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

OBJECTIVE: To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short-term overfeeding in healthy subjects. DESIGN AND METHODS: The analysis of the data collected in several studies in which fasting hepatic glucose production (HGP), hepatic insulin sensitivity index (HISI), and intrahepatocellular lipids (IHCL) had been measured after both 6-7 days on a weight-maintenance diet (control, C; n = 55) and 6-7 days of overfeeding with 1.5 (F1.5, n = 7), 3 (F3, n = 17), or 4 g fructose/kg/day (F4, n = 10), with 3 g glucose/kg/day (G3, n = 11), or with 30% excess energy as saturated fat (fat30%, n = 10). RESULTS: F3, F4, G3, and fat30% all significantly increased IHCL, respectively by 113 ± 86, 102 ± 115, 59 ± 92, and 90 ± 74% as compared to C (all P < 0.05). F4 and G3 increased HGP by 16 ± 10 and 8 ± 11% (both P < 0.05), and F3 and F4 significantly decreased HISI by 20 ± 22 and 19 ± 14% (both P < 0.01). In contrast, there was no significant effect of fat30% on HGP or HISI. CONCLUSIONS: Short-term overfeeding with fructose or glucose decreases hepatic insulin sensitivity and increases hepatic fat content. This indicates short-term regulation of hepatic glucose metabolism by simple carbohydrates.

Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men.

AIMS: The present study aimed to assess the effects of excess fat, fructose and fat-plus-fructose intakes on intrahepatocellular lipid (IHCL). METHODS: Healthy male subjects were studied after an isocaloric diet or a 7-day high-fructose (Fru: +3.5 g fructose/kg fat-free mass/day, +35% energy), high-fat (Fat: +30% energy as saturated-fat) or high-fructose, high-fat diet (FruFat: +3.5 g fructose/kg fat-free mass/day, +30% energy as fat, +65% total energy). IHCL was measured by (1)H magnetic resonance spectroscopy. RESULTS: All hypercaloric diets increased IHCL (Fru: +16%; Fat: +86%; FruFat: +133%; P<0.05). Very low-density lipoprotein (VLDL) triacylglycerols increased after Fru (+58%; P<0.05), but decreased after Fat (-22%; P<0.05), while no change was observed after FruFat. CONCLUSION: Fat and fructose both increased IHCL, but fructose increased, while fat decreased, VLDL triacylglycerols. However, excess fat and fructose combined had additive effects on IHCL and neutralizing effects on VLDL triglycerides. This suggests that fructose stimulates, while fat inhibits, hepatic VLDL triacylglycerol secretion.

Glucose flux in controlled hyperglycaemia before and after oral glucose ingestion in men with mild type 2 diabetes.

AIMS: This study aimed to determine how insufficiently suppressed endogenous glucose production vs. reduced peripheral glucose uptake contribute to postprandial hyperglycaemia in type 2 diabetes (T2D). METHODS: Eight men with T2D (age: 52+/-7 years; BMI: 26.6+/-2.3 kg/m(2); fasting glycaemia: 7.1+/-1.5 mmol/L) were compared with eight non-diabetic controls (age: 51+/-5 years; BMI: 24.6+/-2.9 kg/m(2); fasting glycaemia: 4.9+/-0.4 mmol/L). Their glucose turnover rates and hepatic glucose cycles were measured by monitoring [2H7]glucose infusion, with m+7 and m+6 enrichment, 3 h before and 4 h after the ingestion of [6,6-2H2]-labelled glucose, while maintaining glycaemia at 10 mmol/L using the pancreatic clamp technique. RESULTS: Of the 700 mg/kg oral glucose load, 71% appeared in the systemic circulation of the T2D patients vs. 63% in the controls (NS). Endogenous glucose production and hepatic glucose cycles did not differ from normal either before or after oral glucose ingestion, while peripheral glucose uptake was reduced by 40% in the T2D group both before (P<0.01) and after (P<0.05) ingestion of oral glucose. CONCLUSION: When T2D patients were compared with non-diabetic subjects with similarly controlled levels of hyperglycaemia after oral glucose ingestion, they essentially differed only in peripheral glucose uptake, whereas endogenous glucose production was apparently unaltered.

Protein synthesis in jejunum and liver of neonatal calves fed vitamin A and lactoferrin.

Rates of protein synthesis (PS) and turnover are more rapid during the neonatal period than during any other stage of postnatal life. Vitamin A and lactoferrin (Lf) can stimulate PS in neonates. However, newborn calves are vitamin A deficient and have a low Lf status, but plasma vitamin A and Lf levels increase rapidly after ingestion of colostrum. Neonatal calves (n = 6 per group) were fed colostrum or a milk-based formula without or with vitamin A, Lf, or vitamin A plus Lf to study PS in the jejunum and liver. l-[(13)C]Valine was intravenously administered to determine isotopic enrichment of free (nonprotein-bound) Val (AP(Free)) in the protein precursor pool, atom percentage excess (APE) of protein-bound Val, fractional protein synthesis rate (FSR) in the jejunum and liver, and isotopic enrichment of Val in plasma (APE(Pla)) and in the CO(2) of exhaled air (APE(Ex)). The APE, AP(Free), and FSR in the jejunum and liver did not differ significantly among groups. The APE(Ex) increased, whereas APE(Pla) decreased over time, but there were no group differences. Correlations were calculated between FSR(Jej) and histomorphometrical and histochemical data of the jejunum, and between FSR(Liv) and blood metabolites. There were negative correlations between FSR(Liv) and plasma albumin concentrations and between FSR(Jej) and the ratio of villus height:crypt depth, and there was a positive correlation between FSR(Jej) and small intestinal cell proliferation in crypts. Hence, there were no effects of vitamin A and Lf and no interactions between vitamin A and Lf on intestinal and hepatic PS. However, FSR(Jej) was correlated with histomorphometrical traits of the jejunum and FSR(Liv) was correlated with plasma albumin concentrations.

Effects of colostrum feeding and glucocorticoid administration on insulin-dependent glucose metabolism in neonatal calves.

Colostrum feeding and glucocorticoid administration affect glucose metabolism and insulin release in calves. We have tested the hypothesis that dexamethasone as well as colostrum feeding influence insulin-dependent glucose metabolism in neonatal calves using the euglycemic-hyperinsulinemic clamp technique. Newborn calves were fed either colostrum or a milk-based formula (n=14 per group) and in each feeding group, half of the calves were treated with dexamethasone (30 microg/[kg body weight per day]). Preprandial blood samples were taken on days 1, 2, and 4. On day 5, insulin was infused for 3h and plasma glucose concentrations were kept at 5 mmol/L+/-10%. Clamps were combined with [(13)C]-bicarbonate and [6,6-(2)H]-glucose infusions for 5.5h (i.e., from -150 to 180 min, relative to insulin infusion) to determine glucose turnover, glucose appearance rate (Ra), endogenous glucose production (eGP), and gluconeogenesis before and at the end of the clamp. After the clamp liver biopsies were taken to measure mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate carboxylase (PC). Dexamethasone increased plasma glucose, insulin, and glucagon concentrations in the pre-clamp period thus necessitating a reduction in the rate of glucose infusion to maintain euglycemia during the clamp. Glucose turnover and Ra increased during the clamp and were lower at the end of the clamp in dexamethasone-treated calves. Dexamethasone treatment did not affect basal gluconeogenesis or eGP. At the end of the clamp, dexamethasone reduced eGP and PC mRNA levels, whereas mitochondrial PEPCK mRNA levels increased. In conclusion, insulin increased glucose turnover and dexamethasone impaired insulin-dependent glucose metabolism, and this was independent of different feeding.

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 beta-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

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 Stroop's 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.

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.

Mechanisms of action of beta-glucan in postprandial glucose metabolism in healthy men.

OBJECTIVE: To assess whether beta-glucan (which is fermented in the colon) lowers postprandial glucose concentrations through mechanisms distinct from a delayed carbohydrate absorption and inhibits de novo lipogenesis. DESIGN: Administration of frequent small meals each hour over 9 h allows a rate of intestinal absorption to be reached which is independent of a delayed absorption. A group of 10 healthy men received either an isoenergetic diet containing 8.9 g/day beta-glucan or without beta-glucan for 3 days. On the third day, the diet was administered as fractioned meals ingested every hour for 9 h. SETTING: Laboratory for human metabolic investigations. SUBJECTS: Ten healthy male volunteers. MAIN OUTCOME MEASURES: Plasma glucose and insulin concentrations, glucose kinetics, glucose oxidation, de novo lipogenesis. RESULTS: On the third day, plasma glucose and free fatty acid concentrations, carbohydrate and lipid oxidation, and energy expenditure were identical with beta-glucan and cellulose. Plasma insulin concentrations were, however, 26% lower with beta-glucan during the last 2 h of the 9 h meal ingestion. Glucose rate of appearance at steady state was 12% lower with beta-glucan. This corresponded to a 21% reduction in the systemic appearance rate of exogenous carbohydrate with beta-glucan, while endogenous glucose production was similar with both diets. De novo lipogenesis was similar with and without beta-glucan. CONCLUSION: Administration of frequent meals with or without beta-glucan results in similar carbohydrate and lipid metabolism. This suggests that the lowered postprandial glucose concentrations which are observed after ingestion of a single meal containing beta-glucan are essentially due to a delayed and somewhat reduced carbohydrate absorption from the gut and do not result from the effects of fermentation products in the colon.

In normal men, free fatty acids reduce peripheral but not splanchnic glucose uptake.

Raising plasma free fatty acid (FFA) levels reduces muscle glucose uptake, but the effect of FFAs on splanchnic glucose uptake, total glucose output, and glucose cycling may also be critical to producing lipid-induced glucose intolerance. In eight normal volunteers, we measured glucose turnover and cycling rates ([2H7]glucose infusion) during a moderately hyperglycemic (7.7 mmol/l) hyperinsulinemic clamp, before and after ingestion of a labeled (dideuterated) oral glucose load (700 mg/kg). Each test was performed twice, with either a lipid or a saline infusion; four subjects also had a third test with a glycerol infusion. As shown by similar rates of exogenous glucose appearance, the lipid infusion did not reduce first-pass splanchnic glucose uptake (saline 1.48+/-0.18, lipid 1.69+/-0.17, and glycerol 1.88+/-0.17 mmol/kg per 180 min; NS), but it reduced peripheral glucose uptake by 40% (P < 0.01 vs. both saline and glycerol infusions). Before oral ingestion of glucose, total glucose output was similarly increased by the lipid and glycerol infusions. Total glucose output was significantly increased by FFAs after oral ingestion of glucose (saline 3.68+/-1.15, glycerol 3.68+/-1.70, and lipid 7.92+/-0.88 micromol x kg(-1) x min(-1); P < 0.01 vs. saline and P < 0.05 vs. glycerol). The glucose cycling rate was approximately 2.7 micromol x kg(-1) x min(-1) with the three infusions and tended to decrease all along the lipid infusion, which argues against a stimulation of glucose-6-phosphatase by FFAs. It is concluded that in situations of moderate hyperinsulinemia-hyperglycemia, FFAs reduce peripheral but not splanchnic glucose uptake. Total glucose output is increased by FFAs, by a mechanism that does not seem to involve stimulation of glucose-6-phosphatase.

Effects of free fatty acids on insulin sensitivity and hemodynamics during mental stress.

Mental stress is known to decrease systemic vascular resistance and increase muscle blood flow and to acutely enhance insulin-mediated glucose disposal in healthy humans. These effects are abolished in obese patients. We therefore proposed the hypothesis that elevated free fatty acid levels may be responsible for the abnormal responses to mental stress in obesity by inhibiting endothelial cell function. To test this hypothesis, we studied a group of eight lean females during a hyperinsulinemic clamp study with and without lipid infusion. A 30-min mental stress was applied during 30 min after 150 min of hyperinsulinemia. In the study without lipid infusion, mental stress increased heart rate by 26.5%, blood pressure by 7.9%, and cardiac index (measured with thoracic bioimpedance) by 35.9%; it decreased systemic vascular resistance by 21.9% and increased insulin-mediated glucose disposal by 18.9%. During lipid infusion, the increase in heart rate was not affected, but the increase in cardiac index, the decrease in systemic vascular resistance, and the increase in insulin-mediated glucose disposal were all inhibited. In contrast, the rise in blood pressure was increased about 2-fold (control plus 6 mm Hg vs. lipid plus 13 mm Hg, P: < 0.01). These results indicate that lipid inhibits the stimulation of glucose uptake and enhances the pressor effect of mental stress, presumably by altering endothelial cell function.

Role of Na+-K+-ATPase in insulin-induced lactate release by skeletal muscle.

Hyperinsulinemia increases lactate release by various organs and tissues. Whereas it has been shown that aerobic glycolysis is linked to Na+-K+-ATPase activity, we hypothesized that stimulation by insulin of skeletal muscle Na+-K+-ATPase is responsible for increased muscle lactate production. To test this hypothesis, we assessed muscle lactate release in healthy volunteers from the [13C]lactate concentration in the effluent dialysates of microdialysis probes inserted into the tibialis anterior muscles on both sides and infused with solutions containing 5 mmol/l [U-13C]glucose. On one side, the microdialysis probe was intermittently infused with the same solution additioned with 2.10(-5) M ouabain. In the basal state, [13C]lactate concentration in the dialysate was not affected by ouabain. During a euglycemic-hyperinsulinemic clamp, [13C]lactate concentration increased by 135% in the dialysate without ouabain, and this stimulation was nearly entirely reversed by ouabain (56% inhibition compared with values in the dialysate collected from the contralateral probe). These data indicate that insulin stimulates muscle lactate release by activating Na+-K+-ATPase in healthy humans.

Effects of a glucose meal on energy metabolism in patients with cirrhosis before and after liver transplantation.

HYPOTHESIS: Liver transplantation results in hepatic denervation. This may produce alterations of liver energy and substrate metabolism, which may contribute to weight gain after liver transplantation. DESIGN: Prospective clinical study. SETTING: Liver transplantation clinics in a university hospital. PATIENTS: Seven nondiabetic patients with cirrhosis were recruited while on a waiting list for liver transplantation. Seven healthy subjects were recruited as controls. INTERVENTION: Orthotopic liver transplantation. MAIN OUTCOME MEASURES: Evaluation of energy and substrate metabolism after ingestion of a glucose load with indirect calorimetry was performed before, 2 to 6 weeks after, and 5 to 19 months after transplantation. Whole-body glucose oxidation and storage and glucose-induced thermogenesis were calculated. RESULTS: Patients with cirrhosis had modestly elevated resting energy expenditure and normal glucose-induced thermogenesis and postprandial glucose oxidation and storage. These measures remained unchanged after liver transplantation despite a significant increase in postprandial glycemia. Patients, however, gained an average of 3 kg of body weight after 5 to 19 months compared with their weight before transplantation. CONCLUSION: Liver denervation secondary to transplantation does not lead to alterations of energy metabolism after ingestion of a glucose load.

Effect of diets high or low in unavailable and slowly digestible carbohydrates on the pattern of 24-h substrate oxidation and feelings of hunger in humans.

BACKGROUND: The pattern of substrate utilization with diets containing a high or a low proportion of unavailable and slowly digestible carbohydrates may constitute an important factor in the control, time course, and onset of hunger in humans. OBJECTIVE: We tested the hypothesis that isoenergetic diets differing only in their content of unavailable carbohydrates would result in different time courses of total, endogenous, and exogenous carbohydrate oxidation rates. DESIGN: Two diets with either a high (H diet) or a low (L diet) content of unavailable carbohydrates were fed to 14 healthy subjects studied during two 24-h periods in a metabolic chamber. Substrate utilization was assessed by whole-body indirect calorimetry. In a subgroup of 8 subjects, endogenous and exogenous carbohydrate oxidation were assessed by prelabeling the body glycogen stores with [(13)C]carbohydrate. Subjective feelings of hunger were estimated with use of visual analogue scales. RESULTS: Total energy expenditure and substrate oxidation did not differ significantly between the 2 diets. However, there was a significant effect of diet (P: = 0.03) on the carbohydrate oxidation pattern: the H diet elicited a lower and delayed rise of postprandial carbohydrate oxidation and was associated with lower hunger feelings than was the L diet. The differences in hunger scores between the 2 diets were significantly associated with the differences in the pattern of carbohydrate oxidation among diets (r = -0.67, P: = 0. 006). Exogenous and endogenous carbohydrate oxidation were not significantly influenced by diet. CONCLUSIONS: The pattern of carbohydrate utilization is involved in the modulation of hunger feelings. The greater suppression of hunger after the H diet than after the L diet may be helpful, at least over the short term, in individuals attempting to better control their food intake.

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 4h 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.

Effects of mental stress on insulin-mediated glucose metabolism and energy expenditure in lean and obese women.

The effects of the sympathetic activation elicited by a mental stress on insulin sensitivity and energy expenditure (VO(2)) were studied in 11 lean and 8 obese women during a hyperinsulinemic-euglycemic clamp. Six lean women were restudied under nonselective beta-adrenergic blockade with propranolol to determine the role of beta-adrenoceptors in the metabolic response to mental stress. In lean women, mental stress increased VO(2) by 20%, whole body glucose utilization ([6,6-(2)H(2)]glucose) by 34%, and cardiac index (thoracic bioimpedance) by 25%, whereas systemic vascular resistance decreased by 24%. In obese women, mental stress increased energy expenditure as in lean subjects, but it neither stimulated glucose uptake nor decreased systemic vascular resistance. In the six lean women who were restudied under propranolol, the rise in VO(2), glucose uptake, and cardiac output and the decrease in systemic vascular resistance during mental stress were all abolished. It is concluded that 1) in lean subjects, mental stress stimulates glucose uptake and energy expenditure and produces vasodilation; activation of beta-adrenoceptors is involved in these responses; and 2) in obese patients, the effects of mental stress on glucose uptake and systemic vascular resistance, but not on energy expenditure, are blunted.

Effects of fructose on hepatic glucose metabolism in humans.

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 micromol. kg(-1). min(-1) fructose. Glucose rate of disappearance (GR(d)), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-(2)H(2)]- and [2-(2)H(1)]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-(13)C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GR(d) under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 micromol. kg(-1). min(-1) increase in TGO, a 7.8 micromol. kg(-1). min(-1) increase in NEGP, a 2.2 micromol. kg(-1). min(-1) increase in GC, and a 7.2 micromol. kg(-1). min(-1) decrease in GR(d) (P < 0. 05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.

Effects of enteral carbohydrates on de novo lipogenesis in critically ill patients.

BACKGROUND: Conversion of glucose into lipid (de novo lipogenesis; DNL) is a possible fate of carbohydrate administered during nutritional support. It cannot be detected by conventional methods such as indirect calorimetry if it does not exceed lipid oxidation. OBJECTIVE: The objective was to evaluate the effects of carbohydrate administered as part of continuous enteral nutrition in critically ill patients. DESIGN: This was a prospective, open study including 25 patients nonconsecutively admitted to a medicosurgical intensive care unit. Glucose metabolism and hepatic DNL were measured in the fasting state or after 3 d of continuous isoenergetic enteral feeding providing 28%, 53%, or 75% carbohydrate. RESULTS: DNL increased with increasing carbohydrate intake (f1.gif" BORDER="0"> +/- SEM: 7.5 +/- 1.2% with 28% carbohydrate, 9.2 +/- 1.5% with 53% carbohydrate, and 19.4 +/- 3.8% with 75% carbohydrate) and was nearly zero in a group of patients who had fasted for an average of 28 h (1.0 +/- 0.2%). In multiple regression analysis, DNL was correlated with carbohydrate intake, but not with body weight or plasma insulin concentrations. Endogenous glucose production, assessed with a dual-isotope technique, was not significantly different between the 3 groups of patients (13.7-15.3 micromol * kg(-1) * min(-1)), indicating impaired suppression by carbohydrate feeding. Gluconeogenesis was measured with [(13)C]bicarbonate, and increased as the carbohydrate intake increased (from 2.1 +/- 0.5 micromol * kg(-1) * min(-1) with 28% carbohydrate intake to 3.7 +/- 0.3 micromol * kg(-1) * min(-1) with 75% carbohydrate intake, P: < 0. 05). CONCLUSION: Carbohydrate feeding fails to suppress endogenous glucose production and gluconeogenesis, but stimulates DNL in critically ill patients.

Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls.

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.

Effects of glucocorticoids on hepatic sensitivity to insulin and glucagon in man.

AIMS: This study was undertaken to determine the effects of a short-term dexamethasone treatment on hepatic sensitivities to insulin and glucagon. METHODS: Eleven healthy subjects were studied during one or several of four protocols. In all protocols, somatostatin was infused continuously to inhibit pancreatic hormone secretion. In protocol 1, basal insulin was infused over 300 min while glucagon was infused at a rate of 0.5 mg/kg(-1)/min(-1)during 180 min, then at a rate of 1.5 ng/kg(-1)/min(-1)during 150 min. In protocol 2, the same experiment was performed after a 2 day treatment with 8 mg/day dexamethasone. In protocol 3, the two-step glucagon infusion was performed during insulin infusion at a rate aimed to reproduce the hyperinsulinemia observed during protocol 2. In protocol 4, continuous basal insulin and low glucagon (0.5 mg/kg(-1)/min(-1)) were infused over 330 min. RESULTS: In protocol 1, plasma glucose rose transiently by 2.0 +/- 0.3 mmol/l when the glucagon rate was increased and glucose production increased by 1.4 +/- 0.5 micromol/kg(-1)/min(-1). In protocol 2, the insulin infusion rate (1.85 +/- 0.36 nmol/kg(-1)/min(-1)) required to maintain glycemia was 3.3-fold higher than during protocol 1. Glucagon-induced stimulation of glycemia (by 1.47 +/- 0.5 mmol/l) and endogenous glucose production (by 0.8 +/- 0.3 micromol/kg(-1)/min(-1)) were blunted, but not abolished. In protocol 3, endogenous glucose production was suppressed by 75% by hyperinsulinemia and was not stimulated when the glucagon infusion rate was increased. In protocol 4, endogenous glucose production did not change significantly with time. CONCLUSION: These results indicate that high dose glucocorticoids induce a marked hepatic insulin resistance. Stimulation of glucose production by hyperglucagonemia was maintained in spite of hyperinsulinemia which can be attributed to either hepatic insulin resistance and/or increased hepatic glucagon sensitivity.