PYY-Dependent Restoration of Impaired Insulin and Glucagon Secretion in Type 2 Diabetes following Roux-En-Y Gastric Bypass Surgery.
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SUBMITTER: Ramracheya RD
PROVIDER: S-EPMC5063952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsThe gut hormone peptide tyrosine tyrosine (PYY) is critical for maintaining islet integrity and restoring islet function following Roux-en-Y gastric bypass (RYGB). The expression of PYY and its receptors (NPYRs) in islets has been documented but not fully characterized. Modulation of islet PYY by the proteolytic enzyme dipeptidyl peptidase IV (DPP-IV) has not been investigated and the impact of DPP-IV inhibition on islet PYY function remains unexplored. Here we have addressed these gaps and their effects on glucose-stimulated insulin secretion (GSIS). We have also investigated changes in pancreatic PYY in diabetes and following RYGB.MethodsImmunohistochemistry and gene expression analysis were used to assess PYY, NPYRs and DPP-IV expression in rodent and human islets. DPP-IV activity inhibition was achieved by sitagliptin. Secretion studies were used to test PYY and the effects of sitagliptin on insulin release, and the involvement of GLP-1. Radioimmunoassays were used to measure hormone content in islets.ResultsPYY and DPP-IV localized in different cell types in islets while NPYR expression was confined to the beta-cells. Chronic PYY application enhanced GSIS in rodent and diabetic human islets. DPP-IV inhibition by sitagliptin potentiated GSIS; this was mediated by locally-produced PYY, and not GLP-1. Pancreatic PYY was markedly reduced in diabetes. RYGB strongly increased islet PYY content, but did not lead to full restoration of pancreatic GLP-1 levels.ConclusionLocal regulation of pancreatic PYY, rather than GLP-1, by DPP-IV inhibition or RYGB can directly modulate the insulin secretory response to glucose, indicating a novel role of pancreatic PYY in diabetes and weight-loss surgery.
| S-EPMC5836881 | biostudies-literature
Project description:OBJECTIVE:Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic ?-cells and involved in insulin secretion. We aimed to explore the role of BAs/FXR and TRPA1 in improved GSIS in diabetic rats after RYGB. METHODS:RYGB or sham surgery was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 transgenic mice. Gene and protein expression of islets were assessed by qPCR and western blotting. Electrophysiological properties of single ?-cells were studied using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured using enzyme-linked immunosorbent assays or intravenous glucose tolerance test (IVGTT). RESULTS:RYGB increases GSIS, particularly the first-phase of GSIS in both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. Importantly, the effects of RYGB were attenuated in TRPA1-deficient mice. Moreover, GK ?-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1-/- ?-cells displayed a marked hyperpolarization and decreased glucose-evoked action potential firing, which was associated with impaired GSIS. RYGB restored TRPA1 expression and current in GK ?-cells. This was accompanied by improved glucose-evoked electrical activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of TRPA1. CONCLUSIONS:The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 expression plays a critical role in the enhanced GSIS and remission of diabetes in GK rats after RYGB.
| S-EPMC6728758 | biostudies-literature
Project description:IntroductionPatients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain limited due to the challenges of metabolic evaluation during the early postoperative period. The purpose of this investigation was to determine the role of foregut exclusion in the resolution of type 2 diabetes after RYGB.MethodsPatients with type 2 diabetes (n = 15) undergoing RYGB had a gastrostomy tube (G-tube) placed in their gastric remnant at time of surgery. Patients were randomized to receive a mixed meal tolerance test via oral or G-tube feeding immediately prior to and 2 weeks after surgery in a repeated measures crossover design. Plasma glucose, insulin, C-peptide, incretin responses, and indices of meal-stimulated insulin secretion and sensitivity were determined.ResultsBody weight, fat mass, fasting glucose and insulin, and circulating lipids were significantly decreased 2 weeks after surgery. The glycemic response to feeding was reduced as a function of total area under the curve but not after adjustment for the reduction in fasting glucose. Oral feeding significantly enhanced insulin and incretin secretion after RYGB, which was entirely ablated by G-tube feeding.ConclusionForegut exclusion accounts for the rise in incretin and insulin secretion but may not fully explain the early improvements in glucose metabolism after RYGB surgery.
| S-EPMC8475221 | biostudies-literature
Project description:The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the β-cell response to glucose (Total, 13 ± 1 vs. 11 ± 1 × 10(-9) min(-1), P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.
| S-EPMC3968439 | biostudies-literature
Project description:Metabolic surgery has been increasingly recommended for obese diabetic patients, but questions remain as to its effectiveness for nonobese diabetic patients and its mechanism that leads to glucose homeostasis independently of weight loss. Roux-en-Y gastric bypass (RYGB), as one of the most effective metabolic operations, excludes a portion of stomach with the proximal intestine (biliopancreatic limb, BL) and rearranges the distal end of the intestine into a Y-configuration, in which food can flow from the upper stomach pouch through the Roux limb (RL). To address the above questions to RYGB surgery, we designed a series of surgical procedures in Goto-Kakizaki （GK） rats to assess the relationship between glycemic control independent of weight loss and RL length in the RYGB procedure and studied the molecular mechanism of the RL from a systematic and comprehensive view.
2020-02-10 | GSE126835 | GEO
Project description:OBJECTIVE:Roux-en-Y gastric bypass (RYGB) surgery produces rapid and persistent reductions in plasma triglyceride (TG) levels associated with fewer cardiovascular events. The mechanisms of the reduction in systemic TG levels remain unclear. We hypothesized that RYGB reduces intestinal TG secretion via altered enterocyte lipid handling. METHODS:RYGB or Sham surgery was performed in diet-induced obese, insulin-resistant male Sprague-Dawley rats. First, we tested whether RYGB reduced test meal-induced TG levels in the intestinal lymph, a direct readout of enterocyte lipid secretion. Second, we examined whether RYGB modified TG enterocyte secretion at the single lipid level and in comparison to other lipid subclasses, applying mass spectrometry lipidomics to the intestinal lymph of RYGB and Sham rats (0-21 days after surgery). Third, we explored whether RYGB modulated the metabolic characteristics of primary enterocytes using transcriptional and functional assays relevant to TG absorption, reesterification, storage in lipid droplets, and oxidation. RESULTS:RYGB reduced overall postprandial TG concentrations compared to Sham surgery in plasma and intestinal lymph similarly. RYGB reduced lymphatic TG concentrations more than other lipid subclasses, and shifted the remaining TG pool towards long-chain, unsaturated species. In enterocytes of fasted RYGB rats, lipid uptake was transcriptionally (Fatp4, Fabp2, Cd36) and functionally reduced compared to Sham, whereas TG reesterification genes were upregulated. CONCLUSION:Our results show that RYGB substantially reduces intestinal TG secretion and modifies enterocyte lipid absorption and handling in rats. These changes likely contribute to the improvements in the plasma TG profile observed after RYGB in humans.
| S-EPMC6480308 | biostudies-literature
Project description:ObjectiveRoux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.MethodsWe studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.ResultsWe found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.ConclusionAn early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.
| S-EPMC5642268 | biostudies-literature
Project description:Analysis of changes in gene expression after weight loss. The hypothesis tested in this study was that the weight loss caused by Roux-en-Y Gastric bypass may alter the expression of genes involved in multiple molecular pathways related to obesity. The results will generate important data for studies involving treatment of obesity, which is characterized as a multifactorial disease that affects thousands of individuals worldwide.
2017-09-03 | GSE83223 | GEO
Project description:OBJECTIVE:The long-term changes in insulin sensitivity and ?-cell function in morbidly obese patients with type 2 diabetes mellitus who undergo Roux-en-Y gastric bypass (RYGB) surgery or standard medical care remain unclear. We prospectively studied longitudinal changes of glucostatic parameters in morbidly obese patients with type 2 diabetes mellitus undergoing RYGB surgery or diabetes support and education (DSE). RESEARCH METHODS AND DESIGN:Sixty-one morbidly obese subjects (41.7 ± 0.6 kg/m) with type 2 diabetes mellitus were assigned to RYGB surgery (n = 30) or DSE (n = 31). They were matched for sex, age, and body weight. Insulin sensitivity index (Si) and acute insulin response (AIR) were derived from frequently sampled intravenous glucose tolerance test. Body composition was measured using dual-energy x-ray absorptiometry. General linear model with repeated measures was used to examine the longitudinal changes (baseline, 6 months, 12 months) in these parameters. RESULTS:At 12-month follow-up, significant improvement in obesity measures, body composition, glucose homeostasis, Si, and AIR was observed after RYGB surgery and weight loss. These outcomes were not influenced by preoperative insulin use. Although there were no significant changes in the body composition among DSE subjects, they experienced a decline in the Si and AIR, along with an increase in fasting glucose and HbA1c. The between-group differences in Si and AIR at 12-month follow-up were completely attenuated with adjustment to changes in body weight. CONCLUSIONS:The long-term effects of RYGB surgery on glucostatic parameters are partly dependent on weight loss. In morbidly obese patients with diabetes who were offered DSE, a progressive decline in the glucose homeostasis and glucostatic parameters is observed despite absence of weight gain. (NCT00787670).
| S-EPMC3883916 | biostudies-literature
Project description:The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion - glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss.
| S-EPMC4209356 | biostudies-literature