Objective: To investigate the influence of gastric bypass surgery on expressions of insulin receptor (IRc) and insulin receptor substrate 2 (IRS-2) in islet cells of rats with type 2 diabetes mellitus. Methods: The model of type 2 diabetes mellitus in rats was induced by a high fat and high glucose diet plus intraperitoneal streptozotocin injection, and then the rats with establishment of successful model were divided into model group and gastric bypass group, using the normal rats as normal control group. The rats in gastric bypass group underwent gastrojejunostomy and side-to-side jejunojejunostomy, and those in model group and normal control group underwent sham operation. The fasting glucose and serum insulin levels were measured and insulin sensitivity index (ISI) was calculated before and at 8 weeks after operation, and the IRc and IRS-2 expressions in pancreatic tissues were determined by immunohistochemical staining. Results: The fasting glucose levels were increased and ISI values were decreased significantly in both model group and gastric bypass group compared with normal control group before operation, but these two parameters were significantly improved in gastric bypass group compared with model group after operation (all P<0.05); the serum insulin levels showed no significantly difference among groups before and after operation (both P>0.05). In gastric bypass group at 8 weeks after operation, both IRc and IRS-2 expression levels were significantly higher than those in model group (both P<0.05), but IRc expression level was still lower than that in normal control group (P<0.05), while IRS-2 expression level was approximately equal to that in normal control group (P>0.05). Conclusion: IRc and IRS-2 expressions are decreased in islet cells of rats with type 2 diabetes mellitus, and gastric bypass surgery can increase IRc and IRS-2 expression, which may be one of the mechanisms for the therapeutic effect of this surgical procedure on type 2 diabetes mellitus.