Zinc-induced activation of GPR39 regulates glucose homeostasis through glucose-dependent insulinotropic polypeptide secretion from enteroendocrine K-cells.

The role of Zn-sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn (50 μmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25-34% ( < 0.05- < 0.001) and enhanced glucose-induced insulin release by 46-48% ( < 0.05- < 0.01). In diabetic mice, orally administered Zn lowered glucose by 24-31% ( < 0.01) and augmented insulin release by 32% ( < 0.01). In glucagon like peptide-1 (GLP-1) receptor knockout mice, Zn reduced glucose by 15-28% ( < 0.05- < 0.01) and increased insulin release by 35-43% ( < 0.01). In contrast Zn had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% ( < 0.05) in lean mice. Immunocytochemistry demonstrated GPR39 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Zn had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn. This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.