Role of glucose in the regulation of glutamine metabolism in health and in type 1 insulin-dependent diabetes

To determine the effect of glucose availability on glutamine metabolism, glutamine kinetics were assessed under conditions of hyperglycemia resulting from 1) intravenous infusion of 7.5% dextrose in healthy adults and 2) insulin deficiency in young adults with insulin-dependent diabetes mellitus (IDDM). Eight healthy adults and five young adults with IDDM were studied in the postabsorptive state by use of a primed continuous infusion of D-[U-(14)C]glucose, L-[5,5,5-(2)H(3)]leucine, and L-[3, 4-(13)C]glutamine. Whether resulting from insulin deficiency or dextrose infusion, the rise in plasma glucose was associated with increased glucose turnover (23.5 +/- 0.7 vs. 12.9 +/- 0.3 micromol. kg(-1). min(-1), P < 0.01 and 20.9 +/- 2.5 vs. 12.8 +/- 0.4 micromol. kg(-1). min(-1), P = 0.03, in health and IDDM, respectively). In both cases, high blood glucose failed to alter glutamine appearance rate (R(a)) into plasma [298 +/- 9 vs. 312 +/- 14 micromol. kg(-1). h(-1), not significant (NS) and 309 +/- 23 vs 296 +/- 26 micromol. kg(-1). h(-1), NS, in health and IDDM, respectively] and the estimated fraction of glutamine R(a) arising from de novo synthesis (210 +/- 7 vs. 217 +/- 10 micromol. kg(-1). h(-1), NS and 210 +/- 16 vs. 207 +/- 21 micromol. kg(-1). h(-1), NS, in health and IDDM, respectively). When compared with the euglycemic day, the apparent contribution of glucose to glutamine carbon skeleton increased when high plasma glucose resulted from intravenous dextrose infusion in healthy volunteers (10 +/- 0.8 vs. 4.8 +/- 0.3%, P < 0.01) but failed to do so when hyperglycemia resulted from insulin deficiency in IDDM. We conclude that 1) the contribution of glucose to the estimated rate of glutamine de novo synthesis does not increase when elevation of plasma glucose results from insulin deficiency, and 2) the transfer of carbon from glucose to glutamine may depend on insulin availability.     

Oxidation rate of exogenous carbohydrate during exercise is higher in boys than in men.

To determine whether the relative utilization of exogenous carbohydrate (CHO(exo)) differs between children and adults, substrate utilization during 60 min of cycling at 70% peak O(2) uptake was studied in 12 pre- and early pubertal boys (9.8 +/- 0.1 yr) and 10 men (22.1 +/- 0.5 yr) on two occasions. Subjects consumed either a placebo or a (13)C-enriched 6% CHO(exo) beverage (total volume per trial: 24 ml/kg). Substrate utilization was calculated for the final 30 min of exercise. During both trials, total fat oxidation was higher (5.4 +/- 0.5 vs. 3.0 +/- 0.4 mg x kg(-1) x min(-1), P < 0.001) and total CHO oxidation lower (27.4 +/- 1.5 vs. 34.8 +/- 1.2 mg x kg(-1) x min(-1), P < 0.001) in boys than in men, respectively. During the CHO(exo) trial, CHO(exo) oxidation was higher (P < 0.001) in boys (8.8 +/- 0.5 mg x kg(-1) x min(-1)) than in men (6.2 +/- 0.5 mg x kg(-1) x min(-1)) and provided a greater (P < 0.001) relative proportion of total energy in boys (21.8 +/- 1.4%) than in men (14.6 +/- 0.9%). These results suggest that, although endogenous CHO utilization during exercise is lower, the relative oxidation of ingested CHO is considerably higher in boys than in men. The greater reliance on CHO(exo) in boys may be important in preserving endogenous fuels and may be related to pubertal status.     

Caffeine increases exogenous carbohydrate oxidation during exercise.

Both carbohydrate (CHO) and caffeine have been used as ergogenic aids during exercise. It has been suggested that caffeine increases intestinal glucose absorption, but there are also suggestions that it may decrease muscle glucose uptake. The purpose of the study was to investigate the effect of caffeine on exogenous CHO oxidation. In a randomized crossover design, eight male cyclists (age 27 +/- 2 yr, body mass 71.2 +/- 2.3 kg, maximal oxygen uptake 65.7 +/- 2.2 ml x kg(-1) x min(-1)) exercised at 64 +/- 3% of maximal oxygen uptake for 120 min on three occasions. During exercise subjects ingested either a 5.8% glucose solution (Glu; 48 g/h), glucose with caffeine (Glu+Caf, 48 g/h + 5 mg x kg(-1) x h(-1)), or plain water (Wat). The glucose solution contained trace amounts of [U-13C]glucose so that exogenous CHO oxidation could be calculated. CHO and fat oxidation were measured by indirect calorimetry, and 13C appearance in the expired gases was measured by continuous-flow IRMS. Average exogenous CHO oxidation over the 90- to 120-min period was 26% higher (P < 0.05) in Glu+Caf (0.72 +/- 0.04 g/min) compared with Glu (0.57 +/- 0.04 g/min). Total CHO oxidation rates were higher (P < 0.05) in the CHO ingestion trials compared with Wat, but they were highest when Glu+Caf was ingested (1.21 +/- 0.37, 1.84 +/- 0.14, and 2.47 +/- 0.23 g/min for Wat, Glu, and Glu+Caf, respectively; P < 0.05). There was also a trend (P = 0.082) toward an increased endogenous CHO oxidation with Glu+Caf (1.81 +/- 0.22 g/min vs. 1.27 +/- 0.13 g/min for Glu and 1.12 +/- 0.37 g/min for Wat). In conclusion, compared with glucose alone, 5 mg x kg(-1) x h(-1) of caffeine coingested with glucose increases exogenous CHO oxidation, possibly as a result of an enhanced intestinal absorption.     

Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat.

Exercise improves glucose metabolism and delays the onset and/or reverses insulin resistance in the elderly by an unknown mechanism. In the present study, we examined the effects of exercise training on glucose metabolism, abdominal adiposity, and adipocytokines in obese elderly. Sixteen obese men and women (age = 63 +/- 1 yr, body mass index = 33.2 +/- 1.4 kg/m2) participated in a 12-wk supervised exercise program (5 days/wk, 60 min/day, treadmill/cycle ergometry at 85% of heart rate maximum). Visceral fat (VF), subcutaneous fat, and total abdominal fat were measured by computed tomography. Fat mass and fat-free mass were assessed by hydrostatic weighing. An oral glucose tolerance test was used to determine changes in insulin resistance. Exercise training increased maximal oxygen consumption (21.3 +/- 0.8 vs. 24.3 +/- 1.0 ml.kg(-1).min(-1), P < 0.0001), decreased body weight (P < 0.0001) and fat mass (P < 0.001), while fat-free mass was not altered (P > 0.05). VF (176 +/- 20 vs. 136 +/- 17 cm2, P < 0.0001), subcutaneous fat (351 +/- 34 vs. 305 +/- 28 cm2, P < 0.03), and total abdominal fat (525 +/- 40 vs. 443 +/- 34 cm2, P < 0.003) were reduced through training. Circulating leptin was lower (P < 0.003) after training, but total adiponectin and tumor necrosis factor-alpha remained unchanged. Insulin resistance was reversed by exercise (40.1 +/- 7.7 vs. 27.6 +/- 5.6 units, P < 0.01) and correlated with changes in VF (r = 0.66, P < 0.01) and maximal oxygen consumption (r = -0.48, P < 0.05) but not adipocytokines. VF loss after aerobic exercise training improves glucose metabolism and is associated with the reversal of insulin resistance in older obese men and women.     

Oxidation of exogenous glucose, sucrose, and maltose during prolonged cycling exercise.

The purpose of the present study was to investigate whether combined ingestion of two carbohydrates (CHO) that are absorbed by different intestinal transport mechanisms would lead to exogenous CHO oxidation rates of >1.0 g/min. Nine trained male cyclists (maximal O(2) consumption: 64 +/- 2 ml x kg body wt(-1) x min(-1)) performed four exercise trials, which were randomly assigned and separated by at least 1 wk. Each trial consisted of 150 min of cycling at 50% of maximal power output (60 +/- 1% maximal O(2) consumption), while subjects received a solution providing either 1.8 g/min of glucose (Glu), 1.2 g/min of glucose + 0.6 g/min of sucrose (Glu+Suc), 1.2 g/min of glucose + 0.6 g/min of maltose (Glu+Mal), or water. Peak exogenous CHO oxidation rates were significantly higher (P < 0.05) in the Glu+Suc trial (1.25 +/- 0.07 g/min) compared with the Glu and Glu+Mal trials (1.06 +/- 0.08 and 1.06 +/- 0.06 g/min, respectively). No difference was found in (peak) exogenous CHO oxidation rates between Glu and Glu+Mal. These results demonstrate that, when a mixture of glucose and sucrose is ingested at high rates (1.8 g/min) during cycling exercise, exogenous CHO oxidation rates reach peak values of approximately 1.25 g/min.     

Estimations of muscle interstitial insulin, glucose, and lactate in type 2 diabetic subjects

Previous measurement of insulin in human muscle has shown that interstitial muscle insulin and glucose concentrations are approximately 30-50% lower than in plasma during hyperinsulinemia in normal subjects. The aims of this study were to measure interstitial muscle insulin and glucose in patients with type 2 diabetes to evaluate whether transcapillary transport is part of the peripheral insulin resistance. Ten patients with type 2 diabetes and ten healthy controls matched for sex, age, and body mass index were investigated. Plasma and interstitial insulin, glucose, and lactate (measured by intramuscular in situ-calibrated microdialysis) in the medial quadriceps femoris muscle were analyzed during a hyperinsulinemic euglycemic clamp. Blood flow in the contralateral calf was measured by vein plethysmography. At steady-state clamping, at 60-120 min, the interstitial insulin concentration was significantly lower than arterial insulin in both groups (409 +/- 86 vs. 1,071 +/- 99 pmol/l, P < 0.05, in controls and 584 +/- 165 vs. 1, 253 +/- 82 pmol/l, P < 0.05, in diabetic subjects, respectively). Interstitial insulin concentrations did not differ significantly between diabetic subjects and controls. Leg blood flow was significantly higher in controls (8.1 +/- 1.2 vs. 4.4 +/- 0.7 ml. 100 g(-1).min(-1) in diabetics, P < 0.05). Calculated glucose uptake was less in diabetic patients compared with controls (7.0 +/- 1.2 vs. 10.8 +/- 1.2 micromol. 100 g(-1).min(-1), P < 0.05, respectively). Arterial and interstitial lactate concentrations were both higher in the control group (1.7 +/- 0.1 vs. 1.2 +/- 0.1, P < 0. 01, and 1.8 +/- 0.1 vs. 1.2 +/- 0.2 mmol/l, P < 0.05, in controls and diabetics, respectively). We conclude that, during hyperinsulinemia, muscle interstitial insulin and glucose concentrations did not differ between patients with type 2 diabetes and healthy controls despite a significantly lower leg blood flow in diabetic subjects. It is suggested that decreased glucose uptake in type 2 diabetes is caused by insulin resistance at the cellular level rather than by a deficient access of insulin and glucose surrounding the muscle cell.     

Glucose uptake by adipocytes of obese rats: effect of one bout of acute exercise.

The effect of one bout of acute exercise on impaired glucose metabolism was studied in obese (480 +/- 20 g), untrained rats, at rest (n = 10) and after 60 min of swimming (n = 5). Using the euglycemic, hyperinsulinemic (10 mU.kg-1 x min-1) clamp, glucose clearance rate increased from 7.6 +/- 0.9 at rest to 9.7 +/- 0.5 mL.kg-1 x min-1 after exercise (p < 0.05). Glucose (3-O-[14C]methylglucose) transport (GT) into epididymal adipocytes were incubated with or without insulin. In the absence of insulin, GT was 0.13 +/- 0.02 and 0.26 +/- 0.07 fmol.cell-1 x min-1 at rest and after exercise, respectively. In the presence of insulin (25-1000 microU.mL-1) GT increased at rest from 0.97 +/- 0.08 to 1.13 +/- 0.07 fmol.cell-1 x min-1, and after exercise from 1.35 +/- 0.05 to 1.87 +/- 0.11 fmol.cell-1 x min-1. GT was significantly higher after exercise compared with rest (p < 0.004). At rest, maximal insulin effect was achieved at 100 microU.mL-1, whereas with exercise, GT increased gradually with the insulin dosage. The following may be concluded: (i) the biological effect of insulin is amplified in obese rats by one bout of exercise and (ii) exercise affects GT into enlarged adipocytes by enhancing tissue responsiveness to insulin and by a cellular mechanism unrelated to the insulin action.     

Subsensitivity to insulin in adipocytes from rats submitted to foot-shock stress

We examined the effect of three daily foot-shock stress sessions on glucose homeostasis, insulin secretion by isolated pancreatic islets, insulin sensitivity of white adipocytes, and glycogen stores in the liver and soleus muscle of rats. Stressed rats had plasma glucose (128.3 +/- 22.9 mg/dL) and insulin (1.09 +/- 0.33 ng/mL) levels higher than the controls (glucose, 73.8 +/- 3.5 mg/dL; insulin, 0.53 +/- 0.11 ng/mL, ANOVA plus Fisher's test; p < 0.05). After a glucose overload, the plasma glucose, but not insulin, levels remained higher (area under the curve 8.19 +/- 1.03 vs. 4.84 +/- 1.33 g/dL 30 min and 102.7 +/- 12.2 vs. 93.2 +/- 16.1 ng/mL 30 min, respectively). Although, the area under the insulin curve was higher in stressed (72.8 +/- 9.8 ng/mL) rats than in control rats (34.9 +/- 6.9 ng/mL) in the initial 10 min after glucose overload. The insulin release stimulated by glucose in pancreatic islets was not modified after stress. Adipocytes basal lipolysis was higher (stressed, 1.03 +/- 0.14; control, 0.69 +/- 0.11 micromol of glycerol in 60 min/100 mg of total lipids) but maximal lipolysis stimulated by norepinephrine was not different (stressed, 1.82 +/- 0.35; control, 1.46 +/- 0.09 micromol of glycerol in 60 min/100 mg of total lipids) after stress. Insulin dose-dependently inhibited the lipolytic response to norepinephrine by up to 35% in adipocytes from control rats but had no effect on adipocytes from stressed rats. The liver glycogen content was unaltered by stress, but was lower in soleus muscle from stressed rats than in control rats (0.45 +/- 0.04 vs. 0.35 +/- 0.04 mg/100 mg of wet tissue). These results suggest that rats submitted to foot-shock stress develop hyperglycemia along with hyperinsulinemia as a consequence of insulin subsensitivity in adipose tissue, with no alteration in the pancreatic sensitivity to glucose. Foot-shock stress may therefore provide a useful short-term model of insulin subsensitivity.     

Oxidation of a glucose polymer during exercise: comparison with glucose and fructose

The purpose of this study was to compare the oxidation of 13C-labeled glucose, fructose, and glucose polymer ingested (1.33 g.kg-1 in 19 ml.kg-1 water) during cycle exercise (120 min, 53 +/- 2% maximal O2 uptake) in six healthy male subjects. Oxidation of exogenous glucose and glucose polymer (72 +/- 15 and 65 +/- 18%, respectively, of the 98.9 +/- 4.7 g ingested) was similar and significantly greater than exogenous fructose oxidation (54 +/- 13%). A transient rise in plasma glucose concentration was observed with glucose ingestion only. However, plasma insulin levels were similar with glucose and glucose polymer ingestions and significantly higher than with water or fructose ingestion. Plasma free fatty acid and glycerol responses to exercise were blunted with carbohydrate ingestion. However, fat utilization was not significantly different with water (82 +/- 14 g), glucose (60 +/- 3 g), fructose (59 +/- 11 g), or glucose polymer ingestion (60 +/- 8 g). Endogenous carbohydrate utilization was significantly lower with glucose (184 +/- 22 g), glucose polymer (187 +/- 31 g), and fructose (211 +/- 18 g) than with water (239 +/- 30 g) ingestion. Plasma volume slightly increased with water ingestion (7.4 +/- 4.5%), but the decrease was similar with glucose (-7.6 +/- 5.1%) and glucose polymer (-8.2 +/- 4.6%), suggesting that the rate of water delivery to plasma was similar with the two carbohydrates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes

Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Energy substrate utilization during prolonged exercise with and without carbohydrate intake in preadolescent and adolescent girls.

Little information is available on energy metabolism during exercise in girls, particularly the contribution of exogenous carbohydrate (CHO(exo)). The purpose of this study was to determine substrate utilization during exercise with and without CHO(exo) intake in healthy girls. Twelve-yr-old preadolescent (YG; n = 12) and 14-yr-old adolescent (OG; n = 10) girls consumed flavored water (WT) or (13)C-enriched 6% CHO (CT) while cycling for 60 min at approximately 70% maximal aerobic power (Vo(2max)). Substrate utilization was calculated for the final 15 min of exercise. CHO(exo) decreased fat oxidation by approximately 50% in YG but not in OG (P < 0.001) and decreased endogenous CHO oxidation by approximately 15% in OG but not in YG (P = 0.006). Endogenous CHO oxidation was lower in YG than in OG regardless of trial (P < or = 0.01), whereas fat oxidation was higher in YG only during WT (P < 0.001). CHO(exo) oxidation rate was similar between YG and OG (7.1 +/- 0.5 and 6.8 +/- 0.4 mg.kg(-1).min(-1), respectively, P = 0.67), contributing approximately 19% to total energy expenditure. Serum estradiol levels in all girls correlated with fat (r = -0.50 to -0.59, P = 0.03 to 0.005) and endogenous CHO oxidation (r = 0.50 to 0.63, P = 0.03 to 0.005) but not with CHO(exo) oxidation (r = -0.09, P = 0.71). We conclude that CHO(exo) influences endogenous substrate utilization in an age-dependent manner in healthy girls but that total CHO(exo) oxidation during exercise is not different between YG and OG. Our results also point to potential sex-related differences in energy substrate utilization even during childhood.     

Oxidation of combined ingestion of glucose and fructose during exercise.

The purpose of the present study was to examine whether combined ingestion of a large amount of fructose and glucose during cycling exercise would lead to exogenous carbohydrate oxidation rates >1 g/min. Eight trained cyclists (maximal O(2) consumption: 62 +/- 3 ml x kg(-1) x min(-1)) performed four exercise trials in random order. Each trial consisted of 120 min of cycling at 50% maximum power output (63 +/- 2% maximal O(2) consumption), while subjects received a solution providing either 1.2 g/min of glucose (Med-Glu), 1.8 g/min of glucose (High-Glu), 0.6 g/min of fructose + 1.2 g/min of glucose (Fruc+Glu), or water. The ingested fructose was labeled with [U-(13)C]fructose, and the ingested glucose was labeled with [U-(14)C]glucose. Peak exogenous carbohydrate oxidation rates were approximately 55% higher (P < 0.001) in Fruc+Glu (1.26 +/- 0.07 g/min) compared with Med-Glu and High-Glu (0.80 +/- 0.04 and 0.83 +/- 0.05 g/min, respectively). Furthermore, the average exogenous carbohydrate oxidation rates over the 60- to 120-min exercise period were higher (P < 0.001) in Fruc+Glu compared with Med-Glu and High-Glu (1.16 +/- 0.06, 0.75 +/- 0.04, and 0.75 +/- 0.04 g/min, respectively). There was a trend toward a lower endogenous carbohydrate oxidation in Fruc+Glu compared with the other two carbohydrate trials, but this failed to reach statistical significance (P = 0.075). The present results demonstrate that, when fructose and glucose are ingested simultaneously at high rates during cycling exercise, exogenous carbohydrate oxidation rates can reach peak values of approximately 1.3 g/min.     

Enhancement of beta-cell sensitivity to glucose by oral fat load.

Recent studies have demonstrated that 6 h infusions of lipid emulsion enhance insulin release, whereas 24 h infusions inhibit insulin secretion. How insulin release is modulated after oral fat loading has not yet been elucidated. 17 healthy fasting volunteers were subjected to 3 experiments in random order: test 1 was a frequently sampled i. v. glucose tolerance test (FSIVGTT, 0.3 g/kg glucose), test 2 began with the ingestion of 50 % sunflower oil (1.5 g/kg) followed by FSIVGTT 4 h later. Test 3 was identical to test 2 with i. v. addition of 100 U/kg heparin prior to FSIVGTT. Glucose and insulin data were analyzed by minimal model assumptions - glucose sensitivity of the beta-cells (Theta1), acute insulin response (AIR) (10 min), 3 h insulin release (Theta2), glucose threshold of insulin secretion (h), insulin degradation rate (n), peripheral insulin sensitivity (S(I)), and glucose-dependent glucose disposal (S(G)). After drinking the fat emulsion, FFAs increased to 0.8 +/- 0.3 mmol/l (test 2) and to 3.0 +/- 0.3 mmol/l (test 3). Moderately increased FFA concentrations were associated with elevation of Theta1 (test 1, control 335 +/- 157 vs. test 2: 859 +/- 612 pM x min x mM(-1), p = 0.030). At high plasma FFA levels and in the presence of heparin (test 3), Theta1 was reduced compared to test 2 and unchanged compared to test 1. Theta2 and h were elevated in both tests 2 and 3 compared to test 1. No changes of n, S(I) and S(G) were found. In conclusion, the ingestion of sunflower oil triglyceride emulsion resulted in a 60 % increase in plasma free fatty acids and enhanced the capacity of beta-cells to secrete insulin. Heparin-induced high levels of FFA further augmented the total insulin release and inhibited parameters of glucose responsiveness.     

Small weight gain is not associated with development of insulin resistance in healthy, physically active individuals.

We investigated whether weight gain alters insulin sensitivity and leptin levels in physically active individuals. Six (5 males and 1 female; age 26.6+/-1.0 years; BMI 21.5+/-0.9, body fat 17.4+/-2.2%) healthy individuals were enrolled in an overfeeding study (caloric surplus 22.5-26.5 kcal/kg/day) to achieve up to 10% weight gain over 4-6 week period with subsequent weight maintenance over additional 2 weeks. The participants were requested to maintain their previous physical activity which in all of them included 45-60 min training sessions at the gym 2-3 times/week. RESULTS: BMI increased to 23.4+/-0.9 (4.4 kg weight gain; p<0.05) and body fat to 21.0+/-2.8% (p < 0.05) over the period of active weight gain and remained stable over the two week period of weight maintenance; fasting plasma glucose and serum insulin remained unchanged; serum leptin nearly doubled (3.8+/-1.0 vs 6.4+/-1.9 ng/ mL; p < 0.05); insulin sensitivity, when expressed per kg of the total body (11.1+/-1.6 vs 12.4+/-2.1 mg/kg/min; p = NS), and lean body mass (13.4+/-1.9 vs 15.7+/-2.6 mg/kgLBM/min; p = NS), did not decrease after weight gain. On the contrary, insulin action had improved in 5 out of 6 individuals. In conclusion, the data presented in this preliminary report indicate that a small weight gain due to overfeeding in lean, healthy, physically active individuals is associated with rise in circulating leptin levels but not with worsening of insulin action.     

Glucose clearance in aged trained skeletal muscle during maximal insulin with superimposed exercise.

Insulin and muscle contractions are major stimuli for glucose uptake in skeletal muscle and have in young healthy people been shown to be additive. We studied the effect of superimposed exercise during a maximal insulin stimulus on glucose uptake and clearance in trained (T) (1-legged bicycle training, 30 min/day, 6 days/wk for 10 wk at approximately 70% of maximal O(2) uptake) and untrained (UT) legs of healthy men (H) [n = 6, age 60 +/- 2 (SE) yr] and patients with Type 2 diabetes mellitus (DM) (n = 4, age 56 +/- 3 yr) during a hyperinsulinemic ( approximately 16,000 pmol/l), isoglycemic clamp with a final 30 min of superimposed two-legged exercise at 70% of individual maximal heart rate. With superimposed exercise, leg glucose extraction decreased (P < 0.05), and leg blood flow and leg glucose clearance increased (P < 0.05), compared with hyperinsulinemia alone. During exercise, leg blood flow was similar in both groups of subjects and between T and UT legs, whereas glucose extraction was always higher (P < 0.05) in T compared with UT legs (15.8 +/- 1.2 vs. 14.6 +/- 1.8 and 11.9 +/- 0.8 vs. 8.8 +/- 1.8% for H and DM, respectively) and leg glucose clearance was higher in T (H: 73 +/- 8, DM: 70 +/- 10 ml. min(-1). kg leg(-1)) compared with UT (H: 63 +/- 8, DM: 45 +/- 7 ml. min(-1). kg leg(-1)) but not different between groups (P > 0.05). From these results it can be concluded that, in both diabetic and healthy aged muscle, exercise adds to a maximally insulin-stimulated glucose clearance and that glucose extraction and clearance are both enhanced by training.     

beta-3 adrenergic agonist restores skeletal muscle insulin responsiveness in Sprague-Dawley rats.

Between 7 and 14 weeks of age, male Sprague-Dawley rats develop a greater than 50% loss in insulin-stimulated glucose transport in skeletal muscle. We treated rats aged 14 weeks with the beta-3 adrenergic agonist CL316,243 (1 mg/kg/day by minipump for 14 days). Treatment resulted in a 56% reduction in visceral fat (P < 0.05). Muscle mass and body weight were unchanged. In strips of soleus muscle isolated from rats treated with CL316,243, basal transport of [(3)H]-2-deoxyglucose (2-DOG) was unchanged (105.8 +/- 7.5 nmol/g/min for vehicle vs 122.0 +/- 8.7 for CL316,243). However, in rats treated with CL316,243, the increase in 2-DOG transport in response to a maximal concentration of insulin was substantially increased (55.5 +/- 13.1 nmol/g/min for vehicle vs 102.4 +/- 13.5 for CL316,243, P < 0.03). CL 316,243 caused no significant changes in fasting glucose, insulin, or free fatty acids. Treatment of soleus muscle strips in vitro with CL316,243 (either 0.1 nM or 1.0 nM for 120 min at 37 degrees C) had no effect either on basal 2-DOG transport or on insulin-stimulated transport. We conclude that the CL316,243 causes a reduction in visceral fat and a reversal of muscle insulin resistance. The effect CL 316,243 on muscle insulin responses appears to be indirect, as it did not occur in vitro.     

Increased submaximal insulin-stimulated glucose uptake in mouse skeletal muscle after treadmill exercise.

The primary purpose of this study was to determine the effect of prior exercise on insulin-stimulated glucose uptake with physiological insulin in isolated muscles of mice. Male C57BL/6 mice completed a 60-min treadmill exercise protocol or were sedentary. Paired epitrochlearis, soleus, and extensor digitorum longus (EDL) muscles were incubated with [3H]-2-deoxyglucose without or with insulin (60 microU/ml) to measure glucose uptake. Insulin-stimulated glucose uptake for paired muscles was calculated by subtracting glucose uptake without insulin from glucose uptake with insulin. Muscles from other mice were assessed for glycogen and AMPK Thr172 phosphorylation. Exercised vs. sedentary mice had decreased glycogen in epitrochlearis (48%, P < 0.001), soleus (51%, P < 0.001), and EDL (41%, P < 0.01) and increased AMPK Thr172 phosphorylation (P < 0.05) in epitrochlearis (1.7-fold), soleus (2.0-fold), and EDL (1.4-fold). Insulin-independent glucose uptake was increased 30 min postexercise vs. sedentary in the epitrochlearis (1.2-fold, P < 0.001), soleus (1.4-fold, P < 0.05), and EDL (1.3-fold, P < 0.01). Insulin-stimulated glucose uptake was increased (P < 0.05) approximately 85 min after exercise in the epitrochlearis (sedentary: 0.266 +/- 0.045 micromol x g(-1) x 15 min(-1); exercised: 0.414 +/- 0.051) and soleus (sedentary: 0.102 +/- 0.049; exercised: 0.347 +/- 0.098) but not in the EDL. Akt Ser473 and Akt Thr308 phosphorylation for insulin-stimulated muscles did not differ in exercised vs. sedentary. These results demonstrate enhanced submaximal insulin-stimulated glucose uptake in the epitrochlearis and soleus of mice 85 min postexercise and suggest that it will be feasible to probe the mechanism of enhanced postexercise insulin sensitivity by using genetically modified mice.     

Enzymatic regulation of glucose disposal in human skeletal muscle after a high-fat, low-carbohydrate diet.

Whole body glucose disposal and skeletal muscle hexokinase, glycogen synthase (GS), pyruvate dehydrogenase (PDH), and PDH kinase (PDK) activities were measured in aerobically trained men after a standardized control diet (Con; 51% carbohydrate, 29% fat, and 20% protein of total energy intake) and a 56-h eucaloric, high-fat, low-carbohydrate diet (HF/LC; 5% carbohydrate, 73% fat, and 22% protein). An oral glucose tolerance test (OGTT; 1 g/kg) was administered after the Con and HF/LC diets with vastus lateralis muscle biopsies sampled pre-OGTT and 75 min after ingestion of the oral glucose load. The 90-min area under the blood glucose and plasma insulin concentration vs. time curves increased by 2-fold and 1.25-fold, respectively, after the HF/LC diet. The pre-OGTT fraction of GS in its active form and the maximal activity of hexokinase were not affected by the HF/LC diet. However, the HF/LC diet increased PDK activity (0.19 +/- 0.05 vs. 0.08 +/- 0.02 min(-1)) and decreased PDH activation (0.38 +/- 0.08 vs. 0.79 +/- 0.10 mmol acetyl-CoA.kg wet muscle(-1).min(-1)) before the OGTT vs. Con. During the OGTT, GS and PDH activation increased by the same magnitude in both diets, such that PDH activation remained lower during the HF/LC OGTT (0.60 +/- 0.11 vs. 1.04 +/- 0.09 mmol acetyl-CoA.kg(-1).min(-1)). These data demonstrate that the decreased glucose disposal during the OGTT after the 56-h HF/LC diet was in part related to decreased oxidative carbohydrate disposal in skeletal muscle and not to decreased glycogen storage. The rapid increase in PDK activity during the HF/LC diet appeared to account for the reduced potential for oxidative carbohydrate disposal.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Substrate utilization during exercise with glucose and glucose plus fructose ingestion in boys ages 10--14 yr.

We measured substrate utilization during exercise performed with water (W), exogenous glucose (G), and exogenous fructose plus glucose (FG) ingestion in boys age 10-14 yr. Subjects (n = 12) cycled for 90 min at 55% maximal O(2) uptake while ingesting either W (25 ml/kg), 6% G (1.5 g/kg), or 3% F plus 3% G (1.5 g/kg). Fat oxidation increased during exercise in all trials but was higher in the W (0.28 +/- 0.023 g/min) than in the G (0.24 +/- 0.023 g/min) and FG (0.25 +/- 0.029 g/min) trials (P = 0.04). Conversely, total carbohydrate (CHO) oxidation decreased in all trials and was lower in the W (0.63 +/- 0.05 g/min) than in the G (0.78 +/- 0.051 g/min) and FG (0.74 +/- 0.056 g/min) trials (P = 0.009). Exogenous CHO oxidation, as determined by expired (13)CO(2), reached a maximum of 0.36 +/- 0.032 and 0.31 +/- 0.030 g/min at 90 min in G and FG, respectively (P = 0.04). Plasma insulin levels decrease during exercise in all trials but were twofold higher in G than in W and FG (P < 0.001). Plasma glucose levels decreased transiently after the onset of exercise in all trials and then returned to preexercise values in the W and FG (approximately 4.5 mmol/l) trials but were elevated by approximately 1.0 mmol/l in the G trial (P < 0.001). Plasma lactate concentrations decreased after the onset of exercise in all trials but were lower by approximately 0.5 mmol/l in W than in G and FG (P = 0.02). Thus, in boys exercising at a moderate intensity, the oxidation rate of G plus F is slightly less than G alone, but both spare endogenous CHO and fat to a similar extent. In addition, compared with flavored W, the ingestion of G alone and of G plus F delays exhaustion at 90% peak power by approximately 25 and 40%, respectively, after 90 min of moderate-intensity exercise.