoxidative pathway of glucose disposal; hence, the deposition of glucose, as glycogen, is abnormally low. This defect may be inherited, because it is present in first-degree relatives to NIDDM patients two to three decades before they develop frank diabetes mellitus. The cellular defects responsible for the abnormal insulin action in NIDDM patients is reviewed in this article. The paper focuses mainly on convalent insulin signaling. Insulin is postulated to stimulate glucose storage by initiating a cascade of phosphorylation and dephosphorylation events, which results in dephosphorylation and hence activation of the enzyme glycogen synthase. Glycogen synthase is the key enzyme in regulation of glycogen synthesis in the skeletal muscles of humans. This enzyme is sensitive to insulin, but in NIDDM patients it has been shown to be completely resistant to insulin stimulation when measured at euglycemia. The enzyme seems to be locked in the glucose-6-phosphate (G-6-Independent inactive D-form. This hypothesis is favored by the finding of reduced activity of the glycogen synthase phosphatase and increased activity of the respective kinase cAMP-dependent protein kinase. A reduced glycogen synthase activity has also been found in normoglycemic first-degree relatives of NIDDM patients, indicating that this abnormality precedes development of hyperglycemia in subjects prone to develop NIDDM. Therefore, this defect may be of primary genetic origin. However, it does not appear to be a defect in the enzyme itself, but rather a defect in the covalent activation of the enzyme system. Glycogen synthase is resistant to insulin but may be activated allosterically by G-6-P. This means that the defect in insulin activation can be compensated for by increased intracellular concentrations of G- 6 -P. In fact, we found that both hyperinsulinemia and hyperglycemia are able to increase the G-6-P level in skeletal muscles. Thus, insulin resistance in the nonoxidative pathway of glucose processing can be overcomed (compensated) by hyperinsulinemia and hyperglycemia. In conclusion, we hypothesize that insulin resistance in

FROM THE MEDICAL ENDOCRINOLOGICAL DEPARTMENT, ODENSE UNIVERSITY HOSPITAL, ODENSE, DENMARK. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO HENNING BECK-NIELSEN, PHD, PROFESSOR OF MEDICINE, DEPARTMENT OF ENDOCRINOLOGY M., ODENSE UNIVERSITY HOSPITAL, DK-5000 ODENSE, DENMARK.

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nsulin resistance in skeletal muscles is defined as a lower than expected effect of insulin on glucose disposal, measured in vivo (i.e., during insulin-clamp studies) or in vitro (after isolation of muscles strips). Until 1970 insulin resistance was not believed to play a major clinical role. Since then characterization of the insulin receptor has opened up a new field for the investigation of insulin action. However, studies of insulin action in human skeletal muscles, both in vivo and in vitro (biopsies), were only first initiated in the early 1980s. This means that our experience with the latter type of studies is limited; however, the amount of data produced in this time period are impressive. A compound of insulin resistance in skeletal muscles has recently been shown to be inherited, but it may also develop secondary to metabolic abnormalities (e.g., hyperglycemia, hyperinsulinemia, and increased lipid oxidation; 1). Today insulin resistance, especially in skeletal muscles, is believed to play an important pathophysiological role in the development of non-insulin-dependent diabetes mellitus (NIDDM; 2) and may also be associated with arterial hypertension and dyslipoproteinemia (3). The cellular defects responsible

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for insulin resistance in skeletal muscles have been investigated intensively during the last 10 yr, but these defects are still a matter of debate, despite considerable improvement of our knowledge in this field. One major problem has been, and still is, our inadequate understanding of the physiological mechanisms underlying the actions of insulin at the cellular level. Since we still do not know how insulin signaling takes place inside cells, it is a problem for pathophysiologists to discover the defects in that mechanism. On the other hand, current investigations have improved our physiological knowledge considerably. In this review the physiological mechanisms of the action of insulin will be updated and described, together with cellular defects that are important for the development of insulin resistance in skeletal muscles. In particular, the pathophysiological role of a defect in the enzyme glycogen synthase (GS) will be outlined. The importance of this cellular defect in precipitating hyperglycemia is discussed, together with the compensatory mechanisms present that enable the organism to keep muscle glucose metabolism at a level sufficient to satisfy the energy supply basally and for physical activity. PHYSIOLOGY OF GLUCOSE AND FAT METABOLISM IN SKELETAL MUSCLES— The main function of skeletal muscles is the production of force in a controlled manner. For that purpose muscles metabolize glucose and fatty acids to supply ATP for contractions. Because muscle fibers constitute —40% of body weight, the energy supply to these cells influences whole-body energy metabolism considerably. Muscles take up glucose and free fatty acids (FFA) from the blood, especially after a meal, to store glycogen and triglyceride. The amount of glycogen deposited in skeletal muscles in the postabsorptive state is —250 g, giving a concentration of —1% (g/100 g). The amount of triglyceride deposited is also —250 g.

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GLUCOSE

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Figure 1—Glucose processing in human skeletal muscles. G, glucose; G-6-P, glucose-6phosphate; GT, glucose transporter; GS, glycogen synthase; PFK, phosphofructokinase; PDH, pyruvate dehydrogenase.

At rest and during fasting most energy is produced from oxidation of FFA, but glycogen is also broken down. Glucose uptake is trivial, and the arteriovenous (AV) difference is —1 mg/100 ml (4). Thus, muscles have only a minor influence on glucose turnover in the fasting state at rest, at least at normoglycemia. The situation is different at hyperglycemia, where glucose uptake is increased. During exercise fat acts as the major source of energy, but glucose catalyzed from glycogen is also metabolized. If the muscles are depleted of glycogen, energy production depends on glucose and FFA uptake. Therefore, normal glycogen depots play an important role for normal energy metabolism. After intake of a meal mainly glucose is oxidized, because lipolysis is inhibited. The glucose taken up is predominantly deposited as glycogen. This pathway therefore plays a major role for overall glucose metabolism in the prandial phase (4). Pathways for glucose metabolism in skeletal muscles Glucose is taken up actively in skeletal muscles by glucose transporter (GT) proteins. Skeletal muscles contain mainly insulin-sensitive GTs, GLUT4, but insulinindependent GTs have also been described, GLUT1 (5; Fig. 1). GTs have a

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rate-limiting function with respect to glucose uptake because extracellular glucose concentration is —5 mM, whereas normal intracellular glucose concentration is insignificant in the postabsorptive state. However, this does not exclude the fact that other intracellular pathways or enzymes are rate determining in certain physiological and pathophysiological situations. Km for the glucose transport is ~7mM. When glucose is transported into the cell, it is immediately phosphorylated to glucose-6-phosphate (G-6-P) by hexokinase, an enzyme with a very low Km (90% of obese subjects do not develop the disease.

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