Rapid and body weight-independent improvement of endothelial and high-density lipoprotein function after Roux-en-Y gastric bypass: role of glucagon-like peptide-1.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. METHODS AND RESULTS: Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 µg·kg(-1)·h(-1)). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. CONCLUSIONS: RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.

Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers.

UNLABELLED: Human iron homeostasis is regulated by intestinal iron transport, hepatic hepcidin release, and signals from pathways that consume or supply iron. The aim of this study was to characterize the adaptation of iron homeostasis under hypoxia in mountaineers at the levels of (1) hepatic hepcidin release, (2) intestinal iron transport, and (3) systemic inflammatory and erythropoietic responses. Twenty-five healthy mountaineers were studied. Blood samples and duodenal biopsies were taken at baseline of 446 m as well as on day 2 (MG2) and 4 (MG4) after rapid ascent to 4559 m. Divalent metal-ion transporter 1 (DMT-1), ferroportin 1 (FP-1) messenger RNA (mRNA), and protein expression were analyzed in biopsy specimens by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Serum hepcidin levels were analyzed by mass spectrometry. Serum iron, ferritin, transferrin, interleukin (IL)-6, and C-reactive protein (CRP) were quantified by standard techniques. Serum erythropoietin and growth differentiation factor 15 (GDF15) levels were measured by enzyme-linked immunosorbent assay (ELISA). Under hypoxia, erythropoietin peaked at MG2 (P < 0.001) paralleled by increased GDF15 on MG2 (P < 0.001). Serum iron and ferritin levels declined rapidly on MG2 and MG4 (P < 0.001). Duodenal DMT-1 and FP-1 mRNA expression increased up to 10-fold from baseline on MG2 and MG4 (P < 0.001). Plasma CRP increased on MG2 and MG4, while IL-6 only increased on MG2 (P < 0.001). Serum hepcidin levels decreased at high altitude on MG2 and MG4 (P < 0.001). CONCLUSION: This study in healthy volunteers showed that under hypoxemic conditions hepcidin is repressed and duodenal iron transport is rapidly up-regulated. These changes may increase dietary iron uptake and allow release of stored iron to ensure a sufficient iron supply for hypoxia-induced compensatory erythropoiesis.

Disturbed eating at high altitude: influence of food preferences, acute mountain sickness and satiation hormones.

PURPOSE: Hypoxia has been shown to reduce energy intake and lead to weight loss, but the underlying mechanisms are unclear. The aim was therefore to assess changes in eating after rapid ascent to 4,559 m and to investigate to what extent hypoxia, acute mountain sickness (AMS), food preferences and satiation hormones influence eating behavior. METHODS: Participants (n = 23) were studied at near sea level (Zurich (ZH), 446 m) and on two days after rapid ascent to Capanna Margherita (MG) at 4,559 m (MG2 and MG4). Changes in appetite, food preferences and energy intake in an ad libitum meal were assessed. Plasma concentrations of cholecystokinin, peptide tyrosine-tyrosine, gastrin, glucagon and amylin were measured. Peripheral oxygen saturation (SpO(2)) was monitored, and AMS assessed using the Lake Louis score. RESULTS: Energy intake from the ad libitum meal was reduced on MG2 compared to ZH (643 ± 308 vs. 952 ± 458 kcal, p = 0.001), but was similar to ZH on MG4 (890 ± 298 kcal). Energy intake on all test days was correlated with hunger/satiety scores prior to the meal and AMS scores on MG2 but not with SpO(2) on any of the 3 days. Liking for high-fat foods before a meal predicted subsequent energy intake on all days. None of the satiation hormones showed significant differences between the 3 days. CONCLUSION: Reduced energy intake after rapid ascent to high altitude is associated with AMS severity. This effect was not directly associated with hypoxia or changes in gastrointestinal hormones. Other peripheral and central factors appear to reduce food intake at high altitude.

Roux-en Y gastric bypass is superior to duodeno-jejunal bypass in improving glycaemic control in Zucker diabetic fatty rats.

BACKGROUND: Whilst weight loss results in many beneficial metabolic consequences, the immediate improvement in glycaemia after Roux-en-Y Gastric bypass (RYGB) remains intriguing. Duodenal jejunal bypass (DJB) induces similar glycaemic effects, while not affecting calorie intake or weight loss. We studied diabetic ZDF(fa/fa) rats to compare the effects of DJB and RYGB operations on glycaemia. METHODS: Male ZDF(fa/fa) rats, aged 12 weeks underwent RYGB, DJB or sham operations. Unoperated ZDF(fa/fa) and ZDF(fa/+w)ere used as controls. Body weight, food intake, fasting glucose, insulin and gut hormones were measured at baseline and on postoperative days 2, 10 and 35. An oral glucose tolerance test (OGTT) was performed on days 12 and 26. RESULTS: DJB had similar food intake and body weight to sham-operated and unoperated control ZDF(fa/fa) rats (p = NS), but had lower fasting glucose (p < 0.05). RYGB had lower food intake, body weight and fasting glucose compared to all groups (p < 0.001). DJB prevented the progressive decline in fasting insulin observed in the sham-operated or unoperated ZDF(fa/fa) rats, while RYGB with normalized glycaemia reduced the physiological requirement for raised fasting insulin. CONCLUSIONS: Bypassing the proximal small bowel with the DJB has mild to moderate body weight independent effects on glucose homeostasis and preservation of fasting insulin levels in the medium term. These effects might be further amplified by the additional anatomical and physiological changes after RYGB.

Reduced insulin sensitivity as a marker for acute mountain sickness?

Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS.