Proton pump inhibitors (PPIs) block the parietal cell H+/K+ ATPase, are superior at suppressing acid secretion & promoting peptic ulcer healing, wildly used clinically for the therapy of gastro-esophageal reflex disease, gastritis due to excess stomach acid, and gastric ulcers. After blocking the production of gastric acid, the proton-pump inhibitors indirectly elevate serum gastrin levels via a negative feedback effect. Evidences are reported that gastrin promotes β cell neogenesis in pancreatic ductal complex, modest pancreatic β cell replication and improvement of glucose tolerance in animal models. Some recent clinical studies have shown improved glucose tolerance in type-2 diabetes mellitus (T2DM). Although PPIs may be possible candidates for a new approach in the therapy of diabetes, a prospective, long-term, randomized, double-blind, placebo-controlled study is needed to establish the effect of PPIs on glycemic control in a large number of patients with T2DM.