Gregory Baud

Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells

Bile acids (BA) are signalling molecules which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex BA in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces Glucagon-Like Peptide-1 (GLP-1) production by L-cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L-cells and controls GLP-1 production is unknown. Here we show that FXR activation in L-cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR-deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.

Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study.

Objectives:To compare the long-term benefit of gastric bypass [Roux-en-Y gastric bypass (RYGB)] versus adjustable gastric banding (AGB) on nonalcoholic fatty liver disease (NAFLD) in severely obese patients. Background:NAFLD improves after weight loss surgery, but no histological study has compared the effects of the various bariatric interventions. Methods:Participants consisted of 1236 obese patients (body mass index = 48.4 ± 7.6 kg/m2), enrolled in a prospective longitudinal study for up to 5 years after RYGB (n = 681) or AGB (n = 555). Liver biopsy samples were available for 1201 patients (97.2% of those at risk) at baseline, 578 patients (47.2%) at 1 year, and 413 patients (68.9%) at 5 years. Results:At baseline, NAFLD was present in 86% patients and categorized as severe [NAFLD activity score (NAS) ≥3] in 22% patients. RYGB patients had a higher body mass index (49.8 ± 8.2 vs 46.8 ± 6.5 kg/m2, P < 0.001) and more severe NAFLD (NAS: 2.0 ± 1.5 vs 1.7 ± 1.4, P = 0.004) than AGB patients. Weight loss at 5 years was 25.5% ± 11.8% after RYGB versus 21.4% ± 12.7% after AGB (P < 0.001). When analyzed with a mixed model, all NAFLD parameters improved after surgery (P < 0.001) and improved significantly more after RYGB than after AGB [steatosis (%): 1 year, 7.9 ± 13.7 vs 17.9 ± 21.5, P < 0.001/5 years, 8.7 ± 7.1 vs 14.5 ± 20.8, P < 0.05; NAS: 1 year, 0.7 ± 1.0 vs 1.1 ± 1.2, P < 0.001/5 years, 0.7 ± 1.2 vs 1.0 ± 1.3, P < 0.05]. In multivariate analysis, the superiority of RYGB was primarily but not entirely explained by weight loss. Conclusions:The improvement of NAFLD was superior after RYGB than after AGB.

Bile Diversion in Roux-en-Y Gastric Bypass Modulates Sodium-Dependent Glucose Intestinal Uptake

Gastro-intestinal exclusion by Roux-en-Y gastric bypass (RYGB) improves glucose metabolism, independent of weight loss. Although changes in intestinal bile trafficking have been shown to play a role, the underlying mechanisms are unclear. We performed RYGB in minipigs and showed that the intestinal uptake of ingested glucose is blunted in the bile-deprived alimentary limb (AL). Glucose uptake in the AL was restored by the addition of bile, and this effect was abolished when active glucose intestinal transport was blocked with phlorizin. Sodium-glucose cotransporter 1 remained expressed in the AL, while intraluminal sodium content was markedly decreased. Adding sodium to the AL had the same effect as bile on glucose uptake. It also increased postprandial blood glucose response in conscious minipigs following RYGB. The decrease in intestinal uptake of glucose after RYGB was confirmed in humans. Our results demonstrate that bile diversion affects postprandial glucose metabolism by modulating sodium-glucose intestinal cotransport.

Islet Survival and Function Following Intramuscular Autotransplantation in the Minipig

The liver may not be an optimal site for islet transplantation due to obstacles by an instant blood‐mediated inflammatory response (IBMIR), and low revascularization of transplanted islets. Therefore, intramuscular islet transplantation (IMIT) offers an attractive alternative, based on its simplicity, enabling easier access for noninvasive graft imaging and cell explantation. In this study, we explored the outcome of autologous IMIT in the minipig (n = 30). Using the intramuscular injection technique, we demonstrated by direct histological evidence the rapid revascularization of islets autotransplanted into the gracilius muscle. Islet survival assessment was performed using immunohistochemistry staining for insulin and glucagon up to a period of 6 months. Furthermore, we showed the crucial role of minimizing mechanical trauma to the myofibers and limiting exocrine contamination. Intramuscular islet graft function after transplantation was confirmed by documenting the acute insulin response to intravenous glucose in 5/11 pancreatectomized animals. Graft function after IMIT remained however significantly lower than the function measured in 12 out of 18 minipigs who received a similar islet volume in the liver through intraportal infusion. Collectively, these results demonstrated in a clinically relevant preclinical model, suggest IMIT as a promising alternative to intraportal infusion for the transplantation of β cells in certain medical situations.

Incidence and Predictive Factors of Postprandial Hyperinsulinemic Hypoglycemia After Roux-en-Y Gastric Bypass: A Five year Longitudinal Study.

Background: Postprandial hyperinsulinemic hypoglycemia (PHH) is often reported after Roux-en-Y gastric bypass (RYGB). In the absence of a prospective study, the clinical and biological determinants of PHH remain unclear. Objective: To determine the incidence and predictive factors of PHH after RYGB. Methods: Participants were 957 RYGB patients enrolled in an ongoing longitudinal cohort study. We analyzed the results of an oral glucose tolerance test (OGTT) routinely performed before surgery and 1 and/or 5 years after. PHH was defined as blood glucose < 50 mg/dL AND plasma insulin > 3 mU/L at 120 minutes post glucose challenge. Validated indices of insulin sensitivity (Matsuda index), beta-cell function (Insulinogenic index), and beta-cell mass (fasting C-peptide: glucose ratio) were calculated, from glucose, insulin, and c-peptide values measured during OGTT. Results: OGTT results were available in all patients at baseline, in 85.6% at 12 months and 52.8% at 60 months. The incidence of PHH was 0.5% at baseline, 9.1% * and 7.9%* at 12 months and 60 months following RYGB (*: P < 0.001). In multivariate logistic regression analysis, PHH after RYGB was independently associated with lower age (P = 0.005), greater weight loss (P = 0.031), as well as higher beta-cell function (P = 0.002) and insulin sensitivity (P < 0.001), but not with beta-cell mass (P = 0.381). A preoperative elevated beta-cell function was an independent predictor of PHH after RYGB (receiver operating characteristics curve area under the curve 0.68, P = 0.04). Conclusions: : The incidence of PHH significantly increased after RYGB but remained stable between 1 and 5 years. The estimation of beta-cell function with an OGTT before surgery can identify patients at risk for developing PHH after RYGB.

Sodium glucose transport modulation in type 2 diabetes and gastric bypass surgery

Active sodium-glucose transporters play a role to glucose homeostasis and represent novels targets for the management of type 2 diabetes (T2D). Sodium-glucose cotransporter 1 (SGLT1) is essential for intestinal glucose absorption from the lumen into enterocytes, whereas glucose reabsorption by the kidney is mainly mediated by sodium-glucose cotransporter 2 (SGLT2). SGLT2 inhibitors were developed to occlude SGLT2 glucose reabsorption pathway and cause glycosuria, thereby reducing plasma glucose concentrations. This new class of antidiabetic drugs has been shown to be effective in reducing cardiovascular morbidity and mortality in patients with T2D. Initial clinical studies also suggest that SGLT1 inhibition increases glucagon-like peptide 1 (GLP-1) secretion and decreases postchallenge blood glucose excursion, resulting in a dose-dependent improvement of glucose control. In parallel, we recently identified a previously unknown effect of bile diversion in gastric bypass on sodium glucose transport and postprandial glucose homeostasis, through the modulation of intestinal trafficking of endogenous sodium. This mechanism is consistent with available clinical evidence, and opens up new perspectives in metabolic surgery. More generally, the modulation of intestinal sodium-glucose cotransport appears to be a promising avenue to prevent or treat T2D.

Comparative results of gastric banding in adolescents and young adults

BACKGROUND/PURPOSE Obesity has become a major public health priority. Because of disappointing results obtained with dietary and medical programs, bariatric surgery has been offered to adolescents, although this practice remains controversial. Our aim was to evaluate laparoscopic adjustable gastric banding (LAGB) in adolescents at 2-year follow-up. MATERIAL AND METHODS This prospective study, from 2008 to 2013, compared results between adolescent patients and young adult controls. The LAGB technique and the follow-up program were similar. Weight loss and comorbid disease were analyzed. RESULTS Thirty-six adolescents (mean age at surgery=16.7±1.3years) were operated on and compared to 53 young adults (mean age at surgery=21.7±1.9years). The mean weight and BMI at surgery were 124.4±20.7 and 43.9±5.5kg/m(2), respectively. Among the adolescents, none were diabetic or hypertensive. The mean glycated hemoglobin was 5.6±1.2%. In four cases (11%) dyslipidemia was observed. There was no significant difference between the two groups in terms of initial preoperative weight or BMI. The absolute BMI values at 6, 12 and 24months after surgery were comparable between adolescents and young adults: 38.7 vs 39.8, 36.0 vs 37.6 and 33.5 vs 36.1kg/m(2), respectively. The excess weight loss was higher in adolescents at 12 and 24months: 48.6 vs 37.6% (p=0.03); and 62.3 vs 45.5% (p=0.02). During this period, insulin resistance and dyslipidemia decreased similarly in both groups. CONCLUSION Provided there is careful selection of patients and a supportive multidisciplinary team, satisfying results can be obtained after LAGB in adolescents, comparable to those obtained in young adults at 2-year follow-up.

Roux-en-Y Gastric Bypass and Intestinal Glucose Handling: A Salty Sweet Operation

Q1 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Dear Editors: Gastrointestinal exclusion by Roux-en-Y gastric bypass (RYGB) improves glucose metabolism, beyond weight loss. The underlying mechanisms remain, however, unclear. In their recent article, Cavin et al studied the changes of intestinal glucose handling induced by this procedure. The authors first showed in rats that RYGB reduces the overall blood glucose response to oral glucose. Second, they measured the RNA expression of glucose transporters (SGLT1 and GLUT1-5) in the various intestinal limbs of RYGB, and estimated intestinal glucose uptake in vitro. Overall, Cavin et al concluded that RYGB does not modify the uptake of ingested glucose, but rather increases the intestinal disposal of circulating glucose, as previously suggested by Saeidi et al. Similar to Cavin et al, we recently reported that RYGB decreased the overall blood glucose response after a mixed meal in humans. We also explored the responsible mechanisms in a minipig model mimicking the clinical procedure, but our findings suggest an alternative explanation to the results of Cavin et al.We first observed that themeal-derived glucose was absorbed only in the common intestinal limb (CL), where food meets bile and other gastrointestinal fluids. Indeed, glucose and xylose uptake appeared blunted in the bile-deprived alimentary limb (AL), and restored by the addition of bile. We also found that SGLT1 remained normally expressed and functional in the AL, because phlorizin was able to abrogate the effect of bile on glucose and xylose uptake. However, the luminal content of sodium decreased from the biliary limb to the CL, and was collapsed in the AL. Furthermore, the addition of sodium in the AL had the same effect as bile on glucose and xylose uptake. When added to a mixed meal, sodium also increased the postprandial blood glucose response in consciousminipigs submitted to RYGB. In a very elegant clinical study, Zeevi et al recently reexplored the determinants of postprandial glucose response in physiological conditions. These authors found that, beyond glucose content of the meal and other known risk factors including body mass index, glycated hemoglobin, and age, the meal sodium content is a major determinant of postprandial glucose response in humans. In line with Zeevi et al’s results, our study demonstrated that bile diversion in RYGB affects postprandial glucose homeostasis by decreasing intestinal sodium-dependent glucose transport. More generally, our results suggest that bile and other endogenous fluids are the main source of the sodium circulating daily in the intestine, resulting in the high sodium microclimate required for the active transport of ingested glucose. In their in vitro experiments, Cavin et al incorporated Dglucose (30 mmol/L) in Ringer bicarbonate solution, which contains 130 mEq/L of sodium, a concentration sufficient for