Increase In Muscle Insulin Sensitivity Research Articles

Exercise-induced increase in muscle insulin sensitivity in men is amplified when assessed using a meal test

Aims/hypothesisExercise has a profound effect on insulin sensitivity in skeletal muscle. The euglycaemic–hyperinsulinaemic clamp (EHC) is the gold standard for assessment of insulin sensitivity but it does not reflect the hyperglycaemia that occurs after eating a meal. In previous EHC investigations, it has been shown that the interstitial glucose concentration in muscle is decreased to a larger extent in previously exercised muscle than in rested muscle. This suggests that previously exercised muscle may increase its glucose uptake more than rested muscle if glucose supply is increased by hyperglycaemia. Therefore, we hypothesised that the exercise-induced increase in muscle insulin sensitivity would appear greater after eating a meal than previously observed with the EHC.MethodsTen recreationally active men performed dynamic one-legged knee extensor exercise for 1 h. Following this, both femoral veins and one femoral artery were cannulated. Subsequently, 4 h after exercise, a solid meal followed by two liquid meals were ingested over 1 h and glucose uptake in the two legs was measured for 3 h. Muscle biopsies from both legs were obtained before the meal test and 90 min after the meal test was initiated. Data obtained in previous studies using the EHC (n=106 participants from 13 EHC studies) were used for comparison with the meal-test data obtained in this study.ResultsPlasma glucose and insulin peaked 45 min after initiation of the meal test. Following the meal test, leg glucose uptake and glucose clearance increased twice as much in the exercised leg than in the rested leg; this difference is twice as big as that observed in previous investigations using EHCs. Glucose uptake in the rested leg plateaued after 15 min, alongside elevated muscle glucose 6-phosphate levels, suggestive of compromised muscle glucose metabolism. In contrast, glucose uptake in the exercised leg plateaued 45 min after initiation of the meal test and there were no signs of compromised glucose metabolism. Phosphorylation of the TBC1 domain family member 4 (TBC1D4; p-TBC1D4Ser704) and glycogen synthase activity were greater in the exercised leg compared with the rested leg. Muscle interstitial glucose concentration increased with ingestion of meals, although it was 16% lower in the exercised leg than in the rested leg.Conclusions/interpretationHyperglycaemia after meal ingestion results in larger differences in muscle glucose uptake between rested and exercised muscle than previously observed during EHCs. These findings indicate that the ability of exercise to increase insulin-stimulated muscle glucose uptake is even greater when evaluated with a meal test than has previously been shown with EHCs.Graphical

Surgical Removal of Omental Fat Does Not Improve Insulin Sensitivity and Cardiovascular Risk Factors in Obese Adults

Visceral adipose tissue (VAT) is an important risk factor for the metabolic complications associated with obesity. Therefore, a reduction in VAT is considered an important target of obesity therapy. We evaluated whether reducing VAT mass by surgical removal of the omentum improves insulin sensitivity and metabolic function in obese patients. We conducted a 12-month randomized controlled trial to determine whether reducing VAT by omentectomy in 22 obese subjects increased their improvement following Roux-en-Y gastric bypass (RYGB) surgery in hepatic and skeletal muscle sensitivity to insulin study 1. Improvement was assessed by using the hyperinsulinemic-euglycemic clamp technique. We also performed a 3-month, longitudinal, single-arm study to determine whether laparoscopic omentectomy alone, in 7 obese subjects with type 2 diabetes mellitus (T2DM), improved insulin sensitivity study 2. Improvement was assessed by using the Frequently Sampled Intravenous Glucose Tolerance Test. The greater omentum, which weighed 0.82 kg (95% confidence interval: 0.67-0.97), was removed from subjects who had omentectomy in both studies. In study 1, there was an approximate 2-fold increase in muscle insulin sensitivity (relative increase in glucose disposal during insulin infusion) and a 4-fold increase in hepatic insulin sensitivity 12 months after RYGB alone and RYGB plus omentectomy, compared with baseline values (P<.001). There were no significant differences between groups (P>.87) or group x time interactions (P>.36). In study 2, surgery had no effect on insulin sensitivity (P=.844) or use of diabetes medications. These results demonstrate that decreasing VAT through omentectomy, alone or in combination with RYGB surgery, does not improve metabolic function in obese patients.

IL-6 increases muscle insulin sensitivity only at superphysiological levels

Exercise induces an increase in glucose transport in muscle. As the acute increase in glucose transport reverses, it is replaced by an increase in insulin sensitivity. Interleukin-6 (IL-6) increases with exercise and has been reported to activate AMP-activated protein kinase (AMPK). Based on this information, we hypothesized that IL-6 would result in an increase in muscle insulin sensitivity. Rat epitrochlearis and soleus muscles were incubated with 120 ng/ml IL-6. Exposure to IL-6 induced a modest acute increase in glucose transport and was followed 3.5 h later by an increase in insulin sensitivity in epitrochlearis but not soleus muscles. IL-6 also brought about an increase in AMPK phosphorylation in epitrochlearis muscles. We conclude that exposure of fast-twitch muscle to 120 ng/ml IL-6 increases insulin sensitivity by activating AMPK. However, exposure of epitrochlearis muscles to 10 ng/ml IL-6, a concentration >100-fold higher than that attained in plasma during exercise, had no effect on glucose transport or insulin sensitivity. These findings provide evidence that the increases in glucose transport and insulin sensitivity induced by IL-6 are pharmacological rather than physiological effects. We interpret our results as evidence that the increase in IL-6 during exercise does not play a role in the exercise-induced increases in muscle glucose uptake and insulin sensitivity.

HIGHLIGHTED TOPIC: Role of Exercise in Reducing the Risk of Diabetes and Obesity

Type 2 diabetes is the fifth leading cause of death among adults in the United States ([2][1]). Long-term complications of the disease include blindness, kidney failure, neuropathy, and deterioration of blood vessels leading to tissue necrosis. Individuals born in the year 2000 have an estimated

Exercise-induced increase in muscle insulin sensitivity

Exercise/muscle contraction activates glucose transport. The increase in muscle glucose transport induced by exercise is independent of insulin. As the acute effect of exercise on glucose transport wears off, it is replaced by an increase in insulin sensitivity. An increase in insulin sensitivity results in a shift in the insulin dose-response curve to the left, with a decrease in the concentration of insulin needed to induce 50% of the maximal response. This phenomenon, which plays a major role in rapid muscle glycogen accumulation after exercise, is not mediated by amplification of the insulin signal. Development of the increase in insulin sensitivity after contractions does not require protein synthesis or activation of p38 MAPK. It does require the presence of a serum protein during the period of contractile activity. The effect of exercise on muscle insulin sensitivity is mimicked by hypoxia and by treatment of muscles with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside to activate AMP-activated protein kinase. The postexercise increase in sensitivity of muscle glucose transport to activation is not specific for insulin but also involves an increased susceptibility to activation by a submaximal contraction/hypoxia stimulus. The increase in insulin sensitivity is mediated by translocation of more GLUT4 glucose transporters to the cell surface in response to a submaximal insulin stimulus. Although the postexercise increase in muscle insulin sensitivity has been characterized in considerable detail, the basic mechanisms underlying this phenomenon remain a mystery.

Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice

Fasting readily induces hepatic steatosis. Hepatic steatosis is associated with hepatic insulin resistance. The purpose of the present study was to document the effects of 16 h of fasting in wild-type mice on insulin sensitivity in liver and skeletal muscle in relation to 1) tissue accumulation of triglycerides (TGs) and 2) changes in mRNA expression of metabolically relevant genes. Sixteen hours of fasting did not show an effect on hepatic insulin sensitivity in terms of glucose production in the presence of increased hepatic TG content. In muscle, however, fasting resulted in increased insulin sensitivity, with increased muscle glucose uptake without changes in muscle TG content. In liver, fasting resulted in increased mRNA expression of genes promoting gluconeogenesis and TG synthesis but in decreased mRNA expression of genes involved in glycogenolysis and fatty acid synthesis. In muscle, increased mRNA expression of genes promoting glucose uptake, as well as lipogenesis and beta-oxidation, was found. In conclusion, 16 h of fasting does not induce hepatic insulin resistance, although it causes liver steatosis, whereas muscle insulin sensitivity increases without changes in muscle TG content. Therefore, fasting induces differential changes in tissue-specific insulin sensitivity, and liver and muscle TG contents are unlikely to be involved in these changes.

Activation of p38 MAP kinase enhances sensitivity of muscle glucose transport to insulin

Muscle contractile activity is followed by an increase in the sensitivity of glucose transport to insulin. There is evidence suggesting that activation of p38 MAP kinase (p38) is involved in the stimulation of glucose transport by insulin and contractions. Exercise results in an increase in p38 phosphorylation that lasts for hours. In this context, we tested the hypothesis that activation of p38 results in an increase in insulin sensitivity. Muscles were exposed to anisomycin for 30 min to activate p38. Anisomycin increased p38 phosphorylation approximately 2.5-fold and glucose transport activity 2- to 3-fold. Three hours after anisomycin treatment, by which time the acute effect on glucose transport had partially worn off, sensitivity of muscle glucose transport to 60 microU/ml insulin was markedly increased. Both the activation of p38 and the increase in insulin sensitivity induced by anisomycin were completely prevented by pretreatment of muscles with the p38 inhibitor SB-202190. However, in contrast to the finding with anisomycin, inhibition of p38 activation did not prevent the contraction-induced increase in insulin sensitivity. Thus our results show that activation of p38 is followed by an increase in insulin sensitivity of muscle glucose transport. However, activation of p38 is not necessary for induction of an increase in muscle insulin sensitivity by contractions. This finding provides evidence that contractions have an additional effect that makes p38 activation unnecessary for enhancement of insulin sensitivity by contractile activity.

Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin.

Evidence has accumulated that activation of AMP kinase (AMPK) mediates the acute increase in glucose transport induced by exercise. As the exercise-induced, insulin-independent increase in glucose transport wears off, it is followed by an increase in muscle insulin sensitivity. The major purpose of this study was to determine whether hypoxia and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), which also activate AMPK and stimulate glucose transport, also induce an increase in insulin sensitivity. We found that the increase in glucose transport in response to 30 microU/ml insulin was about twofold greater in rat epitrochlearis muscles that had been made hypoxic or treated with AICAR 3.5 h previously than in untreated control muscles. This increase in insulin sensitivity was similar to that induced by a 2-h bout of swimming or 10 min of in vitro electrically stimulated contractions. Neither phosphatidylinositol 3-kinase activity nor protein kinase B (PKB) phosphorylation in response to 30 microU/ml insulin was enhanced by prior exercise or AICAR treatment that increased insulin sensitivity of glucose transport. Inhibition of protein synthesis by inclusion of cycloheximide in the incubation medium for 3.5 h after exercise did not prevent the increase in insulin sensitivity. Contractions, hypoxia, and treatment with AICAR all caused a two- to three-fold increase in AMPK activity over the resting level. These results provide evidence that the increase in insulin sensitivity of muscle glucose transport that follows exercise is mediated by activation of AMPK and involves a step beyond PKB in the pathway by which insulin stimulates glucose transport.

Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise.

The purpose of this study was to determine whether the increase in insulin sensitivity of skeletal muscle glucose transport induced by a single bout of exercise is mediated by enhanced translocation of the GLUT-4 glucose transporter to the cell surface. The rate of 3-O-[3H]methyl-D-glucose transport stimulated by a submaximally effective concentration of insulin (30 microU/ml) was approximately twofold greater in the muscles studied 3.5 h after exercise than in those of the sedentary controls (0.89 +/- 0.10 vs. 0.43 +/- 0.05 micromol . ml-1 . 10 min-1; means +/- SE for n = 6/group). GLUT-4 translocation was assessed by using the ATB-[2-3H]BMPA exofacial photolabeling technique. Prior exercise resulted in greater cell surface GLUT-4 labeling in response to submaximal insulin treatment (5.36 +/- 0.45 dpm x 10(3)/g in exercised vs. 3.00 +/- 0.38 dpm x 10(3)/g in sedentary group; n = 10/group) that closely mirrored the increase in glucose transport activity. The signal generated by the insulin receptor, as reflected in the extent of insulin receptor substrate-1 tyrosine phosphorylation, was unchanged after the exercise. We conclude that the increase in muscle insulin sensitivity of glucose transport after exercise is due to translocation of more GLUT-4 to the cell surface and that this effect is not due to potentiation of insulin-stimulated tyrosine phosphorylation.

Contraction-induced increase in muscle insulin sensitivity: requirement for a serum factor

The insulin sensitivity of glucose transport is enhanced in skeletal muscle after a bout of exercise. In a previous study, stimulation of washed muscles to contract in vitro, in contrast to exercise, did not result in an increase in insulin sensitivity. The purpose of the present study was to explain this apparent discrepancy. We found that, although rat epitrochlearis muscles stimulated to contract in vitro after 15 min of incubation in Krebs-Henseleit buffer did not develop increased insulin sensitivity, muscles stimulated to contract immediately after being dissected showed a small but significant enhancement of the stimulation of 3-O-methyl-D-glucose transport by 30 microU/ml insulin. Furthermore, muscles stimulated to contract in situ and then allowed to recover in vitro showed as large an increase in insulin sensitivity as that which occurs after a bout of swimming. To follow up these findings suggesting involvement of a humoral factor, we incubated epitrochlearis muscles in serum before and during contractile activity in vitro. Epitrochlearis muscle insulin sensitivity was enhanced to as great an extent after in vitro contractile activity in serum as after swimming. Experiments involving charcoal treatment, ultrafiltration, or trypsin digestion provided evidence that the serum factor that interacts with contractions to enhance insulin sensitivity is a protein.

2 The Insulin-Like Effect of Muscle Contraction

Muscle contraction results in an increase in membrane permeability to glucose. The actual mechanism by which contractile activity increases membrane permeability is unknown. However, kinetic studies suggest that this increase is due to an increase in the number of glucose transporters associated with the plasma membrane. This is also suggested by the recent finding that cytochalsin B, which competitively inhibits the binding of glucose to the glucose transporter in the plasma membrane, prevents activation of the glucose transport process by muscle contraction. Unlike insulin-stimulated glucose transport, in which permeability is reversed rapidly upon removal of the insulin, the increase in membrane permeability following contractile activity can persist for many hours. It has also been reported that the stimulatory effects of insulin and contraction are additive, and that prostaglandin E2 augments the effect of insulin on glucose transport but has no effect on contraction-facilitated glucose transport. Collectively, these findings suggest that insulin and contractile activity increase membrane permeability to glucose by independent mechanisms. An increase in membrane permeability is only partially responsible for the increase in glucose uptake during exercise in vivo. With an increase in muscle activity, there is an increase in delivery of glucose and insulin to the muscle as a result of an increase in muscle blood flow. Glucose uptake may also be facilitated by an increase in the insulin sensitivity of the muscle. The increases in muscle blood flow and insulin sensitivity may be associated with activation of the kinin-prostaglandin system of the muscle. The increase in muscle insulin sensitivity may also involve an increase in insulin binding to its receptors on the sarcolemma. It should be noted that the increase in insulin binding associated with contractile activity requires the presence of epinephrine. Muscle glycogen may also affect the rate of glucose uptake during exercise. During prolonged, moderately intense exercise, glucose uptake increases as the muscle glycogen level declines. This increase in glucose uptake is inversely related to the glucose-6-phosphate concentration of the cell. During high-intensity exercise, the rate of glycogenolysis is rapid, resulting in the accumulation of glucose-6-phosphate and free glucose. Thus, it appears that the rate-limiting step in glucose uptake during exercise is shifted from transport to glucose phosphorylation, and that this shift is mediated by the intracellular glucose-6-phosphate concentration, which is influenced by the rate of muscle glycogen catabolism.