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Although promising therapeutics are in the pipeline, bariatric surgery (also known as metabolic surgery) remains our most effective strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Of the many available options, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are currently the most widely used procedures. RYGB and VSG have very different anatomical restructuring but both surgeries are effective, to varying degrees, at inducing weight loss and T2DM remission. Both weight loss-dependent and weight loss-independent alterations in multiple tissues (such as the intestine, liver, pancreas, adipose tissue and skeletal muscle) yield net improvements in insulin resistance, insulin secretion and insulin-independent glucose metabolism. In a subset of patients, post-bariatric hypoglycaemia can develop months to years after surgery, potentially reflecting the extreme effects of potent glucose reduction after surgery. This Review addresses the effects of bariatric surgery on glucose regulation and the potential mechanisms responsible for both the resolution of T2DM and the induction of hypoglycaemia.Bariatric surgery induces weight loss and can trigger remission of type 2 diabetes mellitus (T2DM) but may also lead to post-bariatric hypoglycaemia. This Review examines surgery-induced changes in glucose regulation and the potential mechanisms responsible for the resolution of T2DM and induction of hypoglycaemia.

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery. Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are the most effective therapy for the treatment of obesity; now bile acids, and the presence of the nuclear bile acid receptor FXR, are shown to underpin the mechanism of VSG action, and the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced if FXR is absent. How weight-loss surgery works The use and misuse of invasive surgery to control obesity and related conditions is much debated. Whatever its merits, the associated costs and risks mean that it is inappropriate in many cases. This study challenges the notion that such surgery elicits weight loss solely by making it physically difficult to consume or absorb calories, and raises the prospect that it may be possible to develop therapies that achieve the same ends without the need for a scalpel. Vertical sleeve gastrectomy (VSG), in which some 80% of the stomach is removed to create a gastric 'sleeve' contiguous with the oesophagus and duodenum, is known to induce loss of body weight and fat mass, and improves glucose tolerance in humans and rodents. Randy Seeley and colleagues show here that the therapeutic effect of VSG in mice arises not from the mechanical restrictions of a smaller stomach but from the associated increase in the levels of circulating bile acids and changes to gut microbial communities. Moreover, in the absence of nuclear bile acid receptor FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced.

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor–deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery.

Key Points Recent findings indicate that neuronal populations in the hypothalamus that had already been identified as being crucial to the regulation of energy balance are also essential for the regulation of glucose homeostasis. The melanocortin system within the arcuate nucleus (ARC) of the hypothalamus has an important role in the integration of signals from circulating hormones to maintain both energy and glucose homeostasis. ATP-sensitive potassium channels, ATP-activated protein kinase and mammalian target of rapamycin act as 'general' fuel sensors — they sense changes in overall energy status through changes in ATP. The sensing of fuel and ATP specifically within the hypothalamus has the capacity to modulate both glucose and energy homeostasis. Neuronal populations outside the ARC (including steroidogenic factor 1 neurons within the ventromedial hypothalamus) and multiple populations of neurons within the hindbrain (melanocortin receptor 4-expressing neurons in the sympathetic nervous system and NMDA receptor-expressing neurons) contribute to the regulation of glucose and energy homeostasis. Within the gut, cholecystokinin and glucagon-like peptide 1 provide a conduit for CNS-induced regulation of energy and glucose homeostasis. A key outstanding question in the field is whether the neuronal circuits that are crucial for body weight regulation and that may be dysregulated in obesity also contribute to the poor glucose homeostasis that eventually results in type 2 diabetes mellitus. New strategies such as optogenetics and DREADD (designer receptors exclusively activated by designer drugs) provide an avenue for further understanding the crossroads of glucose and energy homeostasis. Sandoval and colleagues discuss emerging evidence for a role of the CNS in the regulation of glucose homeostasis and show that this regulation involves several neural circuits and mechanisms that also control energy balance. Disruption of these overlapping pathways may link the metabolic impairments that are associated with obesity and type 2 diabetes. Obesity and type 2 diabetes mellitus (T2DM) — disorders of energy homeostasis and glucose homeostasis, respectively — are tightly linked and the incidences of both conditions are increasing in parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Recent findings indicate that some of the neural circuits and mechanisms underlying energy balance are also essential for the regulation of glucose homeostasis. We propose that disruption of these overlapping pathways links the metabolic disturbances associated with obesity and T2DM. A better understanding of these converging mechanisms may lead to therapeutic strategies that target both T2DM and obesity.

The authors of this Review integrate contributions of both central and peripheral glucagon-like peptide 1 (GLP-1), which is secreted from the intestine in response to nutrient ingestion, in a model of short-term and long-term control of energy balance. This model is discussed with respect to current GLP-1-based therapies and ongoing research that may help maximize the effectiveness of GLP-1-based treatment of obesity. Glucagon-like peptide 1 (GLP-1), a peptide secreted from the intestine in response to nutrient ingestion, is perhaps best known for its effect on glucose-stimulated insulin secretion. GLP-1 is also secreted from neurons in the caudal brainstem, and it is well-established that, in rodents, central administration of GLP-1 potently reduces food intake. Over the past decade, GLP-1 has emerged not only as an essential component of the system that regulates blood glucose levels but also as a viable therapeutic target for the treatment of type 2 diabetes mellitus. However, although GLP-1 receptor agonists are known to produce modest but statistically significant weight loss in patients with diabetes mellitus, our knowledge of how endogenous GLP-1 regulates food intake and body weight remains limited. The purpose of this Review is to discuss the evolution of our understanding of how endogenous GLP-1 modulates energy balance. Specifically, we consider contributions of both central and peripheral GLP-1 and propose an integrated model of short-term and long-term control of energy balance. Finally, we discuss this model with respect to current GLP-1-based therapies and suggest ongoing research in order to maximize the effectiveness of GLP-1-based treatment of obesity. Key Points Animal studies suggest that endogenous, central glucagon-like peptide 1 (GLP-1) regulates both short-term and long-term energy balance, potentially via activation of hindbrain and hypothalamic GLP-1 receptors (GLP1R), respectively Endogenous peripheral GLP-1 may limit meal size by activation of GLP1R on local vagal afferent nerves and stimulation of a gut–brain feedback loop Increasing GLP1R activity by administering GLP-1 receptor agonists reduces food intake and promotes weight loss in humans, but the extent to which endogenous GLP-1 regulates energy balance in humans remains unknown Although diabetes mellitus and obesity appear to be associated with altered GLP-1 system activity, GLP1R agonists retain their efficacy in these contexts, making them a viable therapeutic tool A better understanding of how endogenous central and peripheral GLP-1 regulate energy balance has the potential to maximize our application of GLP-1-based therapies for the treatment of obesity

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15 INT-KO ) mice which were maintained on high-fat diet. FGF15 INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15 INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15 INT-KO . VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15 INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids. The mechanisms that mediate the effects of weight loss surgeries such as vertical sleeve gastrectomy (VSG) are incompletely understood. Here the authors show that intestinal FGF15 is necessary to improve glucose tolerance and to prevent the loss of muscle and bone mass after VSG, potentially via protection against bile acid toxicity.

Arcuate Glucagon-Like Peptide 1 Receptors Regulate Glucose Homeostasis but Not Food Intake Darleen A. Sandoval 1 , Didier Bagnol 2 , Stephen C. Woods 1 , David A. D'Alessio 1 and Randy J. Seeley 1 1 Departments of Psychiatry and Medicine, University of Cincinnati, Cincinnati, Ohio 2 Arena Pharmaceuticals, San Diego, California Corresponding author: Dr. Darleen Sandoval, darleen.sandoval{at}uc.edu Abstract OBJECTIVE— Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the central GLP-1 system regulates glucose tolerance as well. RESEARCH DESIGN AND METHODS— We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to assess the role of the central GLP-1 system on glucose tolerance, insulin secretion, and hepatic and peripheral insulin sensitivity. Finally, in situ hybridization was used to examine colocalization of GLP-1 receptors with neuropeptide tyrosine and pro-opiomelanocortin neurons. RESULTS— We found that central, but not peripheral, administration of low doses of a GLP-1 receptor antagonist caused relative hyperglycemia during a glucose tolerance test, suggesting that activation of central GLP-1 receptors regulates key processes involved in the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and direct administration of GLP-1 into the arcuate, but not the paraventricular, nucleus of the hypothalamus reduced hepatic glucose production. Consistent with a role for GLP-1 receptors in the arcuate, GLP-1 receptor mRNA was found to be expressed in 68.1% of arcuate neurons that expressed pro-opiomelanocortin mRNA but was not significantly coexpressed with neuropeptide tyrosine. CONCLUSIONS— These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis by regulating both insulin secretion and glucose production. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 May 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 8, 2008. Received January 2, 2008. DIABETES

BACKGROUNDBariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1-3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin.METHODSTo identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-Roux-en-Y gastric bypass (post-RYGB) (n = 10), and nonsurgical controls (n = 8).RESULTSIn the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone β-hydroxybutyrate were increased by 30%-80% in PBH versus asymptomatic. Conversely, multiple amino acids (branched-chain amino acids, tryptophan) and polyunsaturated lipids were reduced by 20%-50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced 2- to 10-fold in PBH in the fasting state. Postprandially, plasma serotonin was uniquely increased 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin.CONCLUSIONTogether these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target.FUNDINGNational Institutes of Health (NIH) grant R01-DK121995, NIH grant P30-DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo grant 2018/22111-2.

Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet α cells to generate glucagon. However, the regulatory mechanisms underlying this process remain largely unclear. Here, we report that SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD), a highly conserved protein quality control system responsible for clearing misfolded proteins from the ER, plays a key role in glucagon production by regulating turnover of the nascent proform of the PC2 enzyme (proPC2). Using a mouse model with SEL1L deletion in proglucagon-expressing cells, we observe a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we find that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein in the ER. Here, we identify ERAD as a regulator of PC2 biology and an essential mechanism for maintaining α cell function. Glucagon production in pancreatic islet α cells requires the PC2 enzyme. Here, authors show SEL1L-HRD1 ERAD ensures proper maturation of PC2, highlighting an essential mechanism for maintaining glucagon production.

Aims/hypothesisGlucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis.MethodsWe have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRAΔNull) or is expressed exclusively in the intestine (GcgRAΔVilCre) or pancreas and duodenum (GcgRAΔPDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists.ResultsAdministration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRAΔNull mice and control littermates and in GcgRAΔVilCre and GcgRAΔPDX1Cre mice. The potent GLP-1 receptor antagonist, exendin-[9–39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRAΔPDX1Cre mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRAΔNull or in GcgRAΔVilCre mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRAΔNull mice.Conclusions/interpretationTaken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.