It has been proposed that Roux-en-Y gastric bypass (RYGB) surgery has weight loss independent effects on metabolic function that contribute to remission of type 2 diabetes (T2D). In this non-randomized controlled clinical trial, we evaluated the key metabolic pathways involved in glucose homeostasis and in the pathogenesis of T2D before and after matched (~18%) weight loss induced by RYGB surgery or low-calorie diet (LCD) therapy alone in 22 people with obesity and T2D. The primary outcome was the change in liver insulin sensitivity assessed by using a three-stage, hyperinsulinemic-euglycemic, pancreatic clamp procedure. Secondary outcomes included changes in body composition, metabolic response to meal ingestion, 24-hour glucose and hormonal homeostasis, adipose tissue and skeletal muscle insulin sensitivity, and β-cell function. We also evaluated several factors that have been purported to cause weight-loss independent therapeutic benefits of RYGB surgery, including plasma bile acid, branched chain amino acid concentrations, and the composition of the gut microbiome before and after weight loss. Our data demonstrate that weight loss induced by either RYGB or LCD decreased intra-abdominal adipose tissue volume and IHTG content, and caused marked improvements in integrated 24-hour plasma glucose, fatty acid and insulin profiles, liver, adipose tissue, and skeletal muscle insulin sensitivity, and β-cell function, without differences between treatment groups. These results underscore the profound effect of weight loss on metabolic function, suggest the metabolic benefits of RYGB surgery is due to weight loss per se, and challenge the notion that RYGB surgery has clinically important weight loss-independent therapeutic effects.
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