P. Schneiter

Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.

Fish oil prevents the adrenal activation elicited by mental stress in healthy men

OBJECTIVES A diet rich in n-3 fatty acids (fish oils) is associated with reduced risks of cardiovascular and metabolic diseases, but the mechanisms remain incompletely understood. Sympathoadrenal activation is postulated to be involved in the pathogenesis of these diseases, and may be inhibited by n-3 fatty acids. We therefore evaluated the effects of a diet supplemented with n-3 fatty acids on the stimulation of the sympathetic nervous system and of stress hormones elicited by a mental stress. METHODS Seven human volunteers were studied on two occasions, before and after 3 weeks of supplementation with 7.2 g/day fish oil. On each occasion, the concentrations of plasma cortisol, and catecholamines, energy expenditure (indirect calorimetry), and adipose tissue lipolysis (plasma non esterified fatty acid concentrations) were monitored in basal conditions followed by a 30 min mental stress (mental arithmetics and Stroops test) and a 30 min recovery period. RESULTS In control conditions, mental stress significantly increased heart rate, mean blood pressure, and energy expenditure. It increased plasma epinephrine from 60.9 +/- 6.2 to 89.3 +/- 16.1 pg/ml (p<0.05), plasma cortisol from 291 +/- 32 to 372 +/- 37 micromol/l (p<0.05) and plasma non esterified fatty acids from 409 +/- 113 to 544 +/- 89 micromol/l (p<0.05). After 3 weeks of a diet supplemented with n-3 fatty acids, the stimulation by mental stress of plasma epinephrine, cortisol, energy expenditure, and plasma non esterified fatty acids concentrations, were all significantly blunted. CONCLUSION Supplementation with n-3 fatty acids inhibits the adrenal activation elicited by a mental stress, presumably through effects exerted at the level of the central nervous system.

Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans

Six healthy human subjects were studied during three 75-g oral, [13C]glucose tolerance tests to assess the kinetics of dexamethasone-induced impairment of glucose tolerance. On one occasion, they received dexamethasone (4 × 0.5 mg/day) during the previous 2 days. On another occasion, they received a single dose (0.5 mg) of dexamethasone 150 min before ingestion of the glucose load. On the third occasion, they received a placebo. Postload plasma glucose was significantly increased after both 2 days dexamethasone and single dose dexamethasone compared with control ( P < 0.05). This corresponded to a 20-23% decrease in the metabolic clearance rate of glucose, whereas total glucose turnover ([6,6-2H]glucose), total (indirect calorimetry) and exogenous glucose oxidation (13CO2production), and suppression of endogenous glucose production were unaffected by dexamethasone. Plasma insulin concentrations were increased after 2 days of dexamethasone but not after a single dose of dexamethasone. In a second set of experiments, the effect of a single dose of dexamethasone on insulin sensitivity was assessed in six healthy humans during a 2-h euglycemic hyperinsulinemic clamp. Dexamethasone did not significantly alter insulin sensitivity. It is concluded that acute administration of dexamethasone impairs oral glucose tolerance without significantly decreasing insulin sensitivity.Six healthy human subjects were studied during three 75-g oral, [13C]glucose tolerance tests to assess the kinetics of dexamethasone-induced impairment of glucose tolerance. On one occasion, they received dexamethasone (4 x 0.5 mg/day) during the previous 2 days. On another occasion, they received a single dose (0. 5 mg) of dexamethasone 150 min before ingestion of the glucose load. On the third occasion, they received a placebo. Postload plasma glucose was significantly increased after both 2 days dexamethasone and single dose dexamethasone compared with control (P < 0.05). This corresponded to a 20-23% decrease in the metabolic clearance rate of glucose, whereas total glucose turnover ([6,6-2H]glucose), total (indirect calorimetry) and exogenous glucose oxidation (13CO2 production), and suppression of endogenous glucose production were unaffected by dexamethasone. Plasma insulin concentrations were increased after 2 days of dexamethasone but not after a single dose of dexamethasone. In a second set of experiments, the effect of a single dose of dexamethasone on insulin sensitivity was assessed in six healthy humans during a 2-h euglycemic hyperinsulinemic clamp. Dexamethasone did not significantly alter insulin sensitivity. It is concluded that acute administration of dexamethasone impairs oral glucose tolerance without significantly decreasing insulin sensitivity.

Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans

To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short‐term overfeeding in healthy subjects.

Effect of moderate physical activity on plasma leptin concentration in humans

Abstract In subjects who maintain a constant body mass, the increased energy expenditure induced by exercise must be compensated by a similar increase in energy intake. Since leptin has been shown to decrease food intake in animals, it can be expected that physical exercise would increase energy intake by lowering plasma leptin concentrations. This effect may be secondary either to exercise-induced negative energy balance or to other effects of exercise. To delineate the effects of moderate physical activity on plasma leptin concentrations, 11 healthy lean subjects (4 men, 7 women) were studied on three occasions over 3 days; in study 1 they consumed an isoenergetic diet (1.3 times resting energy expenditure) over 3 days with no physical activity; in study 2 the subjects received the same diet as in study 1, but they exercised twice daily during the 3 days (cycling at 60 W for 30 min); in study 3 the subjects exercised twice daily during the 3 days, and their energy intake was increased by 18% to cover the extra energy expenditure induced by the physical activity. Fasting plasma leptin concentration (measured on the morning of day 4) was unaltered by exercise [8.64 (SEM 2.22) 7.17 (SEM 1.66), 7.33 (SEM 1.72) 1μg · l−1 in studies 1, 2 and 3, respectively]. It was concluded that a moderate physical activity performed over a 3-day period does not alter plasma leptin concentrations, even when energy balance is slightly negative. This argues against a direct effect of physical exercise on plasma leptin concentrations, when body composition is unaltered.

Effects of short-term carbohydrate or fat overfeeding on energy expenditure and plasma leptin concentrations in healthy female subjects

OBJECTIVE: To determine the effects of excess carbohydrate or fat intake on plasma leptin concentrations and energy expenditure.DESIGN: Ten healthy lean females were studied: (a) during a 3 day isoenergetic diet (ISO); (b) during 3 day carbohydrate overfeeding (CHO OF); and (c) during 3 day fat overfeeding (FAT OF). During each test, basal metabolic rate, the energy expended during mild physical activity and recovery, and 24 h energy expenditure (24 h EE) were measured with indirect calorimetry. The concentrations of glucose and lactate were monitored in subcutaneous interstitial fluid over a 24 h period using microdialysis. Plasma hormone and substrate concentrations were measured in a blood sample collected in the morning of the fourth day.RESULTS: CHO OF increased plasma leptin concentrations by 28%, and 24 h EE by 7%. Basal metabolic rate and the energy expended during physical activity were not affected. FAT OF did not significantly change plasma leptin concentrations or energy expenditure. There was no relationship between changes in leptin concentrations and changes in energy expenditure, suggesting that leptin is not involved in the stimulation of energy metabolism during overfeeding. Interstitial subcutaneous glucose and lactate concentrations were not altered by CHO OF and FAT OF.CONCLUSIONS: CHO OF, but not FAT OF, increases energy expenditure and leptin concentration.

Noninvasive assessment of in vivo glycogen kinetics in humans: effect of increased physical activity on glycogen breakdown and synthesis

In vivo glycogen kinetics was estimated with the simultaneous use of indirect calorimetry and tracer technology in healthy humans during 24-h periods with low or moderate physical activity (1 or 3 exercise sessions each day). Two 13C-carbohydrates meals were administered at 9.30 a.m. and 1.30 p.m., and one 12C-carbohydrates meal at 6.30 p.m. Net carbohydrate oxidation (net CHO ox) was measured over a 24 h period by indirect calorimetry and oxidation of 13C-labelled carbohydrates (13C CHO ox) was estimated from 13CO2 production. Glycogen breakdown, assessed for the period 8.15 a.m.-6.30 p.m. as the difference between net CHO ox and 13C CHO ox, was increased 1.6 times with three exercise sessions [123.3 (SEM 8.0) g] versus one session [77.9 (SEM 7.7) g, P<0.0001]. Carbohydrate balances over 24 h were close to zero under both conditions, indicating that glycogen breakdown was matched by an equivalent glycogen synthesis. It was concluded that simultaneous use of indirect calorimetry and tracer technology may make possible the estimation of glycogen kinetics in humans. Moderate physical activity enhanced both glycogen breakdown and synthesis. This stimulation of glycogen metabolism may therefore play a role in the enhanced insulin sensitivity induced by physical exercise.

Evaluation of hepatic and whole body glycogen metabolism in humans during repeated administrations of small loads of 13C glucose

BACKGROUND Postprandial suppression of endogenous glucose production and regulation of glucose homeostasis involve alterations of whole body and hepatic glycogenolysis and glycogen breakdown. These parameters can be estimated by the simultaneous measurement of net total and exogenous, (13)C-labeled, glucose oxidation. METHODS Eight subjects were studied on 3 occasions, while receiving oral loads of 60 mg, 120 or 180 mg (13)C glucose/kg every hour for 4 consecutive hours. Net glucose oxidation was calculated from indirect calorimetry, and exogenous glucose oxidation from (13)CO(2) production. These parameters were evaluated during the hour following the fourth glucose load. Whole body endogenous glycogen breakdown was calculated as (net glucose oxidation) - (exogenous glucose oxidation). Total glycogen synthesis was calculated as (glucose load) - (exogenous glucose oxidation). Whole body glucose turnover was measured with 6.6 (2)H(2) glucose. The systemic appearance of oral, (13)C labeled glucose was monitored, and the suppression of endogenous glucose production was calculated. RESULTS Plasma glucose tracers had reached near steady state during the hour following the fourth glucose load. Glucose ingestion dose-dependently suppressed endogenous glycogen breakdown and stimulated total glycogen synthesis. Endogenous glycogen breakdown was completely inhibited with 180 mg oral glucose/kg. Endogenous glucose production was suppressed in a dose-dependent way, but remained positive with all 3 doses. The first pass splanchnic glucose uptake averaged 25-35%. CONCLUSION Repeated administration of small doses of (13)C labeled glucose allow to reach near steady state conditions after four hours, and to non-invasively evaluate whole body glycogen turnover and hepatic glucose metabolism.

Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients.

Background. The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. Methods. Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP) concentrations were compared after intravenous and oral glucose. Results. After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P <0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P <0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. Conclusions. First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the &bgr;-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

Assessment of postprandial hepatic glycogen synthesis from uridine diphosphoglucose kinetics in obese and lean non-diabetic subjects

BACKGROUND: Obese patients are frequently characterized by insulin resistance and decreased insulin-mediated glycogen synthesis in skeletal muscle. Whether they also have impaired postprandial hepatic glycogen synthesis remains unknown.AIM: To determine whether postprandial hepatic glycogen synthesis is decreased in obese patients compared to lean subjects.METHODS: Lean and obese subjects with impaired glucose tolerance were studied over 4 h after ingestion of a glucose load. Hepatic uridine diphosphoglucose kinetics were assessed using 13C-galactose infusion, with monitoring of urinary acetaminophen–glucuronide isotopic enrichment to estimate hepatic glycogen kinetics.RESULTS: Estimated net hepatic glycogen synthesis amounted to 18.6 and 22.6% of the ingested load in lean and obese subjects, respectively.CONCLUSION: Postprandial hepatic glycogen metabolism is not impaired in non-diabetic obese subjects.