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BACKGROUND/AIMS The effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β-cell function are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure β-cell function, the amount of WL between treatment groups, and baseline β-cell function. The goal of this study was to evaluate the effect of WL after RYGB surgery or reduced energy intake alone on β-cell function in people with obesity with and without type 2 diabetes. METHODS β-cell function (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after: i) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, ii) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and iii) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes. RESULTS Diet-induced progressive WL in people without diabetes progressively decreased β-cell function. Marked WL after LAGB or RYGB in people without diabetes did not alter β-cell function. Marked WL after LCD or RYGB in people with diabetes markedly increased β-cell function, without a difference between the two groups. CONCLUSION Marked WL increases β-cell function in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on β-cell function is not different from the effect of matched WL after LAGB or LCD alone. CLINICAL TRIAL REGISTRATION NUMBERS NCT00981500, NCT02207777, NCT01299519FUNDING. This study was supported by NIH grants R01 DK037948, R01 DK101578, P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), and UL1 TR002345 (Washington University Institute of Clinical and Translational Sciences), and grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011).