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.