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BackgroundAltered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus.MethodsTwo single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g x 2, or 4) no additions.ResultsIn study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones.ConclusionIn RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.

Aim To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans. Materials and Methods We performed an open-label study in 14 obese men (age 38 +/- 11 years, body mass index 32 +/- 4 kg/m(2)) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [F-18]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes. Results Plasma amylase (+7 U/L [95% confidence intervals 3-11],P < .01) and lipase (+19 U/L [7-30],P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm(3)[-8-8],P= .96) and no change in pancreatic cellular infiltration was found (P= .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00-0.17],P= .0507). Conclusions Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes. Keywords

Objectives Gastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the postoperative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release. Methods A specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after, and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin, and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation. Results Plasma postprandial secretin was more than doubled in humans after RYGB (P < 0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased the secretion of secretin in a sodium-glucose cotransporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P < 0.05) from the perfused rat pancreas but affected neither insulin (P = 0.2) nor glucagon (P = 0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P = 0.04), while blood glucose peak time was delayed (from 15 to 45 min) and gastric empty

Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

Postprandial secretion of glucagon-like peptide-1 (GLP-1) is enhanced after Roux-en-Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP-1 secretion through activation of TGR5-receptors. We aimed to evaluate GLP-1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB-operated participants. Eleven participants (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo-controlled, crossover-study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral intake of CDCA increased plasma concentrations of GLP-1, C-peptide, glucagon, peptide YY, neurotensin, total bile acids, and fibroblast growth factor 19 significantly compared with placebo (all P < 0.05 for peak and positive incremental area-under-the-curve (piAUC)). All plasma hormone concentrations were unaffected by UDCA Neither UDCA nor CDCA changed glucose, cholecystokinin or glucose-dependent insulinotropic polypeptide (GIP) concentrations. In conclusion, our findings demonstrate that the primary bile acid chenodeoxycholic acid is able to enhance secretion of gut hormones when administered orally in RYGB-operated patients-even in the absence of nutrients.

Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and beta-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin 9-39 (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose tolerant patients were studied after RYGB in a randomized, placebo-controlled, four-day, cross-over study with standard mixed meal tests and concurrent administration of: placebo, oral sitagliptin, Ex-9 infusion or combined Ex-9/sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated beta-cell function and aggravated postprandial hyperglucagonaemia compared with placebo, whereas sitagliptin had no effect despite 2-3-fold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or beta-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4 sensitive glucose lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.

Roux-en-Y gastric bypass (RYGB) leads to increased peripheral insulin sensitivity. The aim of this study was to investigate the effect of RYGB on expression and regulation of proteins involved in regulation of peripheral glucose metabolism. Skeletal muscle and adipose tissue biopsies from glucose tolerant and type 2 diabetic subjects at fasting and during a hyperinsulinemic-euglycemic clamp before as well as 1 week, 3 and 12 months after RYGB were analyzed for relevant insulin effector proteins/signaling components. Improvement in peripheral insulin sensitivity mainly occurred at 12 months post-surgery when major weight loss was evident and occurred concomitantly with alterations in plasma adiponectin and in protein expression/signaling in peripheral tissues. In skeletal muscle, protein expression of GLUT4, phosphorylated levels of TBC1D4 as well as insulin-induced changes in phosphorylation of Akt and glycogen synthase activity were enhanced 12 months post-surgery. In adipose tissue, protein expression of GLUT4, Akt2, TBC1D4 and acetyl-CoA carboxylase (ACC), phosphorylated levels of AMP-activated protein kinase and ACC as well as insulin-induced changes in phosphorylation of Akt and TBC1D4 were enhanced 12 months post-surgery. Adipose tissue from glucose tolerant subjects was the most responsive to RYGB compared to type 2 diabetic patients, whereas changes in skeletal muscle were largely similar in these two groups. In conclusion, an improved molecular insulin sensitive phenotype of skeletal muscle and adipose tissue appears to contribute to the improved whole body insulin action following a substantial weight loss after RYGB.