BACKGROUND:Alcohol use disorder accounts for 5% of deaths worldwide annually, and there is an urgent need for new therapeutic interventions. Preclinical and initial human studies indicate that the GLP-1 receptor agonist semaglutide might reduce alcohol drinking. This study evaluated the efficacy of semaglutide once-weekly in treatment-seeking patients with alcohol use disorder and comorbid obesity. METHODS:In a 26-week, single-centre, randomised, double-blinded, placebo-controlled trial, treatment-seeking participants with moderate to severe alcohol use disorder and comorbid obesity were assigned (1:1) to receive once-weekly semaglutide (2·4 mg subcutaneously) or placebo (saline subcutaneously), in addition to standard cognitive behavioural therapy. The primary endpoint was a reduction in the number of heavy drinking days assessed after 26 weeks of intervention, analysed with an ANCOVA model. Analysis adhered to the intention-to-treat principle, and missing outcome data were addressed using multiple imputations. Safety was assessed in all treated patients. The trial is registered at ClinicalTrials.govNCT05895643, and is complete. FINDINGS:From June 10, 2023, to Feb 4, 2025, 108 participants (53 women and 55 men) were enrolled, with 54 participants in each of the semaglutide and placebo treatment groups, and all were included in the data analysis. Overall, 88 participants (81%) completed the full intervention. Semaglutide was associated with a reduction in heavy drinking days (-41·1 percentage points from baseline, 95% CI -48·7 to -33·5) compared with placebo (-26·4, -34·1 to -18·6; estimated treatment difference -13·7 percentage points, -22·0 to -5·4; p=0·0015), and had substantial effects on multiple secondary alcohol-related and somatic outcomes. Adverse events were transient, generally mild to moderate gastrointestinal effects, and occurred more frequently in the semaglutide group. INTERPRETATION:Semaglutide showed robust therapeutic effects in treatment-seeking participants with obesity and alcohol use disorder and this trial supports previous preclinical and clinical findings suggesting GLP-1 receptor agonists as a potential novel treatment target for alcohol use disorder. FUNDING:The Research Foundation, Mental Health Services (Capital Region of Denmark), the Novo Nordisk Foundation, the Novavi Foundation, the Hartmann Foundation, and the Augustinus Foundation.

AIMS:To assess the efficacy and safety of an automated insulin-glucagon delivery system (AIGD) compared with an automated insulin delivery system (AID). MATERIALS AND METHODS:In a 33-h, randomised, crossover, inpatient study, 13 participants with type 1 diabetes used the DiaCon system in AIGD and AID modes. Each study period included two overnight stays and standardised challenges: receiving 50% of the calculated insulin bolus for breakfast, 100% bolus for lunch, 130% bolus for dinner, and a 45-min unannounced bicycle exercise at 50% VO2max. Co-primary endpoints were (1) number of 15-g carbohydrate treatments for plasma glucose <3.0 mmol/L, and (2) percentage of time below 3.9 mmol/L. RESULTS:The number of carbohydrate rescues was lower with AIGD versus AID (15 vs. 20, p = 0.02). Percent time below range (mean ± SD 3.7 ± 2.5% vs. 3.9 ± 3.1%, p = 0.49), in range (TIR) 3.9-10.0 mmol/L (68.8 ± 14.9% vs. 66.9 ± 10.2%, p = 0.41) and above range >10.0 mmol/L (27.5 ± 14.8% vs. 29.2 ± 10.4%, p = 0.46) were similar. Mean glucose and coefficient of variation were comparable between AIGD versus AID (p = 0.30). The post hoc analysis demonstrated that AIGD had significantly higher TIR 0-3 h after exercise and fewer hypoglycaemia events (<3.9 mmol/L) 0-3 h after each meal. No differences were observed in nausea, headache, hunger, and palpitation. CONCLUSIONS:Under challenging inpatient conditions, the AIGD system provided similar glucose control as AID but significantly reduced the need for carbohydrate rescue and enhanced TIR after exercise.

Glucagon-like peptide-1 (GLP-1) was discovered as an insulinotropic peptide from the gut during a search for candidates for the incretin effect. It was found to also inhibit glucagon secretion and is now considered an important regulator of glucose metabolism. In further investigations of its physiological effects, GLP-1 also inhibited gastrointestinal secretion and motility and inhibited appetite and food intake. Because of these effects, GLP-1 was eventually shown to be able to improve glucose control and beta cell function in patients with type 2 diabetes mellitus (T2DM) and was even associated with weight loss. Because of a very short half-life in the circulation due to renal clearance and enzymatic degradation, stable analogs were developed allowing long-term treatment. Analogs suitable for weekly administration proved highly effective in improving glycemic control in patients with T2DM, and the analogs showed efficacy with respect to weight loss. Moreover, in cardiovascular outcome trials, the agonists were protective against major cardiovascular events and showed renoprotection and neuroprotection. Several observational studies also indicated protection against psychiatric illnesses and dementia. Thus, GLP-1 receptor agonists seem to be an effective weapon against the obesity-associated cardiovascular-kidney-metabolic syndrome affecting millions of patients.

BACKGROUND:Physical activity helps maintain a healthy stable body weight. One mechanism underlying this beneficial effect could be the improved coupling between energy intake and expenditure, since hunger and satiety are better regulated in active individuals. Whether this enhancement of appetite control by exercise is reflected in overall adaptations in the gut and gut-brain communication remains poorly defined. METHODS:We investigated how increased physical activity alters gut morphology, intestinal endocrine function, and central appetite signalling in C57BL/6NRJ male mice fed ad-libitum chow diet. We assessed intestinal growth, L-cell density, and glucose-stimulated endocrine secretion, as well as circulating levels and gene expression of gut derived peptide hormones. Additionally, we quantified neuronal activity in the brainstem dorsal vagal complex following a fasting-refeeding intervention and examined the effects of PYY, CCK, ghrelin, and GLP-1 administration on food intake in sedentary and physically active mice. Depending on the dataset, unpaired or paired Student's t-tests, two-way ANOVA followed by Bonferroni's post hoc test, simple linear regression or a linear mixed-effects model were applied. Statistical significance was set at P < 0.05. FINDINGS:Physical activity induced a slight growth of the small intestine, increased L-cell density, and enhanced glucose-stimulated GLP-1 secretion. It altered the circulating levels of PYY and ghrelin and increased the dynamic regulation of neuronal activity in the area postrema and nucleus tractus solitarius. Active mice displayed greater sensitivity to gut-derived hormones PYY, CCK, and ghrelin exerting amplified and prolonged effects on food intake, whereas native GLP-1 showed no effect, likely due to its short half-life. Physical activity prevented post-fasting hyperphagia, thereby promoting sustained maintenance of fasting-induced weight loss. INTERPRETATION:The findings demonstrate that physical activity promotes adaptations in the gut and gut-to-brain communication possibly enhancing the responsiveness to appetite-regulating signals. Such adaptations may strengthen the alignment between energy intake and expenditure to support body weight maintenance. FUNDING:This study was supported by Novo Nordisk Foundation (0059436) and Trygfonden Centre for Physical Activity Research (101390, 20045, 125132, and 177225). P.S. is supported by Lundbeck Foundation (R380-2021-1300).

Context Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with potent vasoactive and metabolic effects in adipose tissue, but its effects on splanchnic blood flow (SBF) in humans remain unclear. Investigating potential regional differences is important for understanding the vascular actions of GIP in humans.Objective The aim of this study was to examine the effects of GIP on SBF, both independently and in combination with hyperglycemia and hyperinsulinemia.Methods In a randomized, controlled crossover study, 8 healthy, lean male participants underwent 4 separate experimental conditions. The interventions included intravenous infusions of either GIP at a rate of 1.5 pmol-1 kg-1 minute-1 or saline, administered alone or in combination with a hyperglycemic and hyperinsulinemic clamp, respectively. Splanchnic blood flow was measured by Fick's Principle after catheterization of a hepatic vein, using indocyanine green as indicator.Results Splanchnic blood flow remained comparable across all experimental conditions, including GIP and saline infusions, both with and without the hyperglycemic and hyperinsulinemic clamp (P = .42).Conclusion Under the applied conditions, GIP does not appear to play a substantial role in the acute regulation of net SBF, either alone or in combination with induced hyperglycemia and hyperinsulinemia.

Context Statin use is associated with increased risk of type 2 diabetes (T2D) and mild hyperglycemia. The underlying mechanisms are not well studied, and the effect of statin treatment on glucagon-like peptide 1 (GLP-1) secretion or production is unknown. Objective This work aimed to assess the effects of rosuvastatin on GLP-1 secretion and production. Methods We performed association studies in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) reexamination cohort, in vitro investigations using GLUTag cells and acute and chronic studies in female, normoglycemic C57Bl/6j mice. Results Studies in the MDCS-CC reexamination cohort (n = 3734) revealed that in individuals without T2D, statin usage was associated with higher fasting glucose-dependent insulinotropic peptide (GIP), insulin, glucose, glucagon, and homeostatic model assessment of insulin resistance, but not GLP-1. However, in patients with T2D, statin usage was associated with higher fasting GLP-1 levels. Rosuvastatin treatment or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) knockdown (KD) reduced GLP-1 secretion and increased Gcg messenger RNA in GLUTag cells. Rosuvastatin acutely reduced postprandial GLP-1 secretion, whereas chronic rosuvastatin treatment in mice caused hyperglycemia and increased postprandial GLP-1 levels. The acute effect of Hmgcr KD on GLP-1 secretion could be mimicked by targeting intracellular cholesterol using a PCSK9 inhibitor. Finally, transcriptomic alterations induced by rosuvastatin were limited to genes involved in cholesterol biosynthesis. Conclusion We have established HMGCR as a regulator of GLP-1 secretion and provide a plausible explanation for the clinically observed mild hyperglycemia associated with statin use. Given the negative acute effect on GLP-1 secretion, monitoring of blood glucose levels is recommended after prescribing rosuvastatin.

RUMTOR-derived peptides (RORDEPs) 1 and 2 are polypeptides synthesised by specific strains of the human gut commensal Ruminococcus torques. Preclinical studies have shown that RORDEPs lower blood glucose via an impact on plasma incretins and an improvement of hepatic insulin sensitivity. In a randomised, placebo-controlled, crossover trial, we here explore the safety and tolerability of, as well as any metabolic responses to, a duodenal infusion of recombinant RORDEP1 (r-RORDEP1) given to healthy men after oral intake of a liquid mixed meal. Seventeen healthy, normal-weight men between 18 and 35 years of age were randomised through block randomisation to receive either r-RORDEP1 or placebo as the initial intervention at Gentofte Hospital, Denmark. Exclusion criteria were use of any form of medication, use of antibiotics during the 3 months before intervention, lactose intolerance, smoking, alcohol or drug abuse, or the use of probiotics or creatine as dietary supplements during the study period. Blocks were created prior to trial initiation. Both participants and investigators were blinded to treatment. Following intake of a standardised liquid meal, r-RORDEP1 was given via a naso-duodenal tube as an initial bolus of 0.0108 mg/kg body weight followed by a continuous infusion of 0.25 µg kg−1 min−1 for 170 min. Primary outcomes were changes in plasma concentrations of incretins and peptide YY, while secondary endpoints were safety and tolerability, and changes in plasma insulin, C-peptide and glucose. All 17 participants completed the trial. Duodenal infusion of r-RORDEP1 was well tolerated and without changes in biochemical measures of haematological, liver or renal functions. Compared with placebo, the bolus of r-RORDEP1 induced an early (at 15 or 30 min) rise in plasma glucagon-like peptide-1, insulin and C-peptide (q=0.001, q=0.001 and q=0.003, respectively) and a decline in plasma gastric inhibitory polypeptide and glucose (q=0.02 and q=0.006, respectively), while also increasing whole-body insulin sensitivity as measured with the Matsuda index of insulin sensitivity (p=0.049). Short-term duodenal infusion of r-RORDEP1 is safe and well tolerated and elicits changes in plasma incretins, insulin and glucose, and a measure of whole-body insulin sensitivity, aligning with findings in rodents, supporting the hypothesis that RORDEPs hold a role in impacting host metabolism. ClinicalTrials.gov NCT06923839 EFSD/Lilly European Diabetes Research Programme 2021, RUCILP F-19235-01-64 - NNF21SA0070428 grant and NNF23SA0084103 grant, the latter two from the Novo Nordisk Foundation.

Sleeve gastrectomy (SG) leads to substantial weight loss and improvement in type 2 diabetes, but the underlying mechanisms remain incompletely understood. Given that circulating ghrelin concentrations are reduced after SG, we hypothesized that lower ghrelin levels may contribute to enhanced insulin sensitivity and β-cell function after SG. This was a human, placebo-controlled, randomized, crossover study. We investigated the effect of elevating ghrelin by an intravenous ghrelin infusion on β-cell function and insulin sensitivity using the "Botnia-clamp" (intravenous glucose tolerance test combined with hyperinsulinemic-euglycemic clamp), compared with saline coinfusion. Twelve SG-operated [aged 51 ± 10.9 yr, BMI 32.1 ± 4.6 kg/m2 (means ± SD)], and 10 sex-, age-, and body mass index (BMI)-matched unoperated controls without diabetes were included. Outcomes were peripheral insulin sensitivity (M/I) and β-cell function, assessed as the disposition index (DI), calculated as first phase insulin secretion × M/I. Ghrelin infusion significantly reduced peripheral insulin sensitivity (M/I) by 25% following SG and 29% in controls compared with saline infusion. Beta-cell function was significantly impaired with a 37% and 29% reduced first phase insulin secretion, and a 49% and 48% reduction in DI, respectively. No group differences were observed. Ghrelin infusion impairs insulin sensitivity and β-cell function in individuals who have undergone SG as well as in matched control. However, the present findings do not provide evidence that the lower circulating ghrelin concentrations following SG are directly responsible for improvements, as it remains unclear whether this relationship reflects a simple and reversible mechanism.NEW & NOTEWORTHY In a randomized, placebo-controlled crossover study, intravenous ghrelin infusion impaired insulin sensitivity and β-cell function in individuals with previous sleeve gastrectomy as well as in matched controls. Ghrelin reduced peripheral insulin sensitivity by 25%-29% and decreased β-cell function (disposition index) by 48%-49%. These findings suggest that the postoperative reduction in circulating ghrelin following sleeve gastrectomy may contribute to improved glucose metabolism, while underscoring the complex role of ghrelin in human glucose homeostasis.

Bariatric surgeries, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), improve obesity and type 2 diabetes (T2D). Both surgeries affect the gut microbiota, but their contribution to T2D remission remains unclear. In this subanalysis (RYGB, n = 39; SG, n = 38) of the randomized controlled Oseberg trial ( NCT01778738 ), in which participants underwent either RYGB or SG surgery, we profiled the faecal microbiome of individuals with obesity and T2D before and 12 months after surgery. We show that both surgeries altered the microbiome in the same direction, but with larger changes after RYGB. The SG-associated altered microbiome composition correlated positively with circulating glucagon-like peptide 1 levels, beta-cell function and 5 year T2D remission. Remission was also linked to increased gene richness and metabolic potential for fermentation, methanogenesis and butyrate production. Notably, these associations persisted after accounting for the extent of weight loss. Our findings indicate that surgery-specific microbial adaptations influence metabolic improvements and may help to explain heterogeneity in T2D remission after bariatric surgery.

CONTEXT:Oral glucose tolerance test (OGTT) induces greater acute suppression of bone resorption than isoglycaemic IV glucose infusions (IIGI). OBJECTIVE:To study the separate and combined effects of the gut-derived hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2) on postprandial bone turnover. DESIGN:A randomized, crossover study with 6 experimental days. PARTICIPANTS:Ten individuals with type 2 diabetes (T2D). INTERVENTIONS:Over 6 experimental days, participants underwent an OGTT and subsequently 5 IIGIs with infusions of saline, GIP, GLP-1, GLP-2, and GIP + GLP-1 + GLP-2, respectively. MAIN OUTCOME MEASURES:Changes in plasma concentrations of carboxy-terminal telopeptide of type I collagen (β-CTX-I) and procollagen type I N-terminal propeptide (PINP). RESULTS:β-CTX-I levels were significantly suppressed during OGTT compared to IIGI. Concomitant infusion of GIP + GLP-1 + GLP-2 during IIGI led to a suppression of β-CTX-I comparable to the suppression during the OGTT. During IIGI with infusions of GIP, GLP-1, and GIP + GLP-1 + GLP-2 we observed no reduction in PINP. By contrast, PINP levels were significantly reduced during both OGTT and IIGIs with saline and GLP-2, respectively. CONCLUSION:Our findings suggest that postprandial suppression of bone resorption in individuals with T2D is mediated by the additive effects of GIP, GLP-1, and GLP-2.

Prostaglandins (PGs) are paracrine mediators derived from arachidonic acid. In the gut, they regulate mucosal integrity, epithelial function, and inflammation. Glucose and possibly also prostaglandin E2 (PGE2) stimulate the release of glucagon-like peptide 1 (GLP-1). As PGE2 has been reported to modulate intestinal glucose absorption, the aim of this study was to investigate the acute effect of PGE2 on GLP-1 and GLP-2 secretion as well as intestinal glucose absorption using a physiologically relevant experimental setup-the isolated perfused rat small intestine. Two protocols were employed: A, luminal glucose instillation before and during an intra-arterial infusion of PGE2 (10 µmol/L); and B, same as protocol A, but with the COX inhibitor indomethacin (10 µmol/L) included in the perfusion buffer to block endogenous PG production. Administration of PGE2 stimulated the release of GLP-1 (2.1-fold; P = .002) and GLP-2 (2.5-fold; P = .002) from the perfused intestine vs vehicle. Inclusion of indomethacin in the perfusion buffer neither affected GLP-1 and GLP-2 secretion nor responses to PGE2, consistent with minimal production of PGs in the noninflamed in situ-perfused intestine. We observed a decrease in glucose absorption during administration of PGE2 vs vehicle (P = .043). PGE2 stimulates the secretion of GLP-1 and GLP-2, adding to its established roles in intestinal physiology. Acute administration of PGE2 significantly attenuated small intestinal glucose absorption. Our data confirm that PGE2 stimulates gut hormone release, which could be responsible for some of the effects ascribed to PGE2 and might explain the adverse effects associated with the inhibition of PG synthesis with nonsteroidal anti-inflammatory drugs.

Obesity is associated with impaired physical fitness, including physical functional performance and cardiorespiratory fitness, which affect health-related quality of life and mortality. We aimed to investigate the efficacy of a moderate-to-vigorous intensity exercise program and glucagon-like peptide-1 receptor agonist treatment alone or in combination during weight maintenance for physical fitness. This is secondary analysis of a randomized controlled trial involving 193 adults with obesity (age 18–65 years, body mass index 32–43 kg/m2) without diabetes mellitus who completed an 8-week low-calorie diet and were subsequently randomized (1:1:1:1 ratio) to: exercise plus placebo; glucagon-like peptide-1 receptor agonist liraglutide 3 mg once-daily plus usual activity; exercise plus liraglutide combined; or placebo plus usual activity. The exercise program was a combination of group sessions (interval-based indoor cycling followed by circuit training) and individual sessions of moderate-to-vigorous intensity, designed to meet the World Health Organization recommendations on physical activity for health. Exercise adherence was measured with sports watches and heart rate monitors. Key secondary endpoints related to physical fitness were changes from randomization to the end of treatment (weeks 0–52) in: (1) physical functional performance (time to ascend and descend an 11-step stairway twice); (2) cardiorespiratory fitness (peak oxygen consumption normalized to fat-free mass); and (3) muscle strength (isometric knee extensor peak torque). Participants randomized to exercise performed a median 2.65 session/week (116 min/week at 79

BACKGROUND AND AIMS:Intestinal resection changes nutrient exposure of enteroendocrine cells and may alter gastrointestinal hormone secretion. This study aims to characterize basal and postprandial gastrointestinal hormone profiles across distinct remnant intestinal anatomies after intestinal resection. METHODS:In this single-center, cross-sectional study, 31 patients were grouped according to remnant anatomy: end-jejunostomy (Group 1A, n = 8), ileostomy (1B, n = 8), jejuno-colonic anastomosis (2, n = 7) and jejuno-ileal anastomosis (3, n = 8) and compared with 8 healthy controls. Concentrations of gastrin, CCK, GIP, neurotensin, GLP-1, GLP-2 and PYY were measured before and for 240 min after a standardized meal. RESULTS:Basal gastrin was 6-fold higher in 1A than in controls and correlated inversely with small bowel length. CCK AUC and iAUC were increased in groups 1A and 2 versus controls and correlated negatively with both small bowel and colon length. Neurotensin AUC and iAUC were lowest in 2. GLP-1 and GLP-2 responses were greatest in 3, with GLP-1 AUC 56% higher than in 1A, and GLP-2 AUC approximately twofold higher than in controls. PYY was reduced in 1A versus controls but markedly increased in groups 2 and 3 versus 1A and controls. Basal PYY correlated negatively with small bowel length and positively with colon length. GIP concentrations did not differ across groups. CONCLUSION:Remnant intestinal anatomy is a major determinant of hormone profiles after intestinal resection. Preservation of terminal ileum and/or colon is associated with enhanced distal L cell secretion, consistent with an "ileal brake" phenotype, whereas short jejunum without distal bowel is associated with hypergastrinaemia and increased CCK secretion. CLINICALTRIALS:gov no: NCT07235670.

Rural, agro-pastoralist Maasai in East Africa exhibit low prevalence of diabetes, yet little is known about their physiological response to glucose loads and whether sex has an impact on glucose metabolism, including incretin hormones. We included 58 (29 men, 29 women) adult Maasai without diabetes living in rural Tanzania. Clinical background characteristics were measured, and they were exposed to an oral glucose tolerance test (OGTT) after an overnight fast. Plasma glucose, insulin/C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) were analysed. Mean age was 34.8 (range 17–65) years, and mean body mass index (BMI) was 20.3 (range 14.0-30.9) kg/m2 with two individuals being overweight and 14 being underweight. Men had a higher mean fasting glucose concentration (5.2 vs. 4.9 mmol/L, p = 0.031), while women exhibited a higher OGTT-derived mean GLP-1 concentration at 2-h (8.5 vs. 5.1 pmol/L, p = 0.005). Total area-under-the-curve (tAUC) for GLP-1 was higher in women compared to men (1336 vs. 870 pmol x min, p = 0.011). Sex- and BMI-adjusted regression analyses for tAUC showed higher values of insulin, C-peptide and GLP-1 in women (p < 0.10). Sex differences were found in fasting glucose and OGTT-derived insulin/C-peptide and GLP-1 concentrations. Research using more sophisticated methodology is needed to further explain the glucose metabolism phenotype in Maasai people.

Lactate, a small organic acid related to short-chain fatty acids, is emerging as a key energy metabolite, although much remains unknown about its actions in the gut. In the current study, we specifically tested how oral and parenteral (IV) lactate affects lactoylation of amino acids in humans and whether these clinical results could be reproduced in a perfused rat intestine model. Furthermore, using targeted and untargeted metabolomics, we globally investigated how oral and IV lactate impacts the circulating metabolome to delineate potential circulating messengers and obtain additional mechanistic insights into how oral lactate may potentially induce glucagon-like peptide-1 secretion as well as alternative metabolites correlated to human health. Our findings provide a better understanding of the general effects of lactate in the gut and how it potentially signals to increase satiety in humans.NEW & NOTEWORTHY By investigating the effects of oral versus IV lactate administration, we find that oral lactate elevates plasma l-lactate and strongly increases circulating l-Lac-Phe and l-Lac-Val, potentially via an alternative mechanism than exercise-induced formation. Furthermore, we find that GLP-1 secretion is not directly induced by lactate but may be mediated via increased bile acids and SCFAs in the gut.

OBJECTIVE:Incretin-based obesity medication maintains weight loss by mimicking the appetite-inhibiting hormone GLP-1. Interestingly, chronic exercise may improve postprandial appetite control by increasing late postprandial secretion of endogenous GLP-1. Therefore, we investigated whether an exercise program after weight loss could increase late-phase postprandial GLP-1 secretion. METHODS:This study is an exploratory analysis of adults with obesity (n = 195) who lost 13.1 kg on a low-calorie diet and were randomized to 52 weeks of either usual activity, moderate-to-vigorous intensity exercise, the GLP-1 receptor agonist liraglutide (3.0 mg/day), or the combination. The primary endpoint was change in late-phase GLP-1 response to a 3-h liquid mixed meal test before and after diet-induced weight loss and after 1 year of intervention. RESULTS:Diet-induced weight loss did not change late-phase GLP-1 response (3%; 95% CI, -4%-10%). One year of exercise increased late-phase postprandial GLP-1 response within the group by 37% (95% CI, 20%-57%), and this increase was 25% greater (95% CI, 3%-51%, p = 0.02) compared to the usual activity group. Late-phase postprandial GLP-1 response was unchanged in both groups treated with GLP-1 receptor agonist compared to placebo. CONCLUSIONS:One year of exercise increased late-phase postprandial GLP-1 response, which may prevent increased appetite after weight loss and thereby weight regain. TRIAL REGISTRATION:EudraCT number: 2015-005585-32; ClinicalTrials.gov identifier: NCT04122716.

Gastrointestinal hormones are essential for nutrient handling and regulation of glucose metabolism and may affect postprandial blood redistribution. In a randomized cross-over design in 10 healthy men, the involvement of glucose-dependent insulinotropic polypeptide (GIP) in splanchnic blood flow regulation was investigated using an infusion of GIP receptor antagonist (GIPR-An) GIP(3-30)NH2 during ingestion of oral glucose (75 g). In five separate sessions, we investigated GIP(1-42), GIPR-An with and without oral glucose, oral glucose alone, and a control saline infusion. Blood flow was assessed by phase contrast MRI, hepatic oxygen consumption by T2*, and plasma glucose, insulin, C-peptide, glucagon, GIP, GIPR-An, glucagon-like peptide 2, and bone metabolism markers by frequent blood sampling during all sessions. We found GIP(1-42) to stimulate blood flow in the superior mesenteric artery by ∼10% in the fasting state. Oral glucose alone increased mean blood flow in the superior mesenteric artery by ∼70% and portal vein by ∼40% of baseline. During oral glucose ingestion with concurrent infusion of GIPR-An, blood flow in the superior mesenteric artery was ∼22% lower. The hormone infusions did not affect blood flow in the hepatic artery and the celiac artery. Infusion of GIPR-An during oral glucose ingestion resulted in lower insulin secretion and higher levels of carboxy-terminal collagen crosslinks (bone resorption biomarker) compared with saline infusion, whereas glucagon levels were unaffected by both the injection of GIP and the GIPR-An infusions. We conclude that endogenous GIP increases splanchnic blood flow and contributes to postprandial intestinal hyperemia in healthy men. ARTICLE HIGHLIGHTS:Administration of the gut hormone glucose-dependent insulinotropic polypeptide (GIP) increases splanchnic blood flow. We investigated the role of endogenous GIP in splanchnic blood flow regulation using a receptor antagonist in humans. Oral glucose ingestion increased blood flow in the superior mesenteric artery by ∼70%, and the increase was significantly lower during concurrent infusion of the GIP receptor antagonist. Thus, endogenous GIP contributed ∼22% of the postprandial increase in superior mesenteric artery blood flow. We have identified a novel physiological aspect of vascular biology related to the GIP receptor in humans. Treatments targeting the GIP receptors are likely to affect splanchnic blood flow.

Introduction:Suboptimal clinical responses to metabolic and bariatric surgery include insufficient weight loss (WL), weight regain (WR), and/or comorbidity remission failure or relapse. Gut hormones' role in WR and Type 2 diabetes (T2D) relapse is not fully established. So, our aim was to evaluate the hormone profiles of patients with long-term optimal and suboptimal response after gastric bypass (RYGB). Methods:This cross-sectional study included 43 individuals who underwent RYGB surgery over 10 years ago, divided into two groups: 23 participants with no T2D history but different WR trajectories (cohort 1), and 20 with prior T2D diagnosis and optimal WL (cohort 2), with post-RYGB T2D remission (n=10) or relapse (n=10). Results:Fasting and postprandial glucose, insulin, C-peptide, glucagon, GLP-1 and GIP levels were evaluated during a mixed-meal tolerance test. In cohort 1, fasting glucose, insulin, C-peptide, and glucagon, as well as the postprandial glucose and GIP levels, were significantly positively correlated with %WR. Additionally, postprandial GLP-1 and glucagon levels were negatively correlated with the %WR. In cohort 2, higher postprandial glucose and lower insulin were observed in participants with T2D relapse. No other significant differences were observed. Discussion:In sum, greater WR was associated with higher levels of postprandial glucose and GIP, along with lower GLP-1 and glucagon excursions. Whether these are cause or consequence of WR remains to be clarified. Additionally, GIP and GLP-1 profile of participants with T2D relapse did not differ from those with T2D remission.