Pancreatic Beta Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes

beta-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of beta-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin(+) cells, gastrin expression in humans with T2D occurs in both insulin(+) and somato-statin(+) cells. Genetic lineage tracing in mice indicates that gastrin expression is turned on in a subset of differentiated II-cells after exposure to severe hyperglycemia. Gastrin expression in adult beta-cells does not involve the endocrine progenitor cell regulator neurogenin3 but requires membrane depolarization, calcium influx, and calcineurin signaling. In vivo and in vitro experiments show that gastrin expression is rapidly eliminated upon exposure of beta-cells to normal glucose levels. These results reveal the fetal hormone gastrin as a novel marker for reversible human beta-cell reprogramming in diabetes.