The effect of short-term high versus normal protein intake on whole-body protein synthesis and balance in children following cardiac surgery: a randomized double-blind controlled clinical trial.

BACKGROUND: Infants undergoing cardiac surgery are at risk of a negative protein balance, due to increased proteolysis in response to surgery and the cardiopulmonary bypass circuit, and limited intake. The aim of the study was to quantify the effect on protein kinetics of a short-term high-protein (HP) diet in infants following cardiac surgery. METHODS: In a prospective, double-blinded, randomized trial we compared the effects of a HP (5 g · kg(-1) · d(-1)) versus normal protein (NP, 2 g · kg(-1) · d(-1)) enteral diet on protein kinetics in children <24 months, on day 2 following surgical repair of congenital heart disease. Valine kinetics and fractional albumin synthesis rate (FSRalb) were measured with mass spectrometry using [1-(13)C]valine infusion. The Mann-Whitney U test was used to investigate differences between group medians. Additionally, the Hodges-Lehmann procedure was used to create a confidence interval with a point estimate of median differences between groups. RESULTS: Twenty-eight children (median age 9 months, median weight 7 kg) participated in the study, of whom in only 20 subjects isotopic data could be used for final calculations. Due to underpowering of our study, we could not draw conclusions on the primary outcome parameters. We observed valine synthesis rate of 2.73 (range: 0.94 to 3.36) and 2.26 (1.85 to 2.73) µmol · kg(-1) · min(-1) in the HP and NP diet, respectively. The net valine balance was 0.54 (-0.73 to 1.75) and 0.24 (-0.20 to 0.63) µmol · kg(-1) · min(-1) in the HP and NP group. Between groups, there was no difference in FSRalb. We observed increased oxidation and BUN in the HP diet, compared to the NP diet, as a plausible explanation of the metabolic fate of surplus protein. CONCLUSIONS: It is plausible that the surplus protein in the HP group has caused the increase of valine oxidation and ureagenesis, compared to the NP group. Because too few patients had completed the study, we were unable to draw conclusions on the effect of a HP diet on protein synthesis and balance. We present our results as new hypothesis generating data. TRIAL REGISTRATION: Dutch Trial Register NTR2334.

Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans.

Angiopoietin-like 4 (ANGPTL4) is a regulator of LPL activity. In this study we examined whether different fatty acids have a differential effect on plasma ANGPTL4 levels during hyperinsulinemia in healthy lean males. In 10 healthy lean males, 3 hyperinsulinemic euglycemic clamps were performed during concomitant 6 h intravenous infusion of soybean oil (Intralipid® rich in PUFA), olive oil (Clinoleic® rich in MUFA) and control saline. In 10 other healthy lean males, 2 hyperinsulinemic clamps were performed during infusion of a mixed lipid emulsion containing a mixture of fish oil (FO), medium-chain triglycerides (MCTs), and long-chain triglycerides (LCTs) (FO/MCT/LCT; SMOFlipid®) or saline. FFA levels of approximately 0.5 mmol/l were reached during each lipid infusion. Plasma ANGPTL4 decreased during hyperinsulinemia by 32% (18-52%) from baseline. This insulin-mediated decrease in ANGPTL4 concentrations was partially reduced during concomitant infusion of olive oil and completely blunted during concomitant infusion of soybean oil and FO/MCT/LCT. The reduction in insulin sensitivity was similar between all lipid infusions. In accordance, incubation of rat hepatoma cells with the polyunsaturated fatty acid C22:6 increased ANGPTL4 expression by 70-fold, compared with 27-fold by the polyunsaturated fatty acid C18:2, and 15-fold by the monounsaturated fatty acid C18:1. These results suggest that ANGPTL4 is strongly regulated by fatty acids in humans, and is also dependent on the type of fatty acid.

Effects of a hypercaloric diet on ß-cell responsivity in lean healthy men.

OBJECTIVE: Insulin resistance and hyperinsulinaemia precede the onset of obesity-induced DM2. The early adaptation of the ß-cell during the initial phase of overfeeding and weight gain has only been partly elucidated. We studied the early changes in insulin clearance and ß-cell responsivity during a positive and negative energy balance in lean healthy men. DESIGN: We studied in nine healthy lean men [age, 37 (27-43) years; BMI, 23·6 (20·6-25·6) kg/m(2) ] insulin sensitivity, insulin clearance, insulin secretion and static and dynamic ß-cell responsivity at baseline and after the hypercaloric and subsequent hypocaloric diet. RESULTS: Participants gained 7 [5·1-7·6]% of their initial body weight on the hypercaloric diet. Compared to baseline, insulin sensitivity and insulin clearance decreased, while glucose-stimulated insulin secretion was higher. The GLP-1 response to oral glucose did not change. The dynamic ß-cell responsivity index increased but the basal and static responsivity indexes did not change. Total and static disposition indexes (DIs) in the hypercaloric state showed a trend towards a decrease. During the hypocaloric diet, insulin sensitivity, glucose-stimulated insulin secretion and insulin clearance returned to baseline. The responsivity and the DIs were not different in the hypocaloric phase compared to baseline. CONCLUSION: A positive energy balance resulting in weight gain in lean men induces hyperinsulinaemia, which is explained by a combined effect on insulin clearance and insulin secretion. Increased insulin secretion was related to insulin resistance-induced higher glucose concentrations but also to increased dynamic ß-cell responsivity. Glucose sensitivity of the ß-cell did not change. These early adaptations are completely reversible during a negative energy balance after loss of the gained weight.

Normal rates of whole-body fat oxidation and gluconeogenesis after overnight fasting and moderate-intensity exercise in patients with medium-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Impairments in gluconeogenesis have been implicated in the pathophysiology of fasting hypoglycemia in medium-chain acyl-CoA dehydrogenase deficiency. However, whole body glucose and fat metabolism have never been studied in vivo. METHODS: Stable isotope methodology was applied to compare fat and glucose metabolism between four adult patients with MCADD and four matched controls both at rest and during 1.5 h of moderate-intensity exercise. Additionally, intramyocellular lipid and glycogen content and intramyocellular acylcarnitines were assessed in muscle biopsies collected prior to and immediately after cessation of exercise. RESULTS: At rest, plasma FFA turnover was significantly higher in patients with MCADD, whereas the plasma FFA concentrations did not differ between patients and controls. Blood glucose kinetics did not differ between groups both at rest and during exercise. Palmitate and FFA turnover, total fat and carbohydrate oxidation rates, the use of muscle glycogen and muscle derived triglycerides during exercise did not differ between patients and controls. Plasma FFA oxidation rates were significantly lower in patients at the latter stages of exercise. Free carnitine levels in muscle were lower in patients, whereas no differences were detected in muscle acetylcarnitine levels. CONCLUSIONS: Whole-body or skeletal muscle glucose and fat metabolism were not impaired in adult patients with MCADD. This implies that MCADD is not rate limiting for energy production under the conditions studied. In addition, patients with MCADD have a higher FFA turnover rate after overnight fasting, which may stimulate ectopic lipid deposition and, as such, make them more susceptible for developing insulin resistance.

Type of infectious disease affects glucose metabolism and liver glycogen content in Surinamese children: malaria vs. pneumonia.

BACKGROUND AND AIM: Fasting is an important risk factor for hypoglycemia in children with malaria or pneumonia. Young children are more at risk because of impaired endogenous glucose production presumably due to smaller liver glycogen stores. The aim of this study was to measure the effect of a bolus of glucagon on glucose kinetics, as an indicator of glycogen content, in fasted children with malaria and pneumonia. METHODS: After a 16-h controlled fast, plasma glucose concentration and endogenous glucose production were measured using [6,6-2H2]glucose in six children with severe malaria and 12 children with severe pneumonia who were 1-5 years of age before and after a bolus glucagon. RESULTS: Basal glucose concentration and endogenous glucose production were higher in children with malaria, p=0.034 and p=0.010, respectively. After glucagon, the increase in the plasma glucose concentration was higher in children with malaria (52±26% vs. 31±23%, p=0.029). Also, the increase in glucose production was higher in children with malaria (106±42% vs. 70±52%, p=0.023). There were no differences in the fasting duration or duration of illness. CONCLUSIONS: This is the first study to show infectious disease-related differences in the adaptation of glucose metabolism to fasting in young children. It was found that basal glucose concentration and endogenous glucose production were higher in children with malaria. The increase in plasma glucose concentration and endogenous glucose production in response to glucagon was higher in children with malaria, indicating smaller glycogen stores in children with pneumonia.

Fasting predisposes to hypoglycemia in Surinamese children with severe pneumonia, and young children are more at risk.

The objective of this study was to investigate glucose kinetics during controlled fasting in children with severe pneumonia. Plasma glucose concentration, endogenous glucose production and gluconeogenesis were measured in 12 Surinamese children (six young: 1-3 years, six older: 3-5 years) with severe pneumonia during a controlled 16 h fast using stable isotopes [6,6-(2)H2]glucose and (2)H2O at a hospital-based research facility. On admission, the glucose concentrations were comparable in both groups: young children: 5.1 ± 1.3 mmol/l, older children: 4.8 ± 0.6 mmol/l, p = 0.685, with a decrease during the first 8 h of fasting in the young children only to 3.6 ± 0.5, p = 0.04. Glucose production was comparable in both groups: young: 24.5 ± 8.3, older: 24.9 ± 5.9 µmol/kg(•)min, p = 0.926. Between 8 and 16 h of fasting, the glucose concentration decreased comparably in both groups (young: - 0.9 ± 0.7, p = 0.004; older: -1.0 ± 0.4 mmol/l, p = 0.001), as did glucose production (young: -6.8 ± 6.3, p = 0.003; older: -5.3 ± 3.4 µmol/kg(•)min, p = 0.001). Gluconeogenesis decreased in young children only: -5.0 ± 7.4, p = 0.029. We conclude that fasting predisposes to hypoglycemia in children with severe pneumonia. Young children are more at risk than older children. Glucose production is an important determinant of the plasma glucose concentration in young children with pneumonia, indicating an inability to reduce glucose usage. Our results are largely in agreement with the literature on the adaptation of glucose metabolism in children with malaria, although there seem to be disease-specific differences in the regulation of gluconeogenesis.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver.

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T(3)) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T(3) or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T(3) microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T(3) microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T(3) microdialysis in the PVN increased EGP by 11 +/- 4% (P = 0.020), while EGP decreased by 5 +/- 8% (ns) in vehicle-treated rats (T(3) vs. Veh, P = 0.030). Plasma glucose increased by 29 +/- 5% (P = 0.0001) after T(3) microdialysis versus 8 +/- 3% in vehicle-treated rats (T(3) vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T(3) administration. Effects of PVN T(3) microdialysis were independent of plasma T(3), insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T(3) microdialysis on EGP. We conclude that stimulation of T(3)-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

Dietary saturated fat/cholesterol, but not unsaturated fat or starch, induces C-reactive protein associated early atherosclerosis and ectopic fat deposition in diabetic pigs.

BACKGROUND: Diabetes is thought to accelerate cardiovascular disease depending on the type of diet. This study in diabetic subjects was performed to investigate the metabolic, inflammatory and cardiovascular effects of nutritional components typically present in a Western, Mediterranean or high glycaemic diet. METHODS: Streptozotocin-diabetic pigs (~45 kg) were fed for 10 weeks supplemental (40% of dietary energy) saturated fat/cholesterol (SFC), unsaturated fat (UF) or starch (S) in an eucaloric dietary intervention study. RESULTS: Fasting plasma total, LDL and HDL cholesterol concentrations were 3-5 fold higher (p < 0.01) in SFC compared to UF and S pigs. Fasting plasma NEFA concentrations (mmol/L) were highest (p < 0.05) in SFC (1.09 ± 0.17), intermediate in UF (0.80 ± 0.14) and lowest in S pigs (0.58 ± 0.14) whereas plasma glucose (~13 mmol/L), triglyceride (~0.5 mmol/L) and insulin (~24 pmol/L) concentrations were comparable among SFC, UF and S pigs. The postprandial response area under the curves (AUC, 0-4 h) for glucose but not for insulin and triglyceride responses were intermediate in SFC (617 ± 144) and lowest (p < 0.05) in UF (378 ± 157) compared to S pigs (925 ± 139). Fasting hepatic glucose production, hepatic and peripheral insulin sensitivity and blood pressure were not different among pigs. C-reactive protein (CRP) concentrations (mg/L) were highest (p < 0.05) in SFC (25 ± 4), intermediate in S (21 ± 3) and lowest in UF pigs (14 ± 2). Liver weights, liver and muscle triglyceride concentrations, and the surface area of aorta fatty streaks were highest (p < 0.01) in SFC pigs. A positive correlation between postprandial plasma CRP and aorta fatty streaks was observed in SFC pigs (R(2) = 0.95). Retroperitoneal fat depot weight (g) was intermediate in SFC (260 ± 72), lowest in S (135 ± 51) and highest (p < 0.05) in UF (571 ± 95) pigs. CONCLUSION: Dietary saturated fat/cholesterol induces inflammation, atherosclerosis and ectopic fat deposition whereas an equally high dietary unsaturated fat load does not induce these abnormalities and shows beneficial effects on postprandial glycaemia in diabetic pigs.

Sparse production but preferential incorporation of recently produced naive T cells in the human peripheral pool.

In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although (2)H(2)O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term up- and down-labeling with (2)H(2)O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool.

Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia.

Type 2 diabetes is associated with altered immune and hemostatic responses. We investigated the selective effects of hyperglycemia and hyperinsulinemia on innate immune, coagulation, and fibrinolytic responses during systemic inflammation. Twenty-four healthy humans were studied for 8 hours during clamp experiments in which either plasma glucose, insulin, both, or none was increased, depending on randomization. Target plasma concentrations were 5 versus 12 mM for glucose, and 100 versus 400 pmol/L for insulin. After 3 hours, 4 ng/kg Escherichia coli endotoxin was injected intravenously to induce a systemic inflammatory and procoagulant response. Endotoxin administration induced cytokine release, activation of neutrophils, endothelium and coagulation, and inhibition of fibrinolysis. Hyperglycemia reduced neutrophil degranulation (plasma elastase levels, P < .001) and exaggerated coagulation (plasma concentrations of thrombin-antithrombin complexes and soluble tissue factor, both P < .001). Hyperinsulinemia attenuated fibrinolytic activity due to elevated plasminogen activator-inhibitor-1 levels (P < .001). Endothelial cell activation markers and cytokine concentrations did not differ between clamps. We conclude that in humans with systemic inflammation induced by intravenous endotoxin administration hyperglycemia impairs neutrophil degranulation and potentiates coagulation, whereas hyperinsulinemia inhibits fibrinolysis. These data suggest that type 2 diabetes patients may be especially vulnerable to prothrombotic events during inflammatory states.

Adipocyte-myocyte crosstalk in skeletal muscle insulin resistance; is there a role for thyroid hormone?

PURPOSE OF REVIEW: To review original research studies and reviews that present data on adipocyte-myocyte crosstalk in the development of skeletal muscle insulin resistance with a specific focus on thyroid hormone. RECENT FINDINGS: Adipose tissue communicates with skeletal muscle not only through free fatty acids but also through secretion of various products called adipokines. Adipokines came out as governors of insulin sensitivity and are deregulated in obesity. In addition to well known leptin, adiponectin, interleukin-6 and tumor necrosis factor-alpha, newer adipokines like retinol-binding protein 4 have been associated with insulin resistance. There is mounting evidence that not only adipose tissue but also skeletal muscle produces and secretes biologically active proteins or 'myokines' that facilitate metabolic crosstalk between organ systems. In recent years, increased expression of myostatin, a secreted anabolic inhibitor of muscle growth and development, has been associated with obesity and insulin resistance. Both hypothyroidism and hyperthyroidism affect insulin sensitivity in multiple ways that might overlap adipocyte-myocyte crosstalk. Recent studies have provided new insights in effects of processing of the parent hormone T4 to the active T3 at the level of the skeletal muscle. SUMMARY: Adipocyte-myocyte crosstalk is an important modulator in the development of skeletal muscle insulin resistance. Thyroid disorders are very common and may have detrimental effects on skeletal muscle insulin resistance, potentially by interacting with adipocyte-myocyte crosstalk.

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency.

BACKGROUND: A potential role for muscle in glucose homeostasis was recently suggested based on characterization of extrahepatic and extrarenal glucose-6-phosphatase (glucose-6-phosphatase-beta). To study the role of extrahepatic tissue in glucose homeostasis during fasting glucose kinetics were studied in two patients with a deficient hepatic and renal glycogenolysis and/or gluconeogenesis. DESIGN: Endogenous glucose production (EGP), glycogenolysis (GGL), and gluconeogenesis (GNG) were quantified with stable isotopes in a patient with glycogen storage disease type 1a (GSD-1a) and a patient with fructose-1,6-bisphosphatase (FBPase) deficiency. The [6,6-(2)H(2)]glucose dilution method in combination with the deuterated water method was used during individualized fasting tests. RESULTS: Both patients became hypoglycemic after 2.5 and 14.5 h fasting, respectively. At that time, the patient with GSD-1a had EGP 3.84 micromol/kg per min (30% of normal EGP after an overnight fast), GGL 3.09 micromol/kg per min, and GNG 0.75 micromol/kg per min. The patient with FBPase deficiency had EGP 8.53 micromol/kg per min (62% of normal EGP after an overnight fast), GGL 6.89 micromol/kg per min GGL, and GNG 1.64 micromol/kg per min. CONCLUSION: EGP was severely hampered in both patients, resulting in hypoglycemia. However, despite defective hepatic and renal GNG in both disorders and defective hepatic GGL in GSD-1a, both patients were still able to produce glucose via both pathways. As all necessary enzymes of these pathways have now been functionally detected in muscle, a contribution of muscle to EGP during fasting via both GGL as well as GNG is suggested.

Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production.

OBJECTIVE: The purpose of this study was to investigate the mechanism by which the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) increases high-density lipoprotein cholesterol (HDLc) in treatment-experienced human immunodeficiency virus-1 (HIV-1)-infected patients. METHODS AND RESULTS: Twelve HIV-1 infected patients, with stably suppressed HIV-1 viral load using AZT/3TC/abacavir for > or =6 months, added NVP to their current antiretroviral regimen. Patients received a primed bolus infusion of the stable isotope L-[1-(13)C]-valine for 12 hours before, as well as 6 and 24 weeks after, the addition of NVP to study apolipoprotein A-I (apoA-I) kinetics. Absolute production rate (APR) and fractional catabolic rate (FCR) of apoA-I were calculated using SAAM-II modeling. Major HDLc-modulating enzymes were assessed. Plasma apoA-I and HDLc levels increased significantly after 24 weeks of treatment by, respectively, 13+/-4% (P=0.01) and 16+/-6% (P=0.015). Concomitantly, apoA-I production rate at 24 weeks increased by 17+/-7% (P=0.04). ApoA-I catabolism did not change. A modest increase of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity was observed. CONCLUSIONS: NVP increases apoA-I production, which contributes to the HDLc increase after introduction of NVP-containing regimens. In view of the potent antiatherogenic effects of apoA-I, the observed increase may contribute to the favorable cardiovascular profile of NVP.

Early endotoxemia increases peripheral and hepatic insulin sensitivity in healthy humans.

CONTEXT: Sepsis-induced hypoglycemia is a well known, but rare, event of unknown origin. OBJECTIVE: The aim of the study was to obtain insight into the mechanism of sepsis-induced hypoglycemia, focusing on glucose kinetics and insulin sensitivity measured with stable isotopes by using the model of human endotoxemia. DESIGN: Glucose metabolism was measured during two hyperinsulinemic [insulin levels of 100 pmol/liter (low-dose clamp) and 400 pmol/liter (medium-dose clamp)] euglycemic (5 mmol/liter) clamps on two occasions: without or with lipopolysaccharide (LPS). SETTING: The study was conducted at the Academic Medical Center, Metabolic and Clinical Research Unit (Amsterdam, The Netherlands). PARTICIPANTS: Eighteen healthy male volunteers participated in the study. INTERVENTION: A hyperinsulinemic euglycemic (5 mmol/liter) clamp with LPS (two groups of six subjects; insulin infusion at rates of either 10 or 40 mU.m(-2).min(-1)) or without LPS (n = 6; both insulin infusions in same subjects). MAIN OUTCOME MEASURE: We measured hepatic and peripheral insulin sensitivity. RESULTS: Hepatic insulin sensitivity, defined as a decrease in endogenous glucose production during hyperinsulinemia (100 pmol/liter), was higher in the LPS group compared to the control group (P = 0.010). Insulin-stimulated peripheral glucose uptake was higher in both clamps after LPS compared to the control setting (P = 0.006 and 0.010), despite a significant increase in the plasma concentrations of norepinephrine and cytokines in the LPS group during both clamps. CONCLUSIONS: These data indicate that shortly (2 h) after administration of LPS, peripheral and hepatic insulin sensitivity increase. This may contribute to the hypoglycemia occurring in some patients with critical illness, especially in the setting of intensive insulin therapy.

A rosiglitazone-induced increase in adiponectin does not improve glucose metabolism in HIV-infected patients with overt lipoatrophy.

HIV-infected patients on antiretroviral therapy frequently develop changes in body fat distribution and disturbances in glucose metabolism, associated with reduced adiponectin levels. Because adiponectin, principally the high-molecular-weight (HMW) form, has insulin-sensitizing properties, we investigated the effects of an increase in adiponectin on glucose metabolism in HIV-lipodystrophy. In this randomized, double-blind, placebo-controlled trial, we included HIV-1-infected patients with severe lipoatrophy, with an undetectable viral load and who had received neither protease inhibitors nor stavudine for ≥6 mo. Patients were randomized to rosiglitazone [8 mg daily (n = 8)] to increase adiponectin levels or placebo (n = 5) for 16 wk. Peripheral glucose disposal, glucose production, and lipolysis were measured after an overnight fast and during a hyperinsulinemic-euglycemic clamp using stable isotopes. Body composition was assessed by computed tomography and dual-energy X-ray absorptiometry. Although body fat distribution was unaffected, rosiglitazone increased total plasma adiponectin levels by 107% (P < 0.02) and the ratio of HMW to total adiponectin by 73% (P < 0.001). In the placebo group, neither total adiponectin levels (P = 0.62) nor the ratio of HMW to total adiponectin changed (P = 0.94). The marked increase in adiponectin induced by rosiglitazone was not associated with significant changes in basal endogenous glucose production (P = 0.90), basal lipolysis (P = 0.90), insulin-mediated suppression of glucose production (P = 0.17) and lipolysis (P = 0.54) nor with changes in peripheral glucose disposal (P = 0.13). Acknowledging the limited statistical power of our small study, these findings, if confirmed by larger studies, could question the importance of adiponectin in regulating glucose metabolism in HIV-lipodystrophy.

Muscle acylcarnitines during short-term fasting in lean healthy men.

The transition from the fed to the fasted resting state is characterized by, among other things, changes in lipid metabolism and peripheral insulin resistance. Acylcarnitines have been suggested to play a role in insulin resistance, as well as other long-chain fatty acid metabolites. Plasma levels of long-chain acylcarnitines increase during fasting, but this is unknown for muscle long-chain acylcarnitines. In the present study we investigated whether muscle long-chain acylcarnitines increase during fasting and we investigated their relationship with glucose/fat oxidation and insulin sensitivity in lean healthy humans. After 14 h and 62 h of fasting, glucose fluxes, substrate oxidation, and plasma and muscle acylcarnitines were measured before and during a hyperinsulinaemic-euglycaemic clamp. Hyperinsulinaemia decreased long-chain muscle acylcarnitines after 14 h of fasting, but not after 62 h of fasting. In both the basal state and during the clamp, glucose oxidation was lower and fatty acid oxidation was higher after 62 h compared with 14 h of fasting. Absolute changes in glucose and fatty acid oxidation in the basal compared with hyperinsulinaemic state were not different. Muscle long-chain acylcarnitines did not correlate with glucose oxidation, fatty acid oxidation or insulin-mediated peripheral glucose uptake. After 62 h of fasting, the suppression of muscle long-chain acylcarnitines by insulin was attenuated compared with 14 h of fasting. Muscle long-chain acylcarnitines do not unconditionally reflect fatty acid oxidation. The higher fatty acid oxidation during hyperinsulinaemia after 62 h compared with 14 h of fasting, although the absolute decrease in fatty acid oxidation was not different, suggests a different set point.

Optimal nutrition during the period of mechanical ventilation decreases mortality in critically ill, long-term acute female patients: a prospective observational cohort study.

INTRODUCTION: Optimal nutrition for intensive care patients has been proposed to be the provision of energy as determined by indirect calorimetry, and protein provision of at least 1.2 g/kg pre-admission weight per day. The evidence supporting these nutritional goals is based on surrogate outcomes and is not yet substantiated by patient oriented, clinically meaningful endpoints. In the present study we evaluated the effects of achieving optimal nutrition in ICU patients during their period of mechanical ventilation on mortality. METHODS: This was a prospective observational cohort study in a mixed medical-surgical, 28-bed ICU in an academic hospital. 243 sequential mixed medical-surgical patients were enrolled on day 3-5 after admission if they had an expected stay of at least another 5-7 days. They underwent indirect calorimetry as part of routine care. Nutrition was guided by the result of indirect calorimetry and we aimed to provide at least 1.2 g of protein/kg/day. Cumulative balances were calculated for the period of mechanical ventilation. Outcome parameters were ICU, 28-day and hospital mortality. RESULTS: In women, when corrected for weight, height, Apache II score, diagnosis category, and hyperglycaemic index, patients who reached their nutritional goals compared to those who did not, showed a hazard ratio (HR) of 0.199 for ICU mortality (CI 0.048-0.831; P = 0.027), a HR of 0.079 for 28 day mortality (CI 0.013-0.467; P = 0.005) and a HR of 0.328 for hospital mortality (CI 0.113-0.952; P = 0.04). Achievement of energy goals whilst not reaching protein goals, did not affect ICU mortality; the HR for 28 day mortality was 0.120 (CI 0.027-0.528; P = 0.005) and 0.318 for hospital mortality (CI 0.107-0.945; P = 0.039). No difference in outcome related to optimal feeding was found for men. CONCLUSIONS: Optimal nutritional therapy improves ICU, 28-day and hospital survival in female ICU patients. Female patients reaching both energy and protein goals have better outcomes than those reaching only the energy goal. In the present study men did not benefit from optimal nutrition.

Prolonged fasting induces peripheral insulin resistance, which is not ameliorated by high-dose salicylate.

CONTEXT: Elevated plasma free fatty acids, excess reactive oxygen species, inflammation, and gluco-counterregulatory hormones induce insulin resistance (IR) through activation of Jun NH(2)-terminal kinase and nuclear factor-kappaB inhibitor kappaB kinase, which leads to hyperphosphorylation of the insulin receptor substrate type 1. Aspirin blocks nuclear factor-kappaB inhibitor kappaB kinase and improves IR in type 2 diabetes mellitus. OBJECTIVE: We hypothesized that high-dose aspirin would also attenuate fasting-induced IR in healthy lean subjects. DESIGN: Glucose and glutathione (GHS) metabolism was studied after 12 and 60 h of fasting on two occasions: with and without aspirin (6 g/d). SETTING: The study took place at the Academic Medical Center, Metabolic Research Unit. PARTICIPANTS: Six healthy lean men participated. INTERVENTION: Intervention included 60 h of fasting with or without aspirin ( approximately 6 g/d). MAIN OUTCOME MEASURE: Main outcome measures included glucose and GSH metabolism. RESULTS: Fasting decreased insulin-mediated peripheral glucose uptake by 46% after 60 h (P = 0.03). Aspirin did not alter this effect of 60 h of fasting on insulin sensitivity (P = 0.03). GSH concentration decreased during fasting, but the fractional synthetic rate of GSH was unaffected either with or without aspirin. Fasting did not affect inflammatory parameters, although aspirin increased soluble TNF receptors I and II. CONCLUSION: Prolonged fasting induces profound peripheral IR. In contrast to type 2 diabetes mellitus, high-dose salicylate does not affect fasting-induced peripheral IR.

Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance.

CONTEXT: Complex glycosphingolipids, in majority the ganglioside GM3, surround the insulin receptor in a special membrane compartment (raft) and modulate signaling through this receptor. Increased levels of GM3 in rafts impair insulin signaling, resulting in insulin resistance. Gaucher disease is a lysosomal storage disorder in which impaired breakdown of glucosylceramide leads to its accumulation in macrophages. Secondary to this defect, GM3 concentrations, for which glucosylceramide is the precursor, in plasma and several cell types are elevated. OBJECTIVE: We studied the influence of glycosphingolipid storage on whole body glucose and fat metabolism by measuring insulin-mediated (IMGU) and noninsulin-mediated glucose uptake (NIMGU) and suppression of free fatty acids by insulin. DESIGN AND MAIN OUTCOME MEASURES: We studied six Gaucher patients, either naive to treatment or with considerable remaining burden of disease, and six matched healthy control subjects in the basal state, during an euglycemic and a hyperglycemic clamp with somatostatin measuring NIMGU and during an euglycemic hyperinsulinemic clamp measuring IMGU, using stable isotopes. RESULTS: NIMGU (both during euglycemia and hyperglycemia) did not differ between patients and control subjects. IMGU was lower in Gaucher patients, compared with controls. Suppression of lipolysis by insulin tended to be less effective in Gaucher patients. CONCLUSION: Gaucher disease, a lysosomal glycosphingolipid storage disorder, is associated with (peripheral) insulin resistance, possibly through the influence of glycosphingolipids on insulin receptor functioning.

Muscle adaptation to short-term fasting in healthy lean humans.

CONTEXT: It has been demonstrated repeatedly that short-term fasting induces insulin resistance, although the exact mechanism in humans is unknown to date. Intramyocellular sphingolipids (i.e. ceramide) have been suggested to induce insulin resistance by interfering with the insulin signaling cascade in obesity. OBJECTIVE: Our objective was to study peripheral insulin sensitivity together with muscle ceramide concentrations and protein kinase B/AKT phosphorylation after short-term fasting. MAIN OUTCOME MEASURES AND DESIGN: After 14- and 62-h fasting, glucose fluxes were measured before and after a hyperinsulinemic euglycemic clamp. Muscle biopsies were performed in the basal state and during the clamp to assess muscle ceramide and protein kinase B/AKT. RESULTS: Insulin-mediated peripheral glucose uptake was significantly lower after 62-h fasting compared with 14-h fasting. Intramuscular ceramide concentrations tended to increase during fasting. During the clamp the phosphorylation of protein kinase B/AKT at serine(473) in proportion to the total amount of protein kinase B/AKT was significantly lower. Muscle ceramide did not correlate with plasma free fatty acids. CONCLUSIONS: Fasting for 62 h decreases insulin-mediated peripheral glucose uptake with lower phosphorylation of AKT at serine(473). AKT may play a regulatory role in fasting-induced insulin resistance. Whether the decrease in AKT can be attributed to the trend to higher muscle ceramide remains unanswered.