Carbohydrate metabolism during exercise in females: effect of reduced fat availability

This study examined the effect of reduced plasma free fatty acid (FFA) availability on carbohydrate metabolism during exercise. Six untrained women cycled for 60 minutes at approximately 58% of maximum oxygen uptake after ingestion of a placebo (CON) or nicotinic acid (NA), 30 minutes before exercise (7.4 +/- 0.5 mg.kg(-1) body weight), and at 0 minutes (3.7 +/- 0.3 mg.kg(-1)) and 30 minutes (3.7 +/- 0.3 mg.kg(-1)) of exercise. Glucose kinetics were measured using a primed, continuous infusion of [6,6-(2)H] glucose. Plasma FFA (CON, 0.86 +/- 0.12; NA, 0.21 +/- 0.11 mmol.L(-1) at 60 minutes, P <.05) and glycerol (CON, 0.34 +/- 0.05; NA, 0.10 +/- 0.04 mmol.L(-1) at 60 minutes, P <.05) were suppressed throughout exercise. Mean respiratory exchange ratio (RER) during exercise was higher (P <.05) in NA (0.89 +/- 0.02) than CON (0.83 +/- 0.02). Plasma glucose and glucose production were similar between trials. Total glucose uptake during exercise was greater (P <.05) in NA (1,876 +/- 161 micromol.kg(-1)) than in CON (1,525 +/- 107 micromol.kg(-1)). Total fat oxidation was reduced (P <.05) by approximately 32% during exercise in NA. Total carbohydrate oxidized was approximately 42% greater (P <.05) in NA (412 +/- 40 mmol) than CON (290 +/- 37 mmol), of which, approximately 16% (20 +/- 10 mmol) could be attributed to glucose. Plasma insulin and glucagon were similar between trials. Catecholamines were higher (P <.05) during exercise in NA. In summary, during prolonged moderate exercise in untrained women, reduced FFA availability results in a compensatory increase in carbohydrate oxidation, which appears to be due predominantly to an increase in glycogen utilization, although there was a small, but significant, increase in whole body glucose uptake.     

Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man

Insulin is normally secreted in man in regular pulses every 5 to 15 minutes. Disordered pulsation has been demonstrated in several insulin-resistant states and it is unclear whether this represents a primary beta-cell defect contributing to impairment of peripheral insulin action or rather is a consequence of insulin resistance. Basal or near basal insulin administration by pulsatile infusion augments hypoglycemic effect and improves insulin-mediated glucose uptake compared with insulin by continuous infusion. To date no study has examined whether normal basal insulin pulsatility is required to preserve subsequent insulin sensitivity during hyperinsulinemia. We studied the effect of overnight pulsatile versus continuous basal insulin on a subsequent hyperinsulinemic euglycemic clamp. Nineteen normal volunteers (male:female ratio, 17:2; mean age +/- SEM, 26.1 +/- 2.3 years) were studied on 2 occasions each. Endogenous insulin secretion was inhibited by octreotide (0.43 microg kg(-1). h(-1)) and replaced overnight at 5.4 mU kg(-1). h(-1) either by continuous infusion or in 2-minute pulses every 13 minutes (n = 10) or every 7 minutes (n = 9). Glucagon was replaced at physiological concentration by continuous infusion (30 ng. kg(-1). h(-1)). Venous plasma glucose overnight was not significantly different between the pulsatile and continuous protocols. After discontinuing the overnight insulin infusion, insulin action was assessed during a hyperinsulinemic euglycemic clamp (1 mU kg(-1). h(-1)). Glucose infusion rates at steady-state during the hyperinsulinemic clamp were similar between continuous and both frequencies of pulsatile infusion (continuous 44.6 +/- 4.3 micromol. kg(-1). min(-1) v 13-minute pulsatile 41.7 +/- 5.9 micromol. kg(-1). min(-1), P =.27; continuous 34.6 +/- 2.5 micromol. kg(-1) min(-1) v 7-minute pulsatile 41.4 +/- 3.2 micromol. kg(-1). min(-1), P =.08). We conclude that overnight pulsatile compared with continuous insulin administration has no different effect on subsequent peripheral insulin-mediated glucose uptake. A priming effect cannot therefore explain the previously demonstrated association between endogenous insulin pulse frequency and peripheral insulin action.     

Important role of the hepatic vagus nerve in glucose uptake and production by the liver

We examined the role of the hepatic vagus nerve in hepatic and peripheral glucose metabolism. To assess endogenous glucose production (EGP), hepatic uptake of first-pass glucose infused intraportally (HGU), and the metabolic clearance rate of glucose (MCR), rats were subjected to hepatic vagotomy (HV, n = 7) or sham operation (SH, n = 8), after 10 days, they were then subjected to a euglycemic-hyperinsulinemic clamp together with a portal glucose load in the 24-hour fasting state. Metabolic parameters were determined by the dual-tracer method using stable isotopes. During the experiment, [6,6-2H2]glucose was continuously infused into the peripheral vein. To maintain euglycemia (4.5 mmol/L), insulin (54 pmol x kg(-1) x min(-1)) and glucose were infused peripherally after the 90-minute tracer equilibration and 30-minute basal periods, and glucose containing 5% enriched [U-13C]glucose was infused intraportally (50 micromol x kg(-1) x min(-1)) for 120 minutes (clamp period). EGP was significantly higher in HV rats versus SH rats during the basal period (64.3 +/- 7.6 v 43.6 +/- 5.3 micromol x kg(-1) x min(-1), P < .005)) and was comparable to EGP in SH rats during the clamp period (9.3 +/- 21.5 v 1.1 +/- 11.7 micromol x kg(-1) x min(-1)). HGU was reduced in HV rats compared with SH rats during portal glucose infusion (5.9 +/- 2.4 v 10.1 +/- 3.2 micromol x kg(-1) x min(-1)). The MCR in HV rats was significantly higher than in SH rats in the basal period (11.0 +/- 2.0 v 7.9 +/- 0.8 mL x kg(-1) x min(-1), P < .01)) and was comparable to the MCR in SH rats during the clamp period (41.9 +/- 10.0 and 36.6 +/- 5.7 mL x kg(-1) x min(-1)). We conclude that innervation of the hepatic vagus nerve is important for the regulation of hepatic glucose production in the postabsorptive state and HGU in the postprandial state.     

Regulation of splanchnic and renal substrate supply by insulin in humans

To determine the effects of peripheral insulin infusion on total, hepatic, and renal glucose production and on the percent contribution to glucose production of gluconeogenesis versus glycogenolysis, 10 healthy subjects had arterialized hand and hepatic vein catheterization after an overnight fast and the results were compared with data from 12 age- and weight-matched subjects with renal vein catheterization during a 180-minute infusion of either insulin (0.25 mU/kg x min) with dextrose, or saline. Endogenous, hepatic, and renal glucose production was measured with [6,6(-2)H2]glucose, regional lactate, alanine, and glycerol balance by arteriovenous difference; hepatic blood flow by indocyanine green clearance; and renal blood flow by p-aminohippurate clearance, before and every 30 minutes during each infusion period. Insulin increased from about 42 to 98 pmol/L and blood glucose remained constant in all studies (3.8 +/- 0.2 v4.4 +/- 0.1 micromol/ml, hepatic vrenal vein). In response to insulin infusion, endogenous, hepatic, and renal glucose production decreased immediately (30 minutes) and reached a lower plateau value (10.8 +/- 0.8 v6.4 +/- 0.7, 10.4 +/- 1.1 v7.8 +/- 1.0, and 2.8 +/- 0.6 v 1.5 +/- 0.6 micromol/kg x min, respectively) between 120 and 180 minutes (all P < .05). Net renal uptake of lactate (2.4 +/- 0.4 v0.9 +/- 0.6) decreased earlier (30 minutes) and returned to baseline between 120 and 180 minutes (2.4 +/- 0.5 micromol/kg x min), whereas net splanchnic uptake of lactate (5.7 +/- 0.7 v 0.7 +/- 0.6) and alanine (1.8 +/- 0.1 v 1.0 +/- 0.5 micromol/kg x min) decreased later (120 to 180 minutes). Net renal (0.3 +/- 0.1 v 0.1 +/- 0.1) and splanchnic (0.7 +/- 0.3 v 0.4 +/- 0.2 micromol/kg x min) glycerol uptake decreased 90 to 180 minutes after insulin and increased (P < .05) with saline infusion (0.4 +/- 0.1 v0.6 +/- 0.3 and 1.0 +/- 0.5 v1.8 +/- 0.4 micromol/kg x min, respectively). These data indicate that the rapid suppression of endogenous glucose production by insulin reflects primarily a decrease in hepatic glucose release, most likely due to inhibition of net glycogenolysis, combined with suppression of renal gluconeogenesis. Inhibition of hepatic gluconeogenesis presumably occurs later during hyperinsulinemia. We conclude that peripheral insulin, in addition to its inhibition of glycogen degradation, regulates endogenous glucose production, in part, by modifying the splanchnic and renal substrate supply.     

A single bout of brisk walking increases basal very low-density lipoprotein triacylglycerol clearance in young men

Very low-density lipoprotein triacylglycerol (VLDL-TG) turnover rate was evaluated in the morning, 12 hours after a single bout of brisk walking (90 minutes at approximately 60% of VO2max; EXE), compared to a resting control period (CON) in 10 recreationally active men. VLDL-TG fractional catabolic rate was calculated from the decay in isotopic enrichment after a bolus injection of [2H5]glycerol. Plasma VLDL-TG concentration was 24% lower in the morning after the EXE trial compared to control (0.47+/-0.04 and 0.36+/-0.04 mmol L(-1), for CON and EXE, respectively; P<.01). Serum insulin (7.4+/-0.7 and 5.6+/-0.4 mIU L(-1), CON and EXE, respectively; P<.05) and plasma glucose (5.6+/-0.1 and 5.4+/-0.1 mmol/L, CON and EXE, respectively; P<.05) concentrations were also significantly lower in the EXE trial. Insulin sensitivity (homeostasis model assessment [HOMA] index) was improved by 27% in EXE compared with the CON trial (P<.05).VLDL-apolipoprotein B-100 and plasma fatty acid concentrations were similar in the two trials. Hepatic VLDL-TG secretion rates were not significantly affected by exercise (13.1+/-1.2 and 13.2+/-1.6 micromol.min(-1) for the CON and EXE trials, respectively), whereas VLDL-TG clearance rate increased by 36% (28.1+/-1.3 and 38.1+/-3.5 mL.min(-1) for the CON and EXE trials, respectively; P<.05). It is concluded that the decrease in fasting plasma VLDL-TG concentration observed 12 hours after brisk walking is related mainly to increased VLDL-TG clearance from plasma.     

Use of an alpha-glucosidase inhibitor to maintain glucose homoeostasis during postprandial exercise in intensively treated Type 1 diabetic subjects.

AIM: We evaluated the effects of an alpha-glucosidase inhibitor, acarbose, on glucose homoeostasis during postprandial exercise in Type 1 diabetic subjects. METHODS: Seven Type 1 diabetic subjects with good glycaemic control on ultralente-regular insulin were randomized in a single blind cross-over study to acarbose 100 mg or placebo taken with a mixed meal (600 kcal, 75 g carbohydrates), followed 90 min later by 30 min of exercise at 50% maximum aerobic capacity. Glucose turnover was measured by tracer (d-[6,6,2H2]glucose) methodology, and intestinal glucose absorption was quantified using carbohydrate polymers labelled with [13C]glucose. RESULTS: Acarbose resulted in a significant decrease in the postprandial glycaemic rise (mean +/- SEM 2.9 +/- 0.6 vs. 5.0 +/- 0.7 mmol/l; P < 0.005) and in the glycaemic nadir during exercise (- 0.8 +/- 0.6 vs. 0.9 +/- 1.3 mmol/l below baseline; P < 0.05). Total glucose appearance increased similarly under the two treatments during the postprandial (27.0 vs. 27.9 micromol per kg per min) and exercise (33.9 vs. 33.5 micromol per kg per min) periods. Mean glucose absorption was significantly delayed by acarbose (7.8 vs. 10.2 micromol per kg per min; P < 0.02), but was compensated by the lack of postprandial suppression of hepatic glucose production (106% of basal hepatic glucose production vs. 81%; P < 0.006). Episodes of hypoglycaemia were no different (three vs. six). CONCLUSION: These results indicate that, in Type 1 diabetic subjects, acarbose results in a better glycaemic profile during postprandial exercise and suggest that it could lead to a lower risk of exercise-induced hypoglycaemia due to delayed glucose absorption and less suppression of hepatic glucose production.     

Norepinephrine infusion during moderate-intensity exercise increases glucose production and uptake

A role for the increase in circulating norepinephrine (NE) during intense exercise [IE; > or = 80% maximum O(2) uptake (VO(2max))] in the marked increment in glucose rate of production (Ra) during IE is hypothesized. Seven fit male subjects (27 +/- 2 yr old; body mass index, 23 +/- 1 kg/m(2); VO(2max), 63 +/- 5 mL/kg.min) underwent 40 min of postabsorptive moderate-intensity (53% VO(2max)) cycle ergometer exercise (126 +/- 14 W), once without [control (CON)] and once with NE infusion (0.1 microg/kg.min) from 30-40 min (NE). With infusion, plasma NE reached 15.9 +/- 1.0 nM (8-fold rest, 2-fold CON). Ra doubled to 4.40 +/- 0.44 in CON, but rose to 7.55 +/- 0.68 mg/kg.min with NE infusion (P = 0.003). Ra correlated strongly (r(2) = 0.92, P < 0.02) with plasma NE during and immediately after infusion. With NE infusion, peak glucose uptake [rate of disappearance (Rd), 6.57 +/- 0.59 vs. 4.53 +/- 0.55 mg/kg.min, P < 0.02] and glucose metabolic clearance rate (P < 0.05) were higher than in CON. Glycemia rose minimally during the NE infusion but did not differ between groups at any time during exercise. Glucagon-to-insulin ratio increased minimally, and epinephrine increased approximately 2.5- to 3-fold at peak but did not differ between groups. Thus, NE infusion during moderate exercise led to increments in Ra and Rd in fit individuals, supporting a possible contributory role for the increase of plasma NE in IE. NE effects on Rd and metabolic clearance rate during exercise may differ from its effects at rest.     

Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans

We evaluated insulin action in skeletal muscle (glucose disposal), liver (glucose production), and adipose tissue (lipolysis) in 5 extremely obese women with acanthosis nigricans (AN), who had normal oral glucose tolerance, and 5 healthy lean subjects, by using a 5-stage pancreatic clamp and stable isotopically labeled tracer infusion. Basal plasma insulin concentration was much greater in obese subjects with AN than lean subjects (54.8 +/- 4.5 vs 8.0 +/- 1.3 microU/mL, P < .001), but basal glucose and free fatty acid concentrations were similar in both groups. During stage 1 of the clamp, glucose rate of appearance (R(a)) (2.6 +/- 0.3 vs 3.7 +/- 0.3 micromol x kg FFM(-1) x min(-1), P = .02) and palmitate R(a) (2.4 +/- 0.6 vs 7.0 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < .05) were greater in obese subjects with AN than lean subjects despite slightly greater plasma insulin concentration in subjects with AN (3.0 +/- 0.7 vs 1.1 +/- 0.4 microU/mL, P < .05). The area under the curve for palmitate R(a) (1867 +/- 501 vs 663 +/- 75 micromol x kg FFM(-1) x 600 min(-1), P = .03) and glucose R(a) (1920 +/- 374 vs 1032 +/- 88 micromol x kg FFM(-1) x 600 min(-1), P = .02) during the entire clamp procedure was greater in subjects with AN than lean subjects. During intermediate insulin conditions (plasma insulin, approximately 35 microU/mL), palmitate R(a) was 5-fold greater in subjects with AN than in lean subjects (2.6 +/- 1.1 vs 0.5 +/- 0.2 micromol x kg FFM(-1) x min(-1), P = .05). Maximal glucose disposal was markedly lower in obese subjects with AN than in lean subjects (13.0 +/- 0.8 vs 23.4 +/- 1.8 mg x kg FFM(-1) x min(-1), P = .01) despite greater peak plasma insulin concentration (1842 +/- 254 vs 598 +/- 38 microU/mL, P < .05). These data demonstrate obese young adults with AN have marked insulin resistance in multiple tissues. However, marked insulin hypersecretion can compensate for impaired insulin action, resulting in normal glucose and fatty acid metabolism during basal conditions.     

Fat metabolism during high-intensity exercise in endurance-trained and untrained men

To determine whether trained individuals rely more on fat than untrained persons during high-intensity exercise, six endurance-trained men and six untrained men were studied during 30 minutes of exercise at 75% to 80% maximal oxygen consumption (VO2max). The rates of appearance (Ra) and disappearance (Rd) of glycerol and free fatty acids (FFAs) were determined using [1,1,2,3,3-2H]glycerol and [1-13C]palmitate, respectively, whereas the overall rate of fatty acid oxidation was determined using indirect calorimetry. During exercise, the whole-body rate of lipolysis (ie, glycerol Ra) was higher in the trained group (7.1 +/- 1.2 v 4.5 +/- 0.7 micromol x min(-1) x kg(-1), P < .05), as was the Ra (approximately Rd) of FFA (9.0 +/- 0.9 v 5.0 +/- 1.0 micromol x min(-1) x kg(-1), P < .001). FFA utilization was higher in trained subjects even when expressed as a percentage of total energy expenditure (10% +/- 1% v 7% +/- 1%, P < .05). However, this difference in plasma FFA flux could not account for all of the difference in fatty acid oxidation between trained and untrained subjects (20.8 +/- 3.3 v 7.9 +/- 1.6 micromol x min(-1) x kg(-1), or 23% +/- 3% v 13% +/- 2% of total energy expenditure, both P < .05). Thus, the oxidation of fatty acids derived from some other source also must have been greater in the trained men. We conclude that trained athletes use more fat than untrained individuals even during intense exercise performed at the same percentage of VO2max. The additional fatty acids appear to be derived from both adipose tissue and, presumably, intramuscular triglyceride stores.     

Effects of moderate and high glycemic index meals on metabolism and exercise performance.

The purpose of this study was to determine whether pre-exercise ingestion of meals with moderate and high glycemic indexes (GI) affects glucose availability during exercise and exercise performance time. Six male volunteers (22 +/- 1 years; 80.4 +/- 3.7 kg; VO(2peak), 54.3 +/- 1.2 ml. kg(-1). min(-1)) ingested 75 g of carbohydrate in the form of 2 different breakfast cereals, rolled oats (moderate GI, approximately 61; MOD-GI) or puffed rice (high GI, approximately 82; HI-GI), combined with 300 mL of water; or water alone (control). The trials were randomized, and the meals were ingested 45 minutes before the subjects performed cycling exercise (60% VO(2peak)) to exhaustion. Venous blood samples were drawn to measure glucose, free fatty acids (FFAs), glycerol, insulin (INS), epinephrine (EPI) and norepinephrine (NE) concentrations. A muscle biopsy specimen was obtained from the vastus lateralis before the meal and immediately after exercise for glycogen determination. Before exercise, both test meals elicited significant (P <.05) hyperglycemia and hyperinsulinemia compared with control. The glycemic response was higher (P <.05) at the start of exercise after the HI-GI meal than after the control. During exercise, plasma glucose levels were higher (P <.05) at 60 (5.2 +/- 0.1, 4.2 +/- 0.2, and 4.6 +/- 0.1 mmol. L(-1)) and 90 (4.8 +/- 0.1, 4.1 +/- 0.1, and 4.3 +/- 0.1 mmol. L(-1)) minutes after the MOD-GI meal than after either the HI-GI or control. Total carbohydrate oxidation was greater (P <.05) during the MOD-GI trial than in control and was directly correlated with exercise performance time (r =.95, P <.0001). Pre-exercise plasma FFA levels were suppressed (P <.05) 30 and 45 minutes after ingestion of the HI-GI meal and 45 minutes after the MOD-GI meal compared with control. At 30, 60, and 120 minutes of exercise, FFAs remained suppressed (P <.05) for both test meals compared with control. At exhaustion, plasma glucose, INS, FFA, glycerol, EPI, and NE levels and muscle glycogen use were not different for all trials. Exercise time was prolonged (P <.05) after the MOD-GI meal compared with control, but the HI-GI trial was not different from control (MOD-GI, 165 +/- 11; HI-GI, 141 +/- 8; control, 134 +/- 13 minutes). Thus, in contrast to the HI-GI meal or control, the MOD-GI breakfast cereal ingested 45 minutes before exercise enhanced performance time, maintained euglycemia for a longer period during exercise, and resulted in greater total carbohydrate oxidation during the exercise bout. We conclude that a MOD-GI meal provides a significant performance and metabolic advantage when consumed 45 minutes before exercise.     

Acute elevation of free fatty acids impairs hepatic glucose uptake in conscious rats

To investigate the dose-dependent effect of free fatty acid (FFA) on the hepatic glucose uptake (HGU), we determined hepatic glucose fluxes by a dual tracer technique during the basal state and euglycemic hyperinsulinemic clamp combined with a portal glucose load in three groups of rats given saline (saline), low-dose lipid (lipid-L), or high-dose lipid infusion (lipid-H). In the basal state, lipid infusion dose-dependently increased plasma FFA (saline, 400 +/- 50; lipid-L, 550 +/- 30; lipid-H, 1700 +/- 270 micromol l(-1); mean +/- S.E). Endogenous glucose production (EGP) in lipid-H was 63.5 +/- 5.5 micromol kg(-1) min(-1) and significantly higher than in the saline and lipid-L (40.2 +/- 2.9, 47.6 +/- 3.1 micromol kg(-1) min(-1), respectively). During euglycemic hyperinsulinemic clamp, plasma FFA decreased to 130 +/- 30 micromol l(-1) in saline, but remained at basal levels in lipid-L and lipid-H (470 +/- 30 and 1110 +/- 180 micromol l(-1), respectively). Insulin-suppressed EGP was complete in saline and lipid-L, but impaired in lipid-H (38.0 +/- 6.4 micromol kg(-1) min(-1)). Elevated FFA dose-dependently reduced HGU (saline, 12.2 +/- 0.9; lipid-L, 8.6 +/- 0.6; lipid-H, 4.7 +/- 1.4 micromol kg(-1) min(-1)). In conclusion, acutely elevated FFA impairs HGU as well as insulin-mediated suppression of EGP during hyperinsulinemic clamp with portal glucose loading. Impaired hepatic glucose uptake associated with elevated FFA may contribute to the development of insulin resistance in obesity and type 2 diabetes.     

Effects of low-dose and high-dose glucagon on glucose production and gluconeogenesis in humans

The analysis of mass isotopomers in blood glucose and lactate can be used to estimate gluconeogenesis (Gneo), glucose production (GP), and, by subtraction, nongluconeogenic glucose release by the liver. At 6 AM, 18 normal subjects received a 7-hour primed constant infusion of [U-13C6] glucose. After a 3-hour baseline period (12 hours of fasting), somatostatin, insulin, hydrocortisone, growth hormone (GH), and glucagon were infused for 4 hours. Glucagon was infused at a low-dose (n = 6) or high-dose (n = 6) concentration for 4 hours and was compared with fasting alone (n = 6). Low-dose glucagon infusion increased plasma glucagon (64 +/- 3 v 44 +/- 7 ng/L, low glucagon v baseline). GP increased above baseline (15.5 +/- 0.5 v 13.8 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11 .5 +/- 0.6 micromol/kg/min, P < .05). The elevation in GP was due to a near doubling of nongluconeogenic glucose release compared with fasting alone (8.3 +/- 0.6 v 4.7 +/- 0.5 micromol/kg/min, P < .01). High-dose glucagon infusion (125 +/- 25 ng/L) increased GP above baseline (15.8 +/- 0.6 v 13.5 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11.5 +/- 0.6 micromol/kg/min, P < .05). The increase in GP was due to an increase in Gneo (8.5 +/- 0.5 v 6.8 +/- 0.7 micromol/kg/min, P < .05) and nongluconeogenic glucose release (7.4 +/- 0.5 v 4.7 +/- 0.4 micromol/kg/min, P < .05) compared with fasting. Low-dose glucagon increases GP only by stimulation of nongluconeogenic glucose release. High-dose glucagon increases GP by an increase in both Gneo and nongluconeogenic glucose release.     

Effects of oral contraceptives on glucoregulatory responses to exercise

Some of the effects of oral contraceptives (OCs) to alter glucoregulation may be ameliorated by exercise. To test this premise, the effects of acute aerobic exercise on postprandial glucose, insulin, and C-peptide responses (area under the curve [AUC]) were measured in 8 users of low-dose estrogen and progestin OCs (OC(+)) and 10 women not using OCs (OC(-)). They completed 2 randomly ordered intervention trials: (1) aerobic exercise on 3 consecutive days with a 2.5-hour, 75-g oral glucose tolerance test (OGTT) on day 4, and (2) no exercise for 3 days prior to the OGTT (control trial). The exercise was 50 minutes of treadmill walking at 70% (.-)VO(2max). The groups were similar in age (27 +/- 3 years), waist-to-hip ratio (0.74 +/- 0.01), and cardiorespiratory fitness (32.5 +/- 1.6 mL x kg body mass(-1) x min(-1)). Fasting plasma glucose, C-peptide, and insulin levels were similar (P >.05) between groups in the control trial. In both trials, glucose(AUC) was significantly greater (13%, P <.05) in OC(+). Exercise resulted in a significant (P <.05) decrease in fasting plasma glucose and insulin, insulin(AUC), glucose(AUC) x insulin(AUC), and C-peptide(AUC) in both groups, suggesting enhanced insulin action and/or reduced pancreatic insulin secretion. Hepatic insulin extraction ([C-peptide(AUC) - insulin(AUC)())]/C-peptide(AUC)) was increased following exercise only in OC(+). Thus, insulin action was enhanced in response to exercise in young sedentary women independent of OC use. The mechanisms for the acute exercise effect on insulin action may be different in OC users compared with normally menstruating women.     

Metabolic effect of decreasing nonesterified fatty acid levels with acipimox in hyperthyroid patients.

Glucose intolerance is often found in patients with hyperthyroidism, but the pathogenetic mechanisms are not fully understood. Since lipolysis is increased in hyperthyroidism, elevated plasma nonesterified fatty acids (NEFAs) may contribute to abnormal glucose metabolism in hyperthyroidism. The aim of this study was to investigate whether decreasing the plasma NEFA level with acipimox can affect glucose metabolism in hyperthyroidism. We performed an intravenous glucose tolerance test (IVGTT) with acipimox 250 mg or placebo in six untreated hyperthyroid men and six age- and body mass index (BMI)-matched controls. Fasting plasma NEFA levels were significantly higher in the hyperthyroid patients versus the controls (997.0 +/- 303.4 v290.5 +/- 169.1 micromol/L, P < .001). Plasma NEFAs decreased rapidly with acipimox treatment in both controls and hyperthyroid patients. In the controls, the glucose disappearance constant (K(G)) was not different for acipimox treatment versus placebo (2.18 +/- 0.62 v 2.42 +/- 1.00% x min(-1)). In hyperthyroid patients, acipimox treatment increased the K(G) significantly compared with placebo treatment (2.44 +/- 0.84 v 1.58 +/- 0.37% x min(-1), P < .05). Changes in K(G) values with acipimox treatment were inversely correlated with changes in plasma NEFA levels (r = -.65, P < .05). Acipimox treatment increased the acute insulin response (AIR) in hyperthyroid patients (943 +/- 381 v 698 +/- 279 microU/mL x min, P < .05), whereas it did not change the AIR in controls. Changes in the AIR with acipimox treatment correlated significantly with changes in the K(G) (r = .70, P < .05). There was a weak correlation between changes in the AIR with acipimox treatment and changes in plasma NEFA levels (r = -.55, P = .06). In summary, decreasing the plasma NEFA level with acipimox in hyperthyroid patients increases both the K(G) and AIR during an IVGTT. These findings suggest that the abnormal glucose metabolism in hyperthyroidism could be attributed, at least in part, to the increase of plasma NEFA.     

Regulation of hepatic glucose output during moderate exercise in non-insulin-dependent diabetes

In normal subjects during moderate exercise there is a strong negative correlation between plasma glucose and hepatic glucose output (HGO) suggesting a negative feedback regulation of HGO by plasma glucose. Little information is available about HGO responses to exercise in non-insulin-dependent diabetes mellitus (NIDDM). To determine whether the same feedback relationship is operative, we have compared the glucose turnover responses to moderate exercise (50% Vo2max for 60 minutes) of nonobese non-insulin-dependent diabetic subjects (NIDDM, n = 7) with a group of age-matched controls (n = 5). Glucose turnover responses to exercise in NIDDM were heterogeneous. Plasma glucose showed sustained falls, no change, or sustained rises in different individuals. Similarly, HGO responses ranged from undetectable to responses comparable to those of normal subjects. The mean integrated HGO response in NIDDM was significantly reduced compared with controls (11 +/- 6 [SEM] v 33 +/- 7 mmol/h/70 kg, P less than .05); mean glucose utilization response was also reduced but not significantly different from controls (NIDDM 18 +/- 5 v control 35 +/- 6). In NIDDM there was no significant feedback-control relationship between plasma glucose and HGO (r = -0.20, P = NS) in contrast to controls (r = -0.87, P less than .01). We conclude that feedback control of HGO by plasma glucose during moderate exercise is impaired in NIDDM. This impairment may be due to defective nonpancreatic glucoregulatory mechanisms.     

Creatine supplementation alters insulin secretion and glucose homeostasis in vivo

Dietary creatine supplementation has been used to improve skeletal muscle performance. However, dietary creatine manipulation also affects glucose homeostasis. The aim of this study was to investigate the effect of dietary creatine supplementation on insulin secretion, glucose tolerance, and quadriceps glycogen metabolism in chow-fed rats. Forty-eight rats in total were divided into 2 groups of 24 and were then subdivided into 6 groups of 8. Rats were fed a diet supplemented with 0% (CON) or 2% (CREAT) creatine for 2, 4, or 8 weeks. At these 3 time points an oral glucose tolerance test was performed. Two days later, rats were euthanized and the pancreas and quadriceps muscles were collected. The peak insulin response to a glucose challenge was significantly elevated after both 4 (CON 327 +/- 72 v CREAT 735 +/- 140 pmol/L, P =.01) and 8 (CON 248 +/- 48 v CREAT 588 +/- 136 pmol/L, P =.02) weeks. Fasting insulin levels were also increased by creatine supplementation for 8 weeks (CON 78 +/- 14 v CREAT 139 +/- 14 pmol/L, P =.01). Glucose tolerance was not affected until 8 weeks at which point the peak plasma glucose was elevated in the creatine supplemented group (CON 10.1 +/- 0.6 v CREAT 13.5 +/- 1.5 mmol/L, P =.05). A significant increase in pancreatic total creatine content was seen in supplemented animals at 2 (CON 1.2 +/- 0.1 v CREAT 2.7 +/- 0.1 micromol/g wet wt, P =.005), 4 (CON 1.5 +/- 0.2 v CREAT 2.7 +/- 0.3 micromol/g wet wt, P =.02) and 8 (CON 1.5 +/- 0.1 v CREAT 2.6 +/- 0.1 micromol/g wet wt, P =.005) weeks, whereas no change in quadriceps total creatine or glycogen content was observed at any individual time point. This study shows that prolonged creatine supplementation induces abnormalities in pancreatic insulin secretion and changes in glucose homeostasis.     

Paradoxical changes of muscle glutamine release during hyperinsulinemia euglycemia and hypoglycemia in humans: further evidence for the glucose-glutamine cycle

Insulin suppresses and counterregulatory hormones increase proteolysis. Therefore, if proteolysis were a major factor determining amino acid fluxes in plasma, one would expect release of glutamine into plasma to be suppressed by insulin under euglycemic conditions and to be stimulated under hypoglycemic conditions. However, release of glutamine into plasma remains unaltered or increases during euglycemic hyperinsulinemia and decreases during insulin-induced hypoglycemia. To investigate the mechanisms for these paradoxical observations and the role of skeletal muscle, we infused overnight fasted volunteers with [U-(14)C] glutamine and measured release of glutamine into plasma, its removal from plasma, and forearm glutamine net balance, fractional extraction, uptake and release during 4-hour euglycemic ( approximately 5.0 mmol/L, n = 7) and hypoglycemic ( approximately 3.1 mmol/L, n = 8) hyperinsulinemic ( approximately 230 pmol/L) clamp experiments. During the euglycemic clamps, plasma glutamine uptake and release (both P <.05) and forearm muscle glutamine fractional extraction (P <.05), uptake (P <.02) and release (P <.01) all increased, whereas forearm glutamine net balance remained unchanged. The increase in muscle glutamine release (from 1.85 +/- 0.26 to 2.18 +/- 0.30 micromol. kg(-1). min(-1)) accounted for approximately 60% of the increase in total glutamine release into plasma (from 5.54 +/- 0.47 to 6.10 +/- 0.64 micromol. kg(-1). min(-1)) and correlated positively with the increase in muscle glucose uptake (r = 0.80, P <.03). During the hypoglycemic clamps, plasma glutamine uptake and release and forearm glutamine release remained unaltered, but forearm glutamine fractional extraction and uptake decreased approximately 25% (both P <.01) so that forearm glutamine net release increased from 0.37 +/- 0.06 to 0.61 +/- 0.09 micromol. kg(-1). min(-1) (P <.03). We conclude that skeletal muscle is largely responsible for the increased release of glutamine into plasma during euglycemic hyperinsulinemia in humans, and that this may be due to increased conversion of glucose to glutamine as part of the glucose-glutamine cycle; during hypoglycemic hyperinsulinemia decreased glutamine uptake by skeletal muscle may be important for providing substrate for increased glutamine gluconeogenesis.     

Exogenous nitric oxide increases basal leg glucose uptake in humans

This study addressed the role of blood flow and nitric oxide in leg glucose uptake. Seven subjects (5 men, 2 women) were studied during conditions of resting blood flow and increased blood flow, achieved by infusion of the nitric oxide (NO) donor sodium nitroprusside (SNP) into the femoral artery. Femoral arterial and venous blood samples were obtained and blood flow was determined by infusion of indocyanine green dye. SNP infusion significantly increased leg blood flow (769 +/- 103 v 450 +/- 65 mL. min(-1). leg(-1), P <.001), but did not affect arterial (4.68 +/- 0.13 mmol/L control, 4.63 +/- 0.09 mmol/L SNP) or venous (4.60 +/- 0.14 mmol/L control, 4.54 +/- 0.10 mmol/L SNP) glucose concentrations. Glucose uptake was significantly (P <.01) higher during SNP infusion (65 +/- 6 micromol. min(-1). leg(-1)) than during the basal period (34 +/- 6 micromol. min(-1). leg(-1)), whereas lactate release was unaffected (rest, 45 +/- 11 micromol. min(-1). leg(-1); SNP, 42 +/- 14 micromol. min(-1). leg(-1)). We conclude that blood flow and/or NO increase basal leg glucose uptake.     

The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis

Although metformin has been used worldwide to treat type 2 diabetes for several decades, its mechanism of action on glucose homeostasis remains controversial. To further assess the effect of metformin on glucose metabolism, 10 42-hour-fasted conscious dogs were studied in the absence ([Con] n = 5) and presence ([Met] n = 5) of a portal infusion of metformin (0.15 mg x kg(-1) x min(-1)) over 300 minutes. Hepatic glucose production was measured by both arteriovenous-difference and tracer methods. All dogs were maintained on a pancreatic clamp and in a euglycemic state to ensure that any changes in glucose metabolism would result directly from the effects of metformin. The arterial metformin level was 21 +/- 3 microg/mL during the test period. Net hepatic glucose output (NHGO) decreased in Met dogs from 1.9 +/- 0.2 to 0.7 +/- 0.1 mg x kg(-1) x min(-1) (P < .05). NHGO remained unchanged in Con dogs (1.7 +/- 0.3 to 1.5 +/- 0.3 mg x kg(-1)min(-1)). Tracer-determined glucose production paralleled NHGO. The net hepatic glycogenolytic rate decreased from 1.0 +/- 0.2 to -0.3 +/- 0.2 mg x kg(-1) x min(-1) (P < .05) in Met dogs, but remained unchanged in Con dogs (0.8 +/- 0.2 to 0.8 +/- 0.3 mg x kg(-1) x min(-1)). No significant change in gluconeogenic flux was found in eitherthe Metgroup (1.2 +/- 0.3 to 1.3 +/- 0.3 mg x kg(-1) x min(-1)) or the Con group (1.3 +/- 0.4 to 1.0 +/- 0.3 mg x kg(-1) x min(-1)). No significant changes were observed in glucose utilization or glucose clearance in either group. In conclusion, in the normal fasted dog, (1) the primary acute effect of metformin on glucose metabolism was an inhibition of hepatic glucose production and not a stimulation of glucose utilization; and (2) the inhibition of glucose production was attributable to a decrease in hepatic glycogenolysis and not to an alteration in gluconeogenic flux.     

Glucoregulation during and after intense exercise: effects of alpha-adrenergic blockade

In intense exercise (>80% maximal oxygen consumption [VO2 max]), the 7- to 8-fold increase in glucose production (Ra) is tightly correlated with the greater than 14-fold increase in plasma norepinephrine (NE) and epinephrine (EPI). To distinguish the relative roles of alpha- and beta-adrenergic receptors, the responses of 12 control (C) lean, healthy, fit young male subjects to 87% VO2 max cycle ergometer exercise were compared with those of 7 subjects (at 83% VO2max) receiving intravenous phentolamine (Ph). The Ph group received a 70-microg/kg bolus and then 7 microg/kg/min from -30 minutes, during exercise and for 60 minutes of recovery. The data were analyzed by comparing exercise responses to exhaustion in Ph subjects (11.4 +/- 0.6 min) with those at both 12 minutes and at exhaustion in C subjects (14.6 +/- 0.3 min) and during recovery. There were no significant differences between groups in the plasma glucose response during exercise, but values were higher in C versus Ph subjects during the first 40 minutes of postexercise "recovery." The Ra response during the first 12 minutes of exercise was not different by repeated-measures ANOVA, reaching 10.6 +/- 1.3 mg/kg/min in C and 9.6 +/- 1.5 in Ph subjects at 12 minutes. However, in C subjects, Ra increased significantly to 14.1 +/- 1.2 mg/kg/min by exhaustion, and remained higher versus Ph subjects until 15 minutes of recovery. The Rd during recovery was not different between groups; thus, the higher Ra in C subjects in early recovery was responsible for the greater hyperglycemia observed in C subjects. Ph subjects showed a more rapid, marked increment (P = .002) in both plasma NE (to 64 v38 nmol/L) and EPI at exhaustion, and catecholamine concentrations remained higher in Ph versus C subjects during recovery. Whereas plasma insulin (IRI) declined in the C group, it increased 3-fold (P = .001) in the Ph group during exercise and until 15 minutes of recovery. Ph had no effect on glucagon (IRG). Thus, the glucagon to insulin ratio decreased in Ph subjects from baseline levels during exercise and early recovery, but increased in C subjects. The increase in Ra among Ph subjects despite the decrease in the glucagon to insulin ratio supports our earlier evidence that these hormones are not principal regulators of the Ra in intense exercise. The shorter time to exhaustion and markedly higher catecholamine levels in Ph subjects limited our ability to isolate the effects of alpha-adrenergic receptors on the Ra.alpha-Adrenergic receptors appear to have little influence on the Rd.