Mechanisms of glucose homeostasis after Roux-en-Y gastric bypass surgery in the obese, insulin-resistant Zucker rat.

Obesity is a leading cause of morbidity and mortality worldwide. Morbid obesity, its most severe form, afflicts 23 million Americans.1 Surgery is currently the most effective treatment for morbid obesity.2 The Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure performed in the United States. The RYGB produces durable weight loss and significant improvements in obesity-related medical conditions including: hypertension, hyperlipidemia, sleep apnea, arthritis, infertility, and type 2 diabetes mellitus (T2DM).2–5 Many patients demonstrate significant improvements in T2DM shortly after RYGB surgery, before significant weight loss.6,7 This observation has raised questions regarding the relative importance of decreased food intake, weight loss, changes in fat depots, and/or bypass of the hormonally active foregut in improving obesity-related insulin resistance.8 The current study examines potential mechanisms for early postoperative glucose homeostasis after RYGB using the genetically obese Zucker rat model. Obesity in the Zucker rat is an autosomal recessive trait (fa/fa) caused by defective leptin receptors.9,10 Heterozygous lean Zucker rats are normal, whereas the obese Zucker rat develops progressive insulin resistance, glucose intolerance, hyperlipidemia, and hypertension.11 The obese Zucker rat has been used extensively to study obesity-related insulin resistance and is therefore an excellent model for investigating how RYGB improves glucose homeostasis.12 In the obese Zucker rat, peripheral insulin resistance is characterized by moderately elevated circulating glucose levels, hyperinsulinemia, abnormal glucose tolerance, and increased pancreatic β-cell mass.11 Peripheral insulin resistance in this model is because of defective insulin signaling, reductions in the insulin-sensitive glucose transporter (GLUT4) expression and insulin-stimulated GLUT4 membrane translocation.13,14 Early improvements in glucose homeostasis after RYGB may be because of decreased food intake, weight loss, or changes in body composition. Alterations in the secretion or activity of enteric (incretin) or adipose (adipokine) hormones have also been implicated in the resolution of T2DM after RYGB surgery.15,16 Incretins are peptides secreted by the gut which augment insulin secretion and glycemic control in response to oral (vs. intravenous) glucose, and fat intake.15 Glucose-dependent insulinotropic peptide (GIP) is secreted by K cells in the duodenum and jejunum whereas glucagon-like peptide-1 (GLP-1) is secreted by L cells in the distal small bowel.15 Both GIP and GLP-1 bind specific receptors on pancreatic β-cells to increase islet cell mass and stimulate insulin secretion.15 Extrapancreatic effects of GLP-1 include the stimulation of glucose metabolism in liver and muscle.17,18 GIP levels are not altered in T2DM, but reductions in β-cell GIP receptors and postreceptor defects in GIP signaling have been identified.19 Impaired GLP-1 release and action have also been identified in T2DM.20 Thus, alterations in incretin synthesis or activity represent a potential mechanism for improved insulin sensitivity after RYGB surgery. The quantity and distribution of body fat and the synthesis of adipokines have also been shown to be important in the development of insulin resistance.21 Accumulation of visceral fat in particular is associated with insulin resistance and removal of visceral fat improves insulin sensitivity and glucose homeostasis.22 The secretion of adipokines [tumor necrosis factor (TNFα), interleukin-6 (IL-6), and resistin] by visceral and subcutaneous fat contribute to insulin resistance at the tissue level and are associated with impaired insulin signaling in muscle and other tissues.23 The current study was designed to examine the effects of RYGB and pair-feeding on body weight, adipose tissue depots, glucose tolerance, insulin sensitivity, and incretin production. Our data indicate RYGB-induced changes in gastrointestinal anatomy (foregut bypass and enhanced delivery of undigested nutrients to the ileum) result in improved glucose tolerance and insulin action associated with increased GLP-1 concentration.