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Because skeletal muscle plays a major role in glucose disposal, it may be the primary site of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). Rates of glycogen synthesis (GS), glucose utilization via glycolysis, glycolytic utilization (GU), and glucose transport (GT) were studied in epitrochlearis muscles (EMs) obtained from 10-wk-old nonfasted Sprague-Dawley rats in which NIDDM was neonatally induced with streptozocin. Plasma glucose in NIDDM rats was elevated (P less than 0.001), whereas plasma insulin was similar in NIDDM and control rats. No differences in muscle weight, protein, glycogen, ATP, phosphocreatine, lactate, lactate-pyruvate ratios, or glucose-6-phosphate were noted in EMs of control and NIDDM rats. EMs were incubated in medium containing 5.6 or 11.2 mM glucose with tracer D-[5-3H]glucose and insulin from 0 to 7.18 x 10(-7) M for 1 or 2 h, and GS, GT, and GU were evaluated. Similar rates of basal (non-insulin-mediated) and insulin-stimulated GS, GU, and GT were observed in EMs of NIDDM and control rats incubated in 5.6 mM glucose for 2 h. Insulin dose-response curves revealed similar sensitivities and responsiveness. Increasing glucose concentration (from 5.6 to 11.2 mM) induced significant increases in basal rates of GS, GU, and GT in EMs of control but not NIDDM rats. Insulin dose-response curves for GS and GT revealed decreased sensitivity and no change in responsiveness in EMs of control and NIDDM rats, even though GU of EMs of NIDDM rats was significantly lower at basal and all other insulin concentrations. These data revealed that both insulin resistance and glucose resistance contribute to the impaired glucose metabolism in EMs of the NIDDM rat.

Epitrochlearis muscles obtained from normal male Holtzman rats used as controls (C) and rats with reduced renal mass (Nx) fed isocaloric diets of varying protein content were incubated in Krebs-Ringer buffer containing 5 mM glucose for 1 or 3 h with or without insulin. Alanine (ALA) release rates from muscles of Nx rats were increased 40% above C values after 1 h of incubation regardless of protein intake. Addition of insulin decreased the ALA release from muscles of Nx rats to C values in animals fed 10 and 20% casein and chow but did not in rats fed 40% casein. After 3 h of incubation, all ALA release rates decreased by congruent with40%. The ALA release from muscles of Nx rats fed 10% casein was comparable to C values and decreased further with the addition of insulin. On the other hand, ALA release from muscles of Nx rats fed 20 and 40% casein as well as chow remained significantly elevated above C values, but responded to the addition of insulin with a reduction in release rates to C values, except from the muscles of Nx animals fed 40% casein. Tyrosine (TYR) and phenylalanine (PHE) release rates also were increased in muscles from Nx rats compared with C after 1 h of incubation. Release rates were highest in the Nx group fed 10% casein and decreased with increasing protein intake. Addition of insulin decreased the release rates of Nx rats to C values in each group. After 3 h of incubation, release rates of TYR and PHE in muscles from Nx rats remained significantly above C values for all groups, but responded to the addition of insulin with a decrease to C values. Glutamine and glutamate release were not significantly affected by reduction in renal mass.Base-line glucose uptake by all groups of muscles from Nx rats was significantly greater than corresponding C values, but maximal insulin-stimulated glucose uptake was comparable in all groups. Tissue pool sizes for glycogen, ATP, phosphocreatine, ALA, glutamate, and glutamine were unaffected by reduction in renal mass. The results indicate that Nx is associated with accelerated ALA, TYR, and PHE release from muscle. ALA release rose with increasing protein intake and decreased to values observed from C muscles after addition of insulin except in Nx animals fed 40% casein. TYR and PHE release decreased with increasing protein intake and also decreased to C values with the addition of insulin. The data also suggest that ALA release is not dependent upon glucose uptake in muscles from either C or Nx rats.

The effects of insulin and contraction on glucose transport and metabolism were investigated in rat epitrochlearis muscles in vitro. Insulin dose-response curves showed a threshold (approximately 50 microunits/ml) and saturation-type (approximately 1 mU/ml) kinetics, whereas isometric contraction activated glucose transport and metabolism in a linear fashion with no evidence of a threshold. Insulin and contraction increased the apparent maximal rate of uptake of the hexose transport system with minimal effect on its apparent Km. The stimulatory effects of insulin and contraction were additive; similar results were obtained with 2-deoxy-D-glucose. Contraction stimulated glucose transport in three different preparations of muscles depleted of insulin: 1) exhaustively washed for 2 h, 2) rats infused with anti-insulin serum, and 3) chronically (streptozotocin-induced) diabetic rats. Prostaglandin E2 augmented the effect of a submaximal concentration of insulin on glucose transport without exerting any effect by itself but had no effect on contraction-augmented glucose transport. It is concluded that insulin and contraction activate glucose transport and metabolism via independent mechanisms.

Blood substrate and hormone concentration were determined in 16 children with Reye syndrome prior to and following administration of hypertonic glucose. Baseline concentrations of lactate, pyruvate, alanine, glutamine, glutamate, proline, hydroxyproline, lysine, and aspartate were elevated (p less than 0.01), whereas citrulline and arginine were low. All substrate concentrations were below or within the normal range following 36 hours of therapy except those of lactate, pyruvate, and aspartate. Urea nitrogen excretion was reduced (p less than 0.05) on the second day of therapy. Plasma concentrations of insulin and growth hormone increased and glucagon decreased during the first day. Cortisol remained elevated throughout the study period. We conclude that the high circulating concentrations of substrates are the result of both increased mobilization and decreased clearance and that hypertonic glucose infusion suppresses substrate mobilization. A primary abnormality of the mitochondria could explain the metabolic perturbations that occurred. A possible relationship between the encephalopathy in this disorder and an insult to both brain and brain capillary mitochondria is discussed.

Denervated (1-10 days) rat epitrochlearis muscles were isolated, and basal and insulin-stimulated protein and glucose metabolism were studied. Although basal rates of glycolysis and glucose transport were increased in 1-10-day-denervated muscles, basal glycogen-synthesis rates were unaltered and glycogen concentrations were decreased. Basal rates of protein degradation and synthesis were increased in 1-10-day-denervated muscles. The increase in degradation was greater than that in synthesis, resulting in muscle atrophy. Increased rates of proteolysis and glycolysis were accompanied by elevated release rates of leucine, alanine, glutamate, pyruvate and lactate from 3-10-day-denervated muscles. ATP and phosphocreatine were decreased in 3-10-day-denervated muscles. Insulin resistance of glycogen synthesis occurred in 1-10-day denervated muscles. Insulin-stimulated glycolysis and glucose transport were inhibited by day 3 of denervation, and recovered by day 10. Inhibition of insulin-stimulated protein synthesis was observed only in 3-day-denervated muscles, whereas regulation by insulin of net proteolysis was unaffected in 1-10-day-denervated muscles. Thus the results demonstrate enhanced glycolysis, proteolysis and protein synthesis, and decreased energy stores, in denervated muscle. They further suggest a defect in insulin's action on protein synthesis in denervated muscles as well as on glucose metabolism. However, the lack of concurrent changes in all insulin-sensitive pathways and the absence of insulin-resistance for proteolysis suggest multiple and specific cellular defects in insulin's action in denervated muscle.

Effects of insulin on glycogen synthesis (GS), glycolytic utilization (GU), and glucose uptake (GT) were studied in isolated epitrochlearis muscles from exercise-trained or sedentary rats during recovery from acute exercise or at rest. During the 1st h after acute exercise, the enhanced basal and insulin-stimulated GT was directed mainly toward replenishment of glycogen but basal GU was also increased. During the second through third hours after exercise, basal GS decreased but remained greater than rest and basal GU and GT returned to normal. Insulin sensitivity of these parameters was enhanced. Training alone reduced basal GS but enhanced insulin sensitivity of GT and GU. Training reduced the acute exercise-stimulated increase in basal and insulin sensitivity of GS during recovery from acute exercise, probably due to elevated glycogen stores. Thus recovery from acute exercise or training, either alone or in combination, enhances insulin stimulated GT in muscle; however, the increased glucose is primarily channeled toward GS after acute exercise, which is reduced by prior training and is directed to GU in trained animals either at rest or after acute exercise.

Insulin resistance has been demonstrated in chronic renal failure patients and may be improved by exercise training, but the mechanisms have not been identified. In this study, the response of glucose uptake, glycogen synthesis, and glucose utilization via glycolysis (glycolytic utilization) to stimulation by insulin and/or acute exercise were determined in isolated muscles from rats with moderate renal insufficiency that were exercise trained or remained sedentary. Moderate renal insufficiency had no effect on the basal rate, insulin sensitivity, or insulin responsiveness of glucose uptake, glycogen synthesis, or glycolytic utilization in muscle. The enhanced insulin responsiveness of both glycogen synthesis and glucose uptake following acute exercise, noted in control animals, was less in rats with moderate renal insufficiency, but the enhanced basal rate and insulin sensitivity after exercise were unaffected by moderate renal insufficiency. Exercise training increased the insulin sensitivity and responsiveness of muscle glucose uptake and glycolytic utilization in rats with moderate renal insufficiency and in controls. The effects of acute exercise and exercise training on insulin responsiveness of glucose uptake were additive in controls but not in animals with moderate renal insufficiency. These findings are compatible with the concept that moderate renal insufficiency is associated with a postreceptor defect in insulin's action in muscle, detectable only following maximal stimulation of glucose transport by insulin and exercise, and partially correctable by exercise training.