The long and winding TRAIL to weight loss.

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is in clinical trials for the treatment of cancer. In the present issue of Clinical Science, Bernardi and co-workers report that the administration of TRAIL in mice fed on a high-fat diet resulted in reduced adiposity and improved metabolic responses to a glucose and insulin tolerance test compared with mice without TRAIL. The metabolic improvements were associated with a higher rate of apoptotic fat cells and with a reduction in the levels of pro-inflammatory cytokines. These results suggest that TRAIL could be an exciting new therapeutic for treating obesity, but further studies are required to determine its major mechanisms of action.

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.

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.

Hepatic insulin resistance in antipsychotic naive schizophrenic patients: stable isotope studies of glucose metabolism.

OBJECTIVE: Our objective was to measure insulin sensitivity and body composition in antipsychotic-naive patients with DSM IV schizophrenia and/or schizoaffective disorder compared with matched controls. DESIGN: Seven antipsychotic medication-naive patients fulfilling the DSM IV A criteria for schizophrenia/schizoaffective disorder were matched for body mass index, age, and sex with seven control subjects. We measured endogenous glucose production and peripheral glucose disposal using a hyperinsulinemic euglycemic clamp (plasma insulin concentration approximately 200 pmol/liter) in combination with stable isotopes. Fat content and fat distribution were determined with a standardized single-slice computed tomography scan and whole body dual-energy x-ray absorptiometry. RESULTS: Endogenous glucose production during the clamp was 6.7 micromol/kg x min (sd 2.7) in patients vs. 4.1 micromol/kg x min (sd 1.6) in controls (P = 0.02) (95% confidence interval -5.2 to 0.006). Insulin-mediated peripheral glucose uptake was not different between patients and controls. The amount of sc abdominal fat in patients was 104.6 +/- 28.6 cm(3) and 63.7 +/- 28.0 cm(3) in controls (P = 0.04) (95% confidence interval 4.4-77.2). Intraabdominal fat and total fat mass were not significantly different. CONCLUSIONS: Antipsychotic medication-naive patients with schizophrenia or schizoaffective disorder display hepatic insulin resistance compared with matched controls. This finding cannot be attributed to differences in intraabdominal fat mass or other known factors associated with hepatic insulin resistance and suggests a direct link between schizophrenia and hepatic insulin resistance.

Adiponectin and glucose production in patients infected with Plasmodium falciparum.

Infections are often complicated by an increase in glucose production due to stimulation of the secretion of glucose counter-regulatory hormones and cytokines. Adiponectin, a fat-derived hormone with insulin-sensitizing properties, could play a regulatory role in the degree of stimulation of glucose production by the infectious agent. Therefore, we investigated the possible correlation between glucose production and plasma adiponectin levels in 25 subjects: 7 patients with cerebral malaria, 6 with uncomplicated malaria, and 12 matched controls. Glucose production was significantly higher in patients with malaria compared to healthy controls (P < .001). Adiponectin levels were not different between the patients with malaria and the control group. However, patients with cerebral malaria had significantly higher values for adiponectin than the patients with uncomplicated malaria (P < .005). Glucose production and gluconeogenesis were positively correlated to plasma adiponectin in the patients (r = 0.835, P < .001 and r = 0.846, P < .001, respectively), whereas these correlations were absent in the controls (r = -0.329, NS and r = -0.028, NS, respectively). In conclusion, adiponectin levels were not different between patients with malaria and their matched controls. However, patients infected with Plasmodium falciparum who have higher glucose production also have higher adiponectin levels. In healthy subjects such a correlation was not found. As adiponectin is known to inhibit glucose production, stimulation of adiponectin secretion during infection could be intended to restrain the glucose production stimulating properties of hormones and cytokines secreted during infection.

No damaging effect of chemotherapy in addition to radiotherapy on the thyroid axis in young adult survivors of childhood cancer.

Late effects of treatment for childhood cancer on the thyroid axis are ascribed predominantly to radiotherapy. Whether chemotherapy has an additional detrimental effect is still unclear. Our aim was to evaluate this effect in young adult survivors of a broad spectrum of childhood cancers. The thyroid axis in 205 childhood cancer survivors was evaluated in relation to former use of chemotherapy and radiotherapy (cranial, cranio-spinal, cervical, mediastinal, or thoracic). The mean follow-up time was 17.5 yr. Damage to the thyroid axis was found in 55 patients (26.8%). Thirty-seven patients (18%) had thyroidal disease. Diagnoses varied from TSH elevation to papillary carcinoma. After multivariate analysis, high risk radiation field, irradiation dose, and the diagnosis of non-Hodgkin lymphoma/Hodgkin's disease were found to be significant risk factors for developing thyroid disease. Treatment with chemotherapy did not have an additional negative effect on the thyroid axis. For the development of central (pituitary or hypothalamic) thyroid dysfunction, patients with a brain tumor were at increased risk. Chemotherapy for childhood cancer does not contribute to the damage on the thyroid axis inflicted by radiotherapy during young adulthood.

Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance.

In both rodents and humans, aging-associated reductions in skeletal muscle AMP-activated protein kinase (AMPK) activity and mitochondrial function have been linked to the development of skeletal muscle insulin resistance. However, whether reductions in skeletal muscle AMPK and mitochondrial capacity actually precipitate the development of aging-induced insulin resistance is not known. Mice lacking both isoforms of the AMPK ß-subunit in skeletal muscle (AMPK-MKO) have no detectable AMPK activity and are characterized by large reductions in exercise capacity, mitochondrial content, and contraction-stimulated glucose uptake making them an ideal model to determine whether reductions in AMPK and mitochondrial content promote the development of aging-induced insulin resistance. In the current study we find that a lack of skeletal muscle AMPK results in a life-long reduction in mitochondrial activity but does not affect body mass, body composition, glucose tolerance, or insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp in mice of old age (18 mo). These data demonstrate that reductions in skeletal muscle AMPK and mitochondrial activity do not cause the development of age-induced insulin resistance.

Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans.

In diabetes mellitus and sepsis, low erythrocyte glutathione (GSH) concentrations are found. Whether this is caused by lowered GSH production has not been clarified. To obtain insight in the relationship between erythrocyte GSH concentrations and GSH production, GSH kinetics were measured in healthy male volunteers during 4 different clamps (low-dose or medium-dose insulin [100 or 400 pmol/L] and euglycemia or hyperglycemia [5 or 12 mmol/L]) in a control setting (n = 6; all 4 clamps in the same subject) or after systemic administration of lipopolysaccharide (to mimic sepsis) (4 groups of n = 6; each clamp in a different subject). Hyperinsulinemia decreased erythrocyte GSH concentration (P = .042), but did not affect fractional synthetic rate (FSR) of GSH. Hyperglycemia did not affect erythrocyte GSH concentration, but decreased FSR of GSH (P = .025). Lipopolysaccharide decreased erythrocyte GSH concentration (P < .001), but increased FSR of erythrocyte GSH (P = .035). Depending on the metabolic circumstances, we found either stable GSH concentrations with lower production rates or decreased levels with either no change or an increase in production rate. Based upon these data, it seems inappropriate to infer conclusions about changes in synthesis rate of GSH from changes in its concentration.

Insulin sensitivity in multiple pathways is differently affected during zidovudine/lamivudine-containing compared with NRTI-sparing combination antiretroviral therapy.

OBJECTIVE: The extent and manner by which HIV nucleoside reverse transcriptase inhibitors contribute to insulin resistance is unclear. We evaluated the effect of zidovudine/lamivudine (ZDV/3TC) on glucose metabolism. METHODS: combination antiretroviral therapy-naive men were randomized to lopinavir/ritonavir (LPV/r, 400/100 mg twice a day) + ZDV/3TC or LPV/r (533/133 mg twice a day) + nevirapine (NVP). Computerized tomography, dual-energy X-ray absorptiometry scans, and hyperinsulinemic euglycemic clamps using stable isotopes were performed before and after 3, 12, and 24 months of combination antiretroviral therapy. RESULTS: Insulin-stimulated peripheral glucose disposal decreased by 25% after 3 months in patients on zidovudine/lamivudine/lopinavir/ritonavir (ZDV/3TC/LPV/r) (P < 0.001) and this decreased rate persisted thereafter, followed by a transient decrease in insulin-mediated inhibition of lipolysis. In the nevirapine/lopinavir/ritonavir (NVP/LPV/r) group, hepatic insulin sensitivity had improved compared with baseline after 24 months. After the initial 3 months, limb fat decreased in the ZDV/3TC/LPV/r arm up to 24 months [-849 +/- 345 g (P = 0.017)], and visceral adipose tissue increased over 2 years [+36.2 +/- 13.3 cm2 (P = 0.009)]. In the NVP/LPV/r group, a generalized increase in fat mass was observed. CONCLUSIONS: Treatment with ZDV/3TC/LPV/r versus NVP/LPV/r differentially affects glucose and lipid metabolism. The ZDV/3TC/LPV/r regimen induced peripheral insulin resistance, a transient increase in basal lipolysis and a transient decrease in insulin-mediated inhibition of lipolysis, whereas hepatic insulin sensitivity improved with the NVP/LPV/r regimen.

Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes.

Adiponectin is a fat cell-derived hormone with insulin-sensitizing properties. Low plasma adiponectin levels are associated with insulin resistance as found in obesity. One of the mechanisms for this finding is hampered insulin signaling via phosphatidylinositol 3-kinase (PI3K) with concomitant decreased adiponectin secretion. Because insulin can also stimulate signaling at the level of mammalian target of rapamycin (mTOR) by a mechanism that is dependent on the presence of amino acids, the role of mTOR signaling in adiponectin secretion was studied. In view of the vesicular nature of adiponectin secretion, the role of lysosomes was explored as well. In 3T3-L1 adipocytes, both insulin and amino acids stimulated adiponectin secretion. The stimulation by insulin was PI3K dependent but mTOR independent. The stimulation by amino acids was independent of both PI3K and mTOR. Whereas the effect of insulin via PI3K was mainly on adiponectin secretion from adipocytes, the effect of amino acids was predominantly due to their role as substrates for adiponectin synthesis. The acidotropic agents ammonia and methylamine, but not the lysosomal protease inhibitor leupeptin and the autophagy inhibitor 3-methyladenine, strongly inhibited adiponectin secretion and increased the intracellular adiponectin pool. In conclusion, adiponectin production is substrate driven. Phosphatidylinositol 3-kinase and an acidic lysosomal pH, but not amino acid-mediated mTOR signaling or lysosomal breakdown, are involved in adiponectin secretion.

Hyperglycemia prevents the suppressive effect of hyperinsulinemia on plasma adiponectin levels in healthy humans.

Adiponectin is a fat-derived hormone with insulin-sensitizing properties. In patients with type 2 diabetes plasma adiponectin levels are decreased. Since these patients are characterized by high plasma insulin and glucose concentrations, hyperinsulinemia and hyperglycemia could be responsible for the downregulation of adiponectin. Insulin decreases adiponectin levels in humans. The effect of hyperglycemia is unknown. To determine the selective effects of insulin, glucose, or their combination on plasma adiponectin, clamps were performed in six healthy males on four occasions in a crossover design: 1) lower insulinemic-euglycemic clamp (100 pmol/l insulin, 5 mmol/l glucose) (reference clamp); 2) hyperinsulinemic-euglycemic clamp (400 pmol/l insulin, 5 mmol/l glucose); 3) lower insulinemic-hyperglycemic clamp (100 pmol/l insulin, 12 mmol/l glucose); and 4) hyperinsulinemic-hyperglycemic clamp (400 pmol/l insulin, 12 mmol/l glucose). Adiponectin concentrations and high-molecular-weight (HMW)-to-total adiponectin ratio were measured at the start and end of the 6-h clamps. After the 6-h study period, total plasma adiponectin levels were significantly (P = 0.045) decreased by 0.63 microg/ml in the lower insulinemic-euglycemic clamp (clamp 1). In both euglycemic groups (clamps 1 and 2) adiponectin concentrations significantly declined (P = 0.016) over time by 0.56 microg/ml, whereas there was no change in both hyperglycemic groups (clamps 3 and 4) (P = 0.420). In none of the clamps did the ratio of HMW to total adiponectin change. We conclude that insulin suppresses plasma adiponectin levels already at a plasma insulin concentration of 100 pmol/l. Hyperglycemia prevents the suppressive effect of insulin. This suggests that, in contrast to glucose, insulin could be involved in the downregulation of plasma adiponectin in insulin-resistant patients.