Impact of Pantoprazole on 24-H Glycemic Control and on Post-prandial Glucose Excursion Inpatients With Type 2 Diabetes

Diabetes mellitus is a complex chronic disease associated with an absolute insulin deficiency in type1 diabetes and a progressive deterioration of b-cell function in type 2 diabetes. The pathophysiology of type 2 diabetes includes not only the classical insulin resistance in muscle and liver and progressive b-cell failure but also accelerated lipolysis, incretin deficiency/resistance, hyperglucagonemia, renal increased glucose reabsorption, and brain insulin resistance. Finally, hyperglycemia in both type 1 and 2 diabetes results from an absolute or relative deficit in the pancreatic b -cell mass.

Gastrin has long been considered a candidate incretin hormone, i.e. an enteral factor responsible for the more than 2-fold increase in insulin secretion when glucose is ingested orally than when administered intravenously to match peripheral glucose levels. In healthy humans, acute administration of gastrin to achieve supraphysiological levels leads to a modest release of insulin under basal glucose conditions and a more pronounced potentiation of insulin release when coadministered with glucose. With the identification of gastric inhibitory polypeptide, now known as glucose-dependent insulinotropic polypeptide, and subsequently glucagon-like peptide-1 as more potent incretin hormones whose secretion may be impaired in type 2 diabetes, attention largely shifted away from gastrin playing an important role in the enteroinsular axis.

Like gastric inhibitory polypeptide and glucagon-like peptide-1, gastrin has also been shown to induce b-cell proliferation and neogenesis in various model systems, and also appears to increase the insulin content of individual cells. Zollinger and Ellison's original description of peptic ulcer disease attributable to purported gastrinoma included one case where "the pancreatic tissue removed with the tumor showed normal islands with many large cells...". Examination of another case with resected pancreas adjacent to an antral gastrinoma "showed a marked proliferation of ducts and islet tissue" with "development of islets from cells (nesidioblasts) within the duct epithelium.

Gastrin has demonstrated to be an islet growth factor (like glucagon-like peptide, epidermal growth factor, transforming growth factor) and be able to restore a functional b-cell mass in diabetic animals.

This combination drug therapy, specifically sitagliptin and pantoprazole, induces b-cell neogenesis in adult human pancreatic cells implanted in NOD-severe combined immunodeficient mice. The increased b-cell mass appears to be derived from pancreatic exocrine duct cells.