Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery

Larraufie, Pierre; Roberts, Geoffrey; McGavigan, Anne K.; Kay, Richard G.; Li, Joyce; Leiter, Andrew B.; Melvin, Audrey; Biggs, Emma K.; Ravn, Peter; Davy, Kathleen; Hornigold, David C.; Yeo, Giles S.H.; Hardwick, Richard; Reimann, Frank; Gribble, Fiona M.

doi:10.2139/ssrn.3283706

Cited by 10 publications

(14 citation statements)

References 32 publications

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“…Lastly, inducible knockdown of the β‐cell GLP‐1 receptor in adult mice using the Cre‐loxP system prevented improvements in glucose tolerance and glucose‐stimulated insulin secretion but not weight loss in one study, although there was no impact of a similar genetic disruption on VSG results in another . A recent study with data from lean post‐gastrectomy patients with postprandial hypoglycaemia and a lean VSG mouse model confirms previous studies that pharmacological blockade of GLP‐1 receptor signalling increases glucose and reduces postprandial insulin responses . Although it is true that impaired insulin resistance could confound the ability to detect a role of GLP‐1 in surgical success in mice, there are several problems with extrapolating these recent data to suggest that GLP‐1 is critical for T2DM resolution.…”

Section: Mechanisms For Metabolic Successmentioning

confidence: 52%

Mechanisms for the metabolic success of bariatric surgery

Sandoval

2019

J Neuroendocrinology

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To date, bariatric surgery remains the most effective strategy for the treatment of obesity and its comorbidities. However, given the enormity of the obesity epidemic, and sometimes variable results, it is not a feasible strategy for the treatment of all obese patients. A simple PubMed search for ‘bariatric surgery' reveals over 28 000 papers that have been published since the 1940s when the first bariatric surgeries were performed. However, there is still an incomplete understanding of the mechanisms for the weight loss and metabolic success of surgery. An understanding of the mechanisms is important because it may lead to greater understanding of the pathophysiology of obesity and thus surgery‐alternative strategies for the treatment of all obese patients. In this review, the potential mechanisms that underlie the success of surgery are discussed, with a focus on the potential endocrine, neural and other circulatory factors (eg, bile acids) that have been proposed to play a role.

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Section: Mechanisms For Metabolic Successmentioning

confidence: 52%

Mechanisms for the metabolic success of bariatric surgery

Sandoval

2019

J Neuroendocrinology

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“…The two most widely used types of bariatric surgery are currently VSG and Roux-n-Y-Gastric-Bypass (46). Despite the similar metabolic outcomes between the two procedures, VSG is reported to have lower mortality in mice (47,48), but also allows for gradual weight regain, which is why it was chosen for this study (11,49). Both lean and HFD-induced hyperglycemic models were deployed in order to compare glucocorticoid responses to bariatric surgery in models of health and disease.…”

Section: Discussionmentioning

confidence: 99%

Bariatric surgery normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice

Akalestou

López-Noriega

Christakis

et al. 2020

Preprint

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BackgroundGlucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss.AimTo investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice.MethodsLean mice and HFD mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Glucose and insulin tolerance tests were performed at four and ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11β-HSD1 and GR levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively.ResultsVSG did not cause excess weight loss in lean mice when compared to sham operated mice. However, both lean and HFD VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restores physiological corticosterone production in HFD mice and reduces11β-HSD1 levels at four and ten weeks post-surgery. Additionally, lean mice displayed significantly lowered mRNA levels of 11β-HSD1 in subcutaneous adipose tissue and GR in liver.ConclusionsBariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. The reduction of glucocorticoid exposure may represent an additional contribution to the health benefits of bariatric surgery. These findings point towards a physiologically relevant gut-adrenal axis.

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“…The levels of several gut hormones increase after either sleeve gastrectomy or gastric bypass as consequence of structural and functional changes in the gastrointestinal tract, including accelerated food delivery and absorption. 16 Among these, over the past years, a major role in diabetes remission after surgery, has been attributed to the glucagon-like peptide-1 (GLP-1) 17,18 whose analogues (exenatide, liraglutide, dulaglutide, lixisenatide) are already listed among current anti-diabetic treatments. However, its unique action has been questioned by several knock-out (KO) mouse models 19,20 lacking GLP-1 signalling but still retaining the metabolic benefits of surgery and more recently, by a double KO model in which the combined loss of GLP-1R and NPY2R did not prevent the beneficial effects of RYGB on body weight and glucose homeostasis.…”

Section: Pyy Plays a Key Role In The Improvement In Islet Function Afmentioning

confidence: 99%

PYY, a Therapeutic Option for Type 2 Diabetes?

Guida

Ramracheya

2020

Clin Med Insights Endocrinol Diabetes

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Metabolic surgery leads to rapid and effective diabetes reversal in humans, by weight-independent mechanisms. The crucial improvement in pancreatic islet function observed after surgery is induced by alteration in several factors, including gut hormones. In addition to glucagon-like peptide 1 (GLP-1), increasing lines of evidence show that peptide tyrosine tyrosine (PYY) plays a key role in the metabolic benefits associated with the surgery, ranging from appetite regulation to amelioration of islet secretory properties and survival. Here, we summarize the current knowledge and the latest advancements in the field, which pitch a strong case for the development of novel PYY-based therapy for the treatment of diabetes.

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Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery

Abstract: Increased postprandial GLP-1 triggers higher insulin levels after bariatric surgery d Bariatric surgery does not change enteroendocrine cell identity or hormone content d Increased nutrient flow to the distal gut after surgery enhances GLP-1 secretion

Cited by 10 publications

References 32 publications

Mechanisms for the metabolic success of bariatric surgery

Mechanisms for the metabolic success of bariatric surgery

Bariatric surgery normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice

PYY, a Therapeutic Option for Type 2 Diabetes?

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