Increased muscle glucose uptake after exercise. No need for insulin during exercise

It has recently been shown that insulin sensitivity of skeletal muscle glucose uptake and glycogen synthesis is increased after a single exercise session. The present study was designed to determine whether insulin is necessary during exercise for development of these changes found after exercise. Diabetic rats and controls ran on a treadmill and their isolated hindquarters were subsequently perfused at insulin concentrations of 0, 100, and 20,000 microU/ml. Exercise increased insulin sensitivity of glucose uptake and glycogen synthesis equally in diabetic and control rats, but insulin responsiveness of glucose uptake was noted only in controls. Analysis of intracellular glucose-6-phosphate, glucose, glycogen synthesis, and glucose transport suggested that the exercise effect on responsiveness might be due to enhancement of glucose disposal. After electrical stimulation of diabetic hindquarters in the presence of insulin antiserum, insulin sensitivity of 3-O-methylglucose transport was increased to the same extent as in muscle from healthy rats stimulated in the presence of insulin at 50 microU/ml. Furthermore, in muscle depleted of glycogen by contractions, transport of 3-O-methylglucose was increased in the presence of insulin antiserum and in the absence of increased regional perfusate flow. It is concluded that after exercise, increased sensitivity of muscle glucose metabolism to insulin can be found in the absence of insulin during exercise, but still involves increased membrane transport of glucose. At maximal insulin concentrations, the enhancing effect of exercise on glucose uptake may involve enhancement of glucose disposal, an effect that is probably less in muscle from diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uraemic muscle metabolism at rest and during exercise

The effect of chronic renal failure and the accompanying hyperphosphataemiaon muscle metabolism at rest and during exercise was examinedin a group of undialysed patients suffering from chronic renalfailure. ³¹P magnetic resonance spectroscopy was used to measureintracellular high-energy phosphates in resting muscle as wellas changes in the concentrations of these metabolites duringexercise and recovery from exercise. In resting muscle, cell[Pi] rose with plasma [Pi], and free [ADP] changed such thatthe phosphorylation potential ([ATP]/([ADP]x[Pi])), which probablycontrols mitochondrial oxidation in resting muscle, was preserveddespite a wide variation in cell [Pi]. The maximal oxidativecapacity of the muscle was calculated from the kinetics of phosphocreatinerecovery after exercise. There was no reduction in uraemic muscleoxidative capacity compared to control muscle. This contrastswith our finding of a reduction in the mitochondrial oxidativecapacity in the muscle of patients established on dialysis,suggesting that a substance crucial for mitochondrial functionor substrate supply to mitochondria is removed by dialysis.     

Effect of exercise and diet on triglyceride metabolism in rats with moderate insulin deficiency

The ability of exercise and diet to modify the effects of moderate streptozotocin-induced insulin deficiency on triglyceride metabolism has been studied in the rat. Insulin-deficient rats allowed to run spontaneously in exercise wheel cages had significantly lower (P less than 0.001) plasma glucose levels (187 +/- 19 mg/dl) than either sedentary (374 +/- 24 mg/dl) or sucrose-fed (450 +/- 13 mg/dl) diabetic rats, despite the fact that plasma insulin levels were comparable in all these groups. Plasma triglyceride (TG) levels in exercise-trained rats with diabetes (51 +/- 5 mg/dl) were actually lower than in control rats with normal glucose tolerance (90 +/- 14 mg/dl). In contrast, plasma TG levels were higher than control levels in diabetic sedentary rats (128 +/- 11 mg/dl), and severe hypertriglyceridemia developed in sucrose-fed diabetic rats (369 +/- 35 mg/dl). The ability of exercise training to attenuate diabetic hypertriglyceridemia, which was observed in both chow-fed and sucrose-fed rats, was secondary to a decrease in TG secretion, and appeared to be related to lower plasma FFA concentrations. In contrast, the accentuation of diabetic hypertriglyceridemia seen in sucrose-fed rats was related to a defect in TG catabolism. Adipose tissue lipoprotein lipase (LPL) activities were essentially identical in all diabetic rats, suggesting that the observed difference in TG kinetics could not be attributed to concomitant increases or decreases in adipose tissue LPL activity. These results emphasize the powerful impact of exercise and diet on TG metabolism in rats with moderate degrees of insulin deficiency.     

Alterations of insulin and glucose metabolism during cardiopulmonary bypass under normothermia

Anesthesia, surgical trauma, heparinization, priming volume composition, and temperature control of the heart-lung machine individually affect carbohydrate, protein, or lipid metabolism during cardiac operations. The impact of some of these factors on glucose and insulin regulation was assessed before, during, and after normothermic cardiopulmonary bypass in nondiabetic patients with use of a servo-controlled insulin delivery system. With a glucose-free prime, cardiopulmonary bypass induced a slight hyperglycemia but no endogenous insulin response, suggesting a partial inhibition of insulin secretion. Nonetheless, insulin release could be stimulated by exogenous glucagon. A glucose load in the priming fluid led to marked and persistent hyperglycemia without commensurate insulin release. Elevated stress hormone levels, a concomitant reduction of insulin release and insulin action, and a depression of peripheral glucose utilization, as demonstrated by glucose clamp experiments, contributed to these perturbations of glucose and insulin metabolism. Although the metabolic alterations observed are not critical in routine cardiac operations, they may become clinically significant in postoperative states with unusual persistence of stress conditions.     

Skeletal muscle metabolism during exercise and recovery in patients with respiratory failure.

BACKGROUND--Patients with respiratory failure have early fatiguability which may be due to limitation of oxygen supply for oxidative (mitochondrial) ATP synthesis. Skeletal muscle in exercise and recovery was studied to examine the effect of chronic hypoxia on mitochondrial activity in vivo. METHODS--The skeletal muscle of five patients with respiratory failure (PaO2 < 9 kPa) was studied by phosphorus-31 magnetic resonance spectroscopy and compared with 10 age and sex matched controls. Patients lay in a 1.9 Tesla superconducting magnet with the gastrocnemius muscle overlying a six cm surface coil. Spectra were acquired at rest, during plantar flexion exercise, and during recovery from exercise. Relative concentrations of inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were measured from peak areas, and pH and free ADP concentration were calculated. For the start of exercise, the rates of PCr depletion and estimated lactic acid production were calculated. For the post exercise recovery period, the initial rate of PCr recovery (a quantitative measure of mitochondrial ATP synthesis), the apparent Vmax for mitochondrial ATP synthesis (calculated from initial PCr resynthesis and the end exercise ADP concentration which drives this process), and the recovery half times of PCr, Pi, and ADP (also measures of mitochondrial function) were determined. RESULTS--Considerably greater and faster PCr depletion and intracellular acidosis were found during exercise. This is consistent with limitation of oxygen supply to the muscle and might explain the early fatiguability of these patients. There was no abnormality in recovery from exercise, however, suggesting that mitochondria function normally after exercise. CONCLUSIONS--These results are consistent with one or more of the following: (a) decreased level of activity of these patients; (b) changes in the fibre type of the muscle; (c) decreased oxygen supply to the muscle during exercise but not during recovery. They are not consistent with an intrinsic defect of mitochondrial ATP synthesis in skeletal muscle in respiratory failure.     

Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity

Insulin resistance increases and muscle oxidative capacity decreases during aging, but lifestyle changes-especially physical activity-may reverse these trends. Here we report the effect of a 16-week aerobic exercise program (n = 65) or control activity (n = 37) performed by men and women aged 21-87 years on insulin sensitivity and muscle mitochondria. Insulin sensitivity, measured by intravenous glucose tolerance test, decreased with age (r = -0.32) and was related to abdominal fat content (r = -0.65). Exercise increased peak oxygen uptake (VO(2peak); 10%), activity of muscle mitochondrial enzymes (citrate synthase and cytochrome c oxidase, 45-76%) and mRNA levels of mitochondrial genes (COX4, ND4, both 66%) and genes involved in mitochondrial biogenesis (PGC-1alpha, 55%; NRF-1, 15%; TFAM, 85%). Exercise also increased muscle GLUT4 mRNA and protein (30-52%) and reduced abdominal fat (5%) and plasma triglycerides (25%). None of these changes were affected by age. In contrast, insulin sensitivity improved in younger people but not in middle-aged or older groups. Thus, the muscle mitochondrial response to 4 months of aerobic exercise training was similar in all age-groups, although the older people did not have an improvement in insulin sensitivity.     

血液透析对尿毒症胰岛素拮抗和糖代谢的影响

目的研究血液透析对尿毒症胰岛素拮抗和糖代谢的影响。方法采用口服葡萄糖耐量试验（ＯＧＴＴ）和胰岛素释放试验（ＩＲＴ）方法，检测２２例血透（ＨＤ），２２例非透析（ＮＤ）尿毒症者和１２例正常者胰岛素敏感指数（ＩＳＩ）、机体糖利用率（Ｍ）、糖和胰岛素反应曲线下面积（ＡＵＣＧ和ＡＵＣＩＮＳ）。结果（１）ＨＤ组糖负荷后血糖、胰岛素水平及其ＡＵＣＧ、ＡＵＣＩＮＳ均显著低于ＮＤ组，但仍明显高于正常对照组；（２）ＨＤ组ＩＳＩ、Ｍ值显著高于ＮＤ组，但明显低于正常对照组，其胰岛素拮抗（ＩＲ）和糖耐量异常（ＩＧＴ）发生率均显著低于ＮＤ组：（３）胰岛素拮抗组血透时间显著短于非胰岛素拮抗组，透析时间与ＩＳＩ有正相关趋势；（４）ＨＤ组较ＮＤ组血ｐＨ值、血ＨＣＯ－３水平显著增高，但Ｎ－ＰＴＨ水平显著低下。结论ＨＤ可部分改善尿毒症胰岛素拮抗，高胰岛素血症和糖耐量异常。     

Interaction of insulin and prior exercise in control of hepatic metabolism of a glucose load

To determine if prior exercise enhances insulin-stimulated extraction of glucose by the liver, chronically catheterized dogs were submitted to 150 min of treadmill exercise or rest. After exercise or rest, dogs received portal glucose (18 micro mol x kg(-1) x min(-1)), peripheral somatostatin, and basal portal glucagon infusions from t = 0 to 150 min. A peripheral glucose infusion was used to clamp arterial blood glucose at 8.3 mmol/l. Insulin was infused into the portal vein to create either basal levels or mild hyperinsulinemia. Prior exercise did not increase whole-body glucose disposal in the presence of basal insulin (25.5 +/- 1.5 vs. 20.3 +/- 1.7 micro mol x kg(-1) x min(-1)), but resulted in a marked enhancement in the presence of elevated insulin (97.2 +/- 15.1 vs. 64.4 +/- 7.4 micro mol x kg(-1) x min(-1)). Prior exercise also increased net hepatic glucose uptake in the presence of both basal insulin (7.5 +/- 1.2 vs. 2.9 +/- 2.4 micro mol x kg(-1) x min(-1)) and elevated insulin (22.0 +/- 3.5 vs. 11.5 +/- 1.8 micro mol x kg(-1) x min(-1)). Likewise, net hepatic glucose fractional extraction was increased by prior exercise with both basal insulin (0.04 +/- 0.01 vs. 0.01 +/- 0.01 micro mol x kg(-1) x min(-1)) and elevated insulin (0.10 +/- 0.01 vs. 0.05 +/- 0.01). Hepatic glycogen synthesis was increased by elevated insulin, but was not enhanced by prior exercise. Although the increase in glucose extraction after exercise could be ascribed to increased insulin action, the increase in hepatic glycogen synthesis was independent of it.     

Effects of insulin on brain glucose metabolism in impaired glucose tolerance

OBJECTIVE

Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance.

RESEARCH DESIGN AND METHODS

We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [¹⁸F]fluorodeoxyglucose (for brain glucose metabolism) and [¹⁵O]H₂O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling.

RESULTS

The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group.

CONCLUSIONS

We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance.Peripheral insulin resistance is a hallmark of metabolic syndrome and type 2 diabetes, but it is unclear if the brain also shows insulin resistance. Peripheral insulin crosses the blood-brain barrier via an active transport mechanism and binds to insulin receptors on neurons and glial cells. Insulin has a catabolic effect; in addition, it influences memory functions by modulating neurotransmitter release and synaptic plasticity (1–4). Therefore, determining whether insulin resistance also occurs in the brain in metabolic syndrome is important (5). Obese individuals have a decreased cerebrospinal fluid–to–plasma insulin ratio (6), diminished catabolic responses to intranasal insulin (7), and decreased cortical brain activity after insulin (8), suggesting brain insulin resistance (1,5). However, these indirect studies do not establish the relationship between insulin and brain glucose metabolism, which is important given the role of the brain in glucose sensing (9).Direct evidence on the effects of insulin on the brain may be obtained with positron emission tomography (PET) and ¹⁸F-labeled fluorodeoxyglucose ([¹⁸F]FDG). Studies in healthy subjects have shown that brain glucose metabolism does not increase after increasing plasma insulin concentrations above physiological fasting levels (10,11) but decreases after decreasing plasma insulin concentration below physiological fasting levels (12,13), suggesting that the insulin effect is already saturated at fasting concentrations in healthy subjects. In contrast, Anthony et al. (12) recently demonstrated that reducing plasma insulin does not reduce brain glucose metabolism in patients with impaired glucose tolerance. However, it is not known whether insulin stimulates brain glucose metabolism above fasting levels in these patients or whether this effect is already saturated at fasting levels, as in healthy subjects (12,13).To characterize the dose-response relationship of plasma insulin and brain glucose metabolism in patients with impaired glucose tolerance, we used [¹⁸F]FDG PET to measure brain glucose metabolism in two conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp) in both healthy subjects and patients with impaired glucose tolerance. [¹⁸F]FDG is a glucose analog that is taken up in the brain and trapped after phosphorylation; thus, the measured signal approximates uptake of glucose. The euglycemic-hyperinsulinemic clamp allows close monitoring and adjustment of plasma glucose while inducing a constant insulin stimulation. In a subset of subjects, we also measured the effects of insulin on cerebral blood flow with [¹⁵O]H₂O PET.     

Effect of prolonged uremia on insulin metabolism by isolated liver and muscle.

As the prolonged metabolic clearance rate of insulin in chronic uremia cannot be entirely explained by impaired removal and degradation of insulin by the kidney, we set out to determine whether prolonged uremia depresses other major sites of insulin degradation. The study was conducted with livers and skeletal muscle obtained from normal control rats and uremic rats 4 weeks after 80% nephrectomy. Despite a significant difference between renal function in the control and uremic rats (BUN, 18 vs. 46 mg/dl), there was no significant difference in the clearance of insulin by isolated uremic or control livers perfused with a bloodless medium. Similarly, the 125I-insulin degrading activity of liver homogenates was not depressed by uremia. In contrast, binding and degradation by uremic liver cell membranes was significantly reduced to 58% and 85% of the controls, respectively. Degradation by homogenates of skeletal muscle and by intact epitrochlaris muscle was significantly less in uremics than in controls. These results indicate that chronic uremia depresses skeletal muscle insulin degradation but not hepatic insulin removal or degradation despite a decrease in insulin binding and degradation by liver plasma membranes. It thus appears that depression of insulin degradation by muscle may contribute to the prolonged insulin metabolic clearance rate seen in chronic uremia. Furthermore, it is possible that the impaired binding of insulin to liver membranes may play a role in the insulin resistance of uremia.     

Decreased insulin binding, glucose transport, and glucose metabolism in soleus muscle of rats fed a high fat diet

The relationship between diet and insulin sensitivity was examined in isolated soleus muscle from 10-wk-old lean Zucker rats. Rats were fed either a high fat or high carbohydrate diet that had 67% of calories as fat or carbohydrate, respectively, for 10 days. Plasma insulin but not plasma glucose concentrations were significantly elevated in high-fat-fed rats, indicating that a state of insulin resistance existed. The mechanisms responsible for the insulin resistance were studied by measuring insulin binding, 2-deoxyglucose uptake, and glucose metabolism in soleus muscle. The soleus muscle from the high-fat-fed rats bound significantly less insulin than high carbohydrate control rats under equilibrium binding conditions. The 35% decrease in insulin binding at maximal insulin concentrations resulted from a decrease in insulin receptor number but no change in receptor affinity. Maximal insulin-stimulated 2-deoxyglucose uptake was reduced in soleus muscle from high-fat-fed rats when compared with high carbohydrate controls. A decrease in postmembrane basal and insulin-stimulated glucose utilization was produced by high rat feeding and varied depending upon the pathway involved. An estimate of glycolysis (3H2O) formation from [5-3H]glucose) and glucose oxidation (14CO2 production from 14C-glucose) demonstrated a greater decrease in basal and insulin-stimulated utilization than in [5-3H]glucose conversion to [3H]glycogen. These results suggest that multiple sites are responsible for the observed insulin resistance in soleus muscle after high fat feeding.     

Inhibition of glycogen synthase kinase 3 improves insulin action and glucose metabolism in human skeletal muscle

Glycogen synthase kinase (GSK)-3 has been implicated in the regulation of multiple cellular physiological processes in skeletal muscle. Selective cell-permeable reversible inhibitors (INHs) of GSK-3 (CT98014 and CHIR98023 [Chiron, Emeryville, CA] and LiCl) were used to evaluate the role of GSK-3 in controlling glucose metabolism. Acute treatment (30 min) of cultured human skeletal muscle cells with either INH resulted in a dose-dependent activation of glycogen synthase (GS) with a maximally effective concentration of approximately 2 micromol/l. The maximal acute effect of either INH on GS (103 +/- 25% stimulation over basal) was greater than the maximal insulin response (48 +/- 9%, P < 0.05 vs. INH); LiCl was as effective as insulin. The GSK-3 inhibitor effect, like that of insulin, was on the activation state (fractional velocity [FV]) of GS. Cotreatment of muscle cells with submaximal doses of INH and insulin resulted in an additive effect on GS FV (103 +/- 10% stimulation, P < 0.05 vs. either agent alone). Glucose incorporation into glycogen was also acutely stimulated by INH. While prolonged (6-24 h) insulin exposure led to desensitization of GS, INH continued to activate GS FV for at least 24 h. Insulin and LiCl acutely activated glucose uptake, whereas INH stimulation of glucose uptake required more prolonged exposure, starting at 6 h and continuing to 24 h. Chronic (4-day) treatment with INH increased both basal (154 +/- 32% of control) and insulin-stimulated (219 +/- 74%) glucose uptake. Upregulation of uptake activity occurred without any change in total cellular GLUT1 or GLUT4 protein content. Yet the same chronic treatment resulted in a 65 +/- 6% decrease in GSK-3 protein and a parallel decrease (61 +/- 11%) in GSK-3 total activity. Together with the INH-induced increase in insulin-stimulated glucose uptake, there was an approximately 3.5-fold increase (P < 0.05) in insulin receptor substrate (IRS)-1 protein abundance. Despite upregulation of IRS-1, maximal insulin stimulation of Akt phosphorylation was unaltered by INH treatment. The results suggest that selective inhibition of GSK-3 has an impact on both GS and glucose uptake, including effects on insulin action, using mechanisms that differ from and are additive to those of insulin.     

Carnitine metabolism during exercise in patients on chronic hemodialysis.

Patients on hemodialysis (HD) have impaired exercise performance. Carnitine homeostasis is also abnormal in this population. As carnitine is an important cofactor for muscle energy metabolism, exercise performance and skeletal muscle carnitine metabolism were characterized in eight HD patients, and in five age-matched controls. Each patient underwent graded bicycle exercise testing to define maximal performance, and prolonged exercise at 70% of their peak work capacity. Muscle (vastus lateralis) total carnitine content (carnitine plus all acylcarnitines) at rest was lower in HD patients than in controls (2320 +/- 1190 vs. 3800 +/- 940 nmol/g, P less than 0.05). In patients on HD, muscle carnitine content was inversely correlated to time on HD (r = -0.74, P less than 0.05), and positively correlated to peak exercise performance (r = 0.77, P less than 0.05). In patients on HD, 8 +/- 7% of the muscle carnitine pool at rest was short-chain acylcarnitines (similar to the distribution in controls), but 32 +/- 5% of the plasma carnitine pool consisted of short-chain acylcarnitines. With high-intensity exercise in patients on HD, muscle short-chain acylcarnitine content increased from 130 +/- 130 to 1380 +/- 820 nmol/g (P less than 0.01). The change in muscle short-chain acylcarnitine content with exercise was correlated with the increase in muscle lactate content (r = 0.88, P less than 0.01). In summary, patients on HD had a lower muscle total carnitine content than control subjects which was correlated to exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans.

The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.     

Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin.

Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes.