Raising Serum Gastrin to Improve Glycemic Control in (Type 2) Diabetes: Another Limb of the Enteroinsular Axis?

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 iv 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 (1), evidence supporting an incretin role for gastrin. Nevertheless, resection of the gastric antrum as part of Whipple’s operation that reduced serum gastrin levels to very low or undetectable levels was not associated with any diminution of the incretin effect (2), suggesting that whatever role gastrin played was dispensable, at least in nondiabetic individuals. 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 -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...” (3). 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 (4). More recently, Meier et al. (5) showed that in cases of intrapancreatic gastrinoma, there was an increase in fractional -cell area and -cell replication in pancreatic tissue adjacent to but not distant from gastrin-producing tumors, suggesting that either an extremely elevated level of gastrin acting in a paracrine fashion or some other growth factor released by the tumor is required for such trophic -cell effects in humans (and perhaps only in those predisposed to endocrine neoplasia). In isolated human islets, a combination of epidermal growth factor and gastrin but not gastrin alone was required to increase the numbers of -cells in culture, although both gastrin and epidermal growth factor independently increased the insulin content of islets (6). Thus, evidence exists to support an effect of gastrin on increasing insulin production in human -cells. By blocking gastric acid production, proton pump inhibitors (PPIs) remove negative feedback on gastrin production by enterochromaffin cells. In a rodent model of type 2 diabetes treatment with the PPI lansoprazole increased serum gastrin that was associated with improved glycemia and increased pancreatic insulin content (7). Now comes a randomized placebo-controlled trial of the PPI pantoprazole in type 2 diabetes that reduced the glycosylated hemoglobin by approximately 1 percentage point (8). The improvement in glycemic control was associated with a decrease in fasting glucose and increase in fasting insulin such that homeostasis model assessment surrogate measures suggested an improvement in -cell function and no change in insulin sensitivity. Although