Sleeve gastrectomy rapidly enhances islet function independently of body weight

Douros, Jonathan D.; Niu, Jingjing; Sdao, Sophia M.; Gregg, Trillian; Fisher‐Wellman, Kelsey H.; Bharadwaj, Manish S.; Molina, Anthony J.A.; Arumugam, Ramamani; Martin, Mackenzie D.; Petretto, Enrico; Merrins, Matthew J.; Herman, Mark A.; Tong, Jenny; Campbell, Jonathan E.; D’Alessio, David A.

doi:10.1172/jci.insight.126688

Cited by 29 publications

(41 citation statements)

References 69 publications

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“…2 g,h). Our results are similar to those obtained after vertical sleeve gastrectomy in high fat diet-fed mice suggesting that, as in ob/ob mice, sensitivity to incretin stimuli may not be enhanced at the receptor expression level as discussed elsewhere [ 10 , 78 ].…”

Section: Discussionsupporting

confidence: 89%

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

et al. 2020

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Background Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. Methods We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca 2+ -imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. Findings EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca 2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. Interpretation Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. Funding European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030–188447), Fondation de l'Avenir.

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Section: Discussionsupporting

confidence: 89%

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

et al. 2020

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“…Interestingly, ob/ob mice do not have similar decrease in food intake, energy expenditure or changes in body composition following bariatric surgery, making them a unique model for establishing weight-independent effects of surgical interventions. The EGA procedure in the current study produced decreases in food intake and body weight, along with rapid improvement in glucose tolerance, that is in line with previous results from this group [2] , and other reports using RYGB [3] or vertical sleeve gastrectomy [4] in preclinical models. Indeed, it is remarkable that multiple different interventions that are varied in their alterations of the gut anatomy ubiquitously produce similar improvements in metabolic outcomes in preclinical models and clinical populations.…”

supporting

confidence: 92%

“…Using microarray to assess the transcriptome of pancreatic islets, they identified 458 genes that were differentially expressed between ob/ob sham controls and EGA treated mice, many of which were involved in essential β-cell functions. These data support the hypothesis that bariatric surgery induces intrinsic changes in islets, a conclusion that strongly aligns with previous work in high-fat fed mice following vertical sleeve gastrectomy [4] . In an effort to take the transcriptomic data one step further, the investigators conducted a series of assays to test β-cell function ex vivo and correlated the results with some of the identified differentially expressed genes.…”

supporting

confidence: 92%

Could micro changes in β-cells enable major changes in metabolism?

Capozzi

Campbell

2020

eBioMedicine

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“…There is a rapid glycemic benefit of bariatric surgery that occurs prior to weight loss in many patients [2], and is sustained for extended time periods as body-weight decreases [3]. The acute, weight-independent benefit of surgery has been attributed to multiple mechanisms [4] including enhanced insulin sensitivity [5], [6], islet function [7], [8], and incretin secretion [9], [10]. While each of these factors can contribute to the improvements in glucose control after surgery [6], [11], [12], it is unclear whether the regulation of these key glucoregulatory factors is modified over the postoperative time-course independent of caloric restriction.…”

Section: Introductionmentioning

confidence: 99%

Temporal plasticity of insulin and incretin secretion and insulin sensitivity following sleeve gastrectomy contribute to sustained improvements in glucose control

Douros

Niu

Sdao

et al. 2019

Molecular Metabolism

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ObjectiveBariatric surgery acutely improves glucose control, an effect that is generally sustained for years in most patients. The acute postoperative glycemic reduction is at least partially mediated by enhanced incretin secretion and islet function, and occurs independent of caloric restriction, whereas the sustained improvement in glucose control is associated with increased insulin sensitivity. However, studies in humans with bariatric surgery suggest that these elevations are not static but undergo coordinated regulation throughout the postoperative time course. The studies described here test the hypothesis that incretin secretion, islet function, and peripheral insulin sensitivity undergo temporal regulation following bariatric surgery as a means to regulate glucose homeostasis.MethodsIncretin secretion, islet function, and insulin sensitivity in mice with vertical sleeve gastrectomy (VSG) were compared to sham-operated controls that were pair-fed for 90d, matching food consumption and body-weight between groups.ResultsGlucose clearance and insulin secretion were enhanced in VSG mice compared to controls during mixed-meal tolerance tests (MMTT) at 12 and 80 days postoperatively, as were prandial GLP-1, GIP, and glucagon levels. Insulin sensitivity was comparable between groups 14d after surgery, but significantly greater in the VSG group at day 75, despite similar body-weight gain between groups. Glucose stimulated insulin secretion was greater in VSG mice compared to controls in vivo (I.P. glucose injection) and ex vivo (islet perifusion) indicating a rapid and sustained enhancement of β-cell function after surgery. Notably, glycemia following a MMTT was progressively higher over time in the control animals but improved in the VSG mice at 80d despite weight regain. However, meal-stimulated incretin secretion decreased in VSG mice from 10 to 80 days postoperative, as did meal-stimulated and I.P. glucose-stimulated insulin secretion. This occurred over the same time period that insulin sensitivity was enhanced in VSG mice, suggesting postoperative islet output is tightly regulated by insulin demand.ConclusionsThese data demonstrate a dynamic, multifactorial physiology for improved glucose control after VSG, whereby rapidly elevated insulin secretion is complimented by later enhancements in insulin sensitivity. Critically, the glucose lowering effect of VSG is demonstrably larger than that of caloric-restriction, suggesting these adaptations are mediated by surgical modification of gastrointestinal anatomy and not weight-loss per se.

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Sleeve gastrectomy rapidly enhances islet function independently of body weight

Cited by 29 publications

References 69 publications

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

Could micro changes in β-cells enable major changes in metabolism?

Temporal plasticity of insulin and incretin secretion and insulin sensitivity following sleeve gastrectomy contribute to sustained improvements in glucose control

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