Gastric bypass up-regulates insulin signaling pathway

Objective: In the severely obese, Roux-en-Y gastric bypass (RYGB) reverses diabetes before body weight loss occurs. We determined changes in protein expression of insulin receptor (IR), its substrates (IRS1 and IRS2), and their phosphorylated state (p-IR and p-IRS1/2) in skeletal muscle (SM), liver and adipose tissue (AT), and GLUT4 in SM and AT, 14 and 28 d after RYGB to gaining insight into the time-related dynamics of insulin transduction pathway that may contribute to diabetes resolution. Background: RYGB induces a rapid weight loss followed by a slower weight loss period, leading to reversal of diabetes. We hypothesize that diabetes reversal is due to RYGB-induced up-regulation of insulin signaling pathway. Methods: Diet-induced obese rats had RYGB or sham-operation (obese-controls). Daily food intake, body weight, glucose, insulin, and adiponectin were measured. IR, IRS1, IRS2, p-IR, and p-IRS1/2 were measured in SM, liver, and AT and GLUT4 in SM and AT, 14 and 28 d after RYGB, respectively, reflecting the rapid and slower weight loss periods after RYGB. Results: On day 14, in RYGB rats versus obese-controls, food intake, body weight, and fat mass decreased. Rats became normo-glycemic and had low insulin levels and elevated glucose:insulin ratio and decreased adiponectin concentrations. This persisted to day 28, except that adiponectin rose. No change in IR occurred on day 14, in RYGB rats versus obese-controls. By day 28 RYGB rats had a higher IR expression in SM and liver, but no changes in AT. RYGB induced a time-related increase in p-IR in liver and in pIRS1/2 in SM and liver. An increase in GLUT4 occurred by day 28 in SM and AT. Conclusions: Improvement in diabetes occurred after RYGB due to up-regulation in key insulin pathway proteins at several levels, predominantly in SM and liver in association with ongoing caloric restriction, body weight, and fat mass loss. (C) 2011 Elsevier Inc. All rights reserved.