Jean-Marc Schwarz

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Metabolic effects of indinavir in healthy HIV-seronegative men

BackgroundTherapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition. MethodsIndinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy. ResultsFasting glucose (4.9 ± 0.1 versus 5.2 ± 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 ± 12.2 versus 83.9 ± 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 ± 1.7 versus 15.9 ± 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 ± 0.3 versus 2.8 ± 0.5; P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 ± 0.4 versus 6.5 ± 0.6 mmol/l; P < 0.05) and insulin levels (223.1 ± 48.8 versus 390.3 ± 108.8 pmol/l; P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 ± 1.4 versus 8.6 ± 1.2 mg/kg ⋅ min per μU/ml insulin; 95% confidence interval 0.6–3.0; P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 ± 1.4 versus 15.2 ± 1.4 kg; P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography. ConclusionsIn the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.

Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study.

Background Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers. Methods Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies. Results There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60−−180 min) insulin reached comparable levels (394 ± 13 versus 390 ± 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 ± 2.2 μM and the 2-h area under the curve was 13.5 ± 3.1 μM⋅h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg⋅min per μ UI/ml (95% confidence interval for change, 3.7–6.1;P < 0.001) on indinavir (average decrease, 34.1 ± 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg⋅min (P < 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies. Conclusions A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.

Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection.

Short-term alterations in dietary carbohydrate (CHO) energy are known to alter whole-body fuel selection in humans, but the metabolic mechanisms remain unknown. We used stable isotope-mass spectrometric methods with indirect calorimetry in normal subjects to quantify the metabolic response to six dietary phases (5 d each), ranging from 50% surplus CHO (+50% CHO) to 50% deficient CHO (-50% CHO), and 50% surplus fat (+50% fat). Fasting hepatic glucose production (HGP) varied by > 40% from deficient to surplus CHO diets (1.78 +/- 0.08 vs 2.43 +/- 0.09 mg/kg per min, P < 0.01). Increased HGP on surplus CHO occurred despite significantly higher serum insulin concentrations. Lipolysis correlated inversely with CHO intake as did the proportion of whole-body lipolytic flux oxidized. Fractional de novo hepatic lipogenesis (DNL) increased more than 10-fold on surplus CHO and was unmeasurable on deficient CHO diets; thus, the preceding 5-d CHO intake could be inferred from DNL. Nevertheless, absolute hepatic DNL accounted for < 5g fatty acids synthesized per day even on +50% CHO. Whole-body CHO oxidation increased sixfold and fat oxidation decreased > 90% on surplus CHO diets. CHO oxidation was highly correlated with HGP (r2= 0.60). HGP could account for 85% of fasting CHO oxidation on +25% CHO and 67% on +50% CHO diets. Some oxidation of intracellular CHO stores was therefore also occurring. +50% fat diet had no effects on HGP, DNL, or fuel selection. We conclude that altered CHO intake alters HGP specifically and in a dose-dependent manner, that HGP may mediate the effects of CHO on whole-body fuel selection both by providing substrate and by altering serum insulin concentrations, that altered lipolysis and tissue oxidation efficiency contribute to changes in fat oxidation, and that surplus CHO is not substantially converted by the liver to fat as it spares fat oxidation, but that fractional DNL may nevertheless be a qualitative marker of recent CHO intake.

The metabolic effects of lopinavir/ritonavir in HIV-negative men.

Background: Therapy with HIV protease inhibitors (PI) has been shown to worsen glucose and lipid metabolism, but whether these changes are caused by direct drug effects, changes in disease status, or body composition is unclear. Therefore, we tested the effects of the PI combination lopinavir and ritonavir on glucose and lipid metabolism in HIV-negative subjects. Methods: A dose of 400 mg lopinavir/100 mg ritonavir was given twice a day to 10 HIV-negative men. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance, insulin sensitivity by euglycemic hyperinsulinemic clamp, and body composition were determined before and after lopinavir/ritonavir treatment for 4 weeks. Results: On lopinavir/ritonavir, there was an increase in fasting triglyceride (0.89 ± 0.15 versus 1.63 ± 0.36 mmol/l; P = 0.007), free fatty acid (FFA; 0.33 ± 0.04 versus 0.43 ± 0.06 mmol/l; P = 0.001), and VLDL cholesterol (15.1 ± 2.6 versus 20 ± 3.3 mg/dl; P = 0.05) levels. There were no changes in fasting LDL, HDL, IDL, lipoprotein (a), or total cholesterol levels. Fasting glucose, insulin, and insulin-mediated glucose disposal were unchanged, but on a 2 h oral glucose tolerance test glucose and insulin increased. There were no changes in weight, body fat, or abdominal adipose tissue by computed tomography. Conclusion: Treatment with 4 weeks of lopinavir/ritonavir in HIV-negative men causes an increase in triglyceride levels, VLDL cholesterol, and FFA levels. Lopinavir/ritonavir leads to a deterioration in glucose tolerance at 2 h, but there is no significant change in insulin-mediated glucose disposal rate by euglycemic hyperinsulinemic clamp.

Effects of isoenergetic glucose-based or lipid-based parenteral nutrition on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patients.

OBJECTIVE To compare the effects of isocaloric, isonitrogenous carbohydrate nutrition vs. lipid-based total parenteral nutrition on respiratory gas exchange and intermediary metabolism in critically ill patients. DESIGN Prospective, clinical trial. SETTING Surgical intensive care unit in a major university hospital in Switzerland. PATIENTS Sixteen patients admitted to the surgical intensive care unit. INTERVENTIONS Patients were randomized to receive isocaloric isonitrogenous total parenteral nutrition (TPN) containing 75% (TPN-glucose) or 15% (TPN-lipid) glucose over a 5-day period. MEASUREMENTS AND MAIN RESULTS Indirect glucose metabolism was assessed from plasma carbon-13 (13C)-labeled glucose and 13C-labeled CO2 production during a tracer infusion of uniformly 13C-labeled glucose, and de novo lipogenesis was estimated from the incorporation of 13C into palmitate-very low density lipoproteins (VLDL) during a tracer infusion of 1-(13)C acetate. Compared with TPN-lipid, TPN-glucose increased plasma glucose more (by 26% vs. 7%, p < .05), increased insulin more (by 284% vs. 40%, p < .01), and increased total CO2 more (by 15% vs. 0%, p < .01). Both nutrient mixtures failed to inhibit endogenous glucose production and net protein oxidation, suggesting absence of suppression of gluconeogenesis. Fractional de novo lipogenesis was markedly increased by TPN-glucose to 17.4% vs. 3.3% with TPN lipids. CONCLUSIONS The rate of glucose administration commonly used during TPN of critically ill patients does not suppress endogenous glucose production or net protein loss, but markedly stimulates de novo lipogenesis and CO2 production. Increasing the proportion of fat may be beneficial, provided that lipid emulsion has no adverse effects.

Adverse metabolic effects of dietary fructose: results from the recent epidemiological, clinical, and mechanistic studies.

Purpose of review The effects of dietary sugar on risk factors and the processes associated with metabolic disease remain a controversial topic, with recent reviews of the available evidence arriving at widely discrepant conclusions. Recent findings There are many recently published epidemiological studies that provide evidence that sugar consumption is associated with metabolic disease. Three recent clinical studies, which investigated the effects of consuming relevant doses of sucrose or high-fructose corn syrup along with ad libitum diets, provide evidence that consumption of these sugars increase the risk factors for cardiovascular disease and metabolic syndrome. Mechanistic studies suggest that these effects result from the rapid hepatic metabolism of fructose catalyzed by fructokinase C, which generates substrate for de novo lipogenesis and leads to increased uric acid levels. Recent clinical studies investigating the effects of consuming less sugar, via educational interventions or by substitution of sugar-sweetened beverages for noncalorically sweetened beverages, provide evidence that such strategies have beneficial effects on risk factors for metabolic disease or on BMI in children. Summary The accumulating epidemiological evidence, direct clinical evidence, and the evidence suggesting plausible mechanisms support a role for sugar in the epidemics of metabolic syndrome, cardiovascular disease, and type 2 diabetes.

Mechanisms of action of β-glucan in postprandial glucose metabolism in healthy men

Objective: To assess whether β-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 β-glucan or without β-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 β-glucan and cellulose. Plasma insulin concentrations were, however, 26% lower with β-glucan during the last 2 h of the 9 h meal ingestion. Glucose rate of appearance at steady state was 12% lower with β-glucan. This corresponded to a 21% reduction in the systemic appearance rate of exogenous carbohydrate with β-glucan, while endogenous glucose production was similar with both diets. De novo lipogenesis was similar with and without β-glucan.Conclusion: Administration of frequent meals with or without β-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 β-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.European Journal of Clinical Nutrition (2001) 55, 327–333

The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with Human Immunodeficiency Virus-Associated Lipoatrophy and Hypoleptinemia

CONTEXT Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities. OBJECTIVE The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia. DESIGN This was a 6-month, open-label, proof-of-principle pilot study. SETTING Metabolic ward studies were performed before and 3 and 6 months after leptin treatment. PARTICIPANTS Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml. INTERVENTION Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods). OUTCOME MEASURES Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety. RESULTS Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass. CONCLUSIONS Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.

Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans

BackgroundProspective studies in humans examining the effects of fructose consumption on biological markers associated with the development of metabolic syndrome are lacking. Therefore we investigated the relative effects of 10 wks of fructose or glucose consumption on plasma uric acid and RBP-4 concentrations, as well as liver enzyme (AST, ALT, and GGT) activities in men and women.MethodsAs part of a parallel arm study, older (age 40–72), overweight and obese male and female subjects (BMI 25–35 kg/m2) consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wks. Fasting and 24-h blood collections were performed at baseline and following 10 wks of intervention and plasma concentrations of uric acid, RBP-4 and liver enzyme activities were measured.ResultsConsumption of fructose, but not glucose, led to significant increases of 24-h uric acid profiles (P < 0.0001) and RBP-4 concentrations (P = 0.012), as well as plasma GGT activity (P = 0.04). Fasting plasma uric acid concentrations increased in both groups; however, the response was significantly greater in subjects consuming fructose (P = 0.002 for effect of sugar). Within the fructose group male subjects exhibited larger increases of RBP-4 levels than women (P = 0.024).ConclusionsThese findings suggest that consumption of fructose at 25% of energy requirements for 10 wks, compared with isocaloric consumption of glucose, may contribute to the development of components of the metabolic syndrome by increasing circulating uric acid, GGT activity, suggesting alteration of hepatic function, and the production of RBP-4.