Background: Obesity surgery is effective for obesity and type 2 diabetes (T2DM). However, many patients do not achieve sustained diabetes remission following surgery. Liraglutide, a GLP-1 analogue, improves glycaemia and reduces body weight. Our aim was to evaluate the safety and effectiveness of Liraglutide 1•8 mg in patients with persistent or recurrent T2DM after surgery. Methods: In this double-blind, placebo-controlled trial, adults with HbA1c >48 mmol/mol (>6•5%) at least one year after surgery were randomised 2:1 to once-daily subcutaneous Liraglutide 1•8 mg or Placebo, together with a reduced-calorie diet and increased physical activity. The primary outcome was the change in HbA1c from baseline to 26 weeks. EudraCT 2014-003923-23 and ISRCTN 13643081. Findings: Between February 2016 and November 2018, we assigned 80 patients to receive Liraglutide (n=53) or Placebo (n=27). Seventy-one (89%) participants completed the study up to week 26 (complete-cases population). A multivariable linear regression analysis taking baseline HbA1c and type of surgery into account as covariates showed that Liraglutide was associated with a difference in HbA1c change of-13•3 mmol/mol or-1•22%, 95% CI-19•7 to-7•0, p<0•001) vs Placebo at 26 weeks. Liraglutide was associated with a difference in the change of weight of-4•23 kg [95% CI-6•81 to-1•64, p<0•001) vs Placebo. No significant influence of type of surgery was noted. Interpretation: This is the first randomised controlled trial of adjunctive Liraglutide treatment in patients with diabetes mellitus after metabolic surgery. The results support the use of Liraglutide therapy in this clinical context. Funding: JP Moulton Charitable Foundation 3 surgery. We have previously shown that the acute peripheral administration of the GLP-1 RA Exendin-4 in rodent models of RYGB has additive effects to the already enhanced endogenous GLP-1 secretion as demonstrated by an additional reduction in food intake 11. Indeed, data from retrospective non-randomised studies in humans support this hypothesis: the administration of GLP-1 RAs in patients with and without T2DM and a suboptimal response to metabolic surgery was associated with weight loss and glycaemic improvements 12-15. This RCT was therefore designed to investigate the safety and efficacy of pharmacological administration of the GLP-1 RA Liraglutide on glycaemic control in patients with persistent or recurrent T2DM after RYGB or VSG surgery. Methods Study population This was a prospective randomised double-blinded placebo-controlled clinical trial. Eighty patients with obesity and persistent or recurrent T2DM that had undergone RYGB or VSG surgery at least 12 months before randomisation were recruited from the

Type 2 diabetes prevalence is increasing dramatically worldwide. Metabolic surgery is the most effective treatment for selected patients with diabetes and/or obesity. When compared to intensive medical therapy and lifestyle intervention, metabolic surgery has shown superiority in achieving glycemic improvement, reducing number of medications and cardiovascular risk factors, which translates in long-term benefits on cardiovascular morbidity and mortality. The mechanisms underlying diabetes improvement after metabolic surgery have not yet been clearly understood but englobe a complex interaction among improvements in beta cell function and insulin secretion, insulin sensitivity, intestinal gluconeogenesis, changes in glucose utilization, and absorption by the gut and changes in the secretory pattern and morphology of adipose tissue. These are achieved through different mediators which include an enhancement in gut hormones release, especially, glucagon-like peptide 1, changes in bile acids circulation, gut microbiome, and glucose transporters expression. Therefore, this review aims to provide a comprehensive appraisal of what is known so far to better understand the mechanisms through which metabolic surgery improves glycemic control facilitating future research in the field.

Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODSA total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTSBoth groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONSThe findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.Roux-en-Y gastric bypass (RYGB) is now a recognized and recommended treatment option for patients with type 2 diabetes (T2D) (1). RYGB can cause major and