Lean, M. E. et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 391, 541–551 (2018).

Article  PubMed  Google Scholar 

Taheri, S. et al. Effect of intensive lifestyle intervention on bodyweight and glycaemia in early type 2 diabetes (DIADEM-I): an open-label, parallel-group, randomised controlled trial. Lancet 6, 477–489 (2020).

Google Scholar 

Look AHEAD Research Group. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity 22, 5–13 (2014).

Article  Google Scholar 

Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374, 1677–1686 (2009).

Article  PubMed Central  Google Scholar 

Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy for diabetes – 5-year outcomes. N. Engl. J. Med. 376, 641–651 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Perdomo, C. M., Cohen, R. V., Sumithran, P., Clément, K. & Frühbeck, G. Contemporary medical, device, and surgical therapies for obesity in adults. Lancet 401, 1116–1130 (2023).

Article  PubMed  Google Scholar 

Ikramuddin, S. et al. Lifestyle intervention and medical management with vs without Roux-en-Y gastric bypass and control of hemoglobin A1c, LDL cholesterol, and systolic blood pressure at 5 years in the Diabetes Surgery study. JAMA 319, 266–278 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Mingrone, G. et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386, 964–973 (2015).

Article  PubMed  Google Scholar 

World Health Organization. WHO European regional obesity report. (WHO, 2022).

Cohen, R. V. et al. Gastric bypass versus best medical treatment for diabetic kidney disease: 5 years follow up of a single-centre open label randomised controlled trial. EClinicalMedicine 53, e200420 (2022).

Article  Google Scholar 

Tan, T. M. M. Co-agonist therapeutics come of age for obesity. Nat. Rev. Endocrinol. 19, 66–67 (2022).

Article  Google Scholar 

Hinke, S. A. et al. Identification of a bioactive domain in the amino-terminus of glucose-dependent insulinotropic polypeptide (GIP). Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1547, 143–155 (2001).

Article  CAS  Google Scholar 

Mojsov, S., Weir, G. C. & Habener, J. F. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest. 79, 616–619 (1987).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gribble, F. M. & Reimann, F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat. Rev. Endocrinol. 15, 226–237 (2019).

Article  CAS  PubMed  Google Scholar 

Nauck, M. A., Homberger, E., Eberghard, S. G., Allen, R. C. & Eaton, P. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J. Clin. Endocrinol. Metab. 63, 492–498 (1986).

Article  CAS  PubMed  Google Scholar 

Gasbjerg, L. S. et al. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 125, 170183 (2020).

Article  CAS  PubMed  Google Scholar 

Nauck, M., Stöckmann, F., Ebert, R. & Creutzfeldt, W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29, 46–52 (1986).

Article  CAS  PubMed  Google Scholar 

Højberg, P. V. et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52, 199–207 (2009).

Article  PubMed  Google Scholar 

Vilsbøll, T., Agersø, H., Krarup, T. & Holst, J. J. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J. Clin. Endocrinol. Metab. 88, 220–224 (2003).

Article  PubMed  Google Scholar 

Kjems, L. L., Holst, J. J., Vølund, A. & Madsbad, S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52, 380–386 (2003).

Article  CAS  PubMed  Google Scholar 

Mentis, N. et al. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 60, 1270–1276 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kimball, C. & Murlin, J. R. Aqueous extracts of pancreas: III. Some precipitation reactions of insulin. J. Biol. Chem. 58, 337–346 (1923).

Article  CAS  Google Scholar 

Wewer Albrechtsen, N. J. et al. 100 years of glucagon and 100 more. Diabetologia 66, 1378–1394 (2023).

Article  CAS  PubMed  Google Scholar 

Svendsen, B. et al. Insulin secretion depends on intra-islet glucagon signaling. Cell Rep. 25, 1127–1134.e2 (2018).

Article  CAS  PubMed  Google Scholar 

Kim, T. et al. Hepatic glucagon receptor signaling enhances insulin-stimulated glucose disposal in rodents. Diabetes 67, 2157–2166 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cegla, J. et al. Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes 63, 3711–3720 (2014).

Article  CAS  PubMed  Google Scholar 

Flint, A., Raben, A., Astrup, A. & Holst, J. J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 101, 515–520 (1998).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Turton, M. et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72 (1991).

Article  Google Scholar 

Verdich, C. et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J. Clin. Endocrinol. Metab. 86, 4382–4389 (2001).

CAS  PubMed  Google Scholar 

Drucker, D. J. GLP-1 physiology informs the pharmacotherapy of obesity. Mol. Metab. 57, 101351 (2022).

Article  CAS  PubMed  Google Scholar 

Varin, E. M. et al. Distinct neural sites of GLP-1R expression mediate physiological versus pharmacological control of incretin action. Cell Rep. 27, 3371–3384.e3 (2019).

Article  CAS  PubMed  Google Scholar 

Sisley, S. et al. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J. Clin. Invest. 124, 2456–2463 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Meyer-Gerspach, A. C. et al. Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: a pilot study. Diabetes Obes. Metab. 20, 2330–2338 (2018).

Article  CAS  PubMed  Google Scholar 

Ten Kulve, J. S. et al. Elevated postoperative endogenous GLP-1 levels mediate effects of Roux-en-Y gastric bypass on neural responsivity to food cues. Diabetes Care 40, 1522–1529 (2017).

Article  PubMed  Google Scholar 

De Silva, A. et al. The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab. 14, 700–706 (2011).

Article  PubMed  PubMed Central  Google Scholar 

Steinert, R. E. et al. Effect of glucagon-like peptide-1 receptor antagonism on appetite and food intake in healthy men. Am. J. Clin. Nutr. 100, 514–523 (2014).

Article  CAS  PubMed  Google Scholar 

Borgmann, D. et al. Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism. Cell Metab. 33, 1466–1482.e7 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Asmar, M. et al. On the role of glucose-dependent insulintropic polypeptide in postprandial metabolism in humans. Am. J. Physiol. Endocrinol. Metab. 298, 614–621 (2010).

Article  Google Scholar 

Bergmann, N. C. et al. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia 62, 665–675 (2019).

Article  CAS  PubMed  Google Scholar 

Bergmann, N. C. et al. No acute effects of exogenous glucose-dependent insulinotropic polypeptide on energy intake, appetite, or energy expenditure when added to treatment with a long-acting glucagon-like peptide 1 receptor agonist in men with type 2 diabetes. Diabetes Care 43, 588–596 (2020).

Article  CAS  PubMed  Google Scholar 

Mroz, P. A. et al. Optimized GIP analog