Endocrine Abstracts

It has been proposed that cellular Ca²⁺ signals activate hormone secretion. In pancreatic β cells, which produce insulin, Ca²⁺ signals have been known to contribute to insulin secretion. Prior to this study, we confirmed that Calbindin-D9k (CaBP-9k) was responsible for regulation of the distribution of free calcium in the cytoplasm. We also confirmed that insulin-secreting β cells express CaBP-9k, and assumed that CaBP-9k play a role in β cell insulin synthesis or secretion. Using CaBP-9k knock out (KO) mice, we demonstrated that ablation of CaBP-9k causes type 1 diabetes by reducing insulin secretion and increasing serum glucose. To compare the role of CaBP-9k with type 2 diabetes pathophysiological conditions, we exposed wt and CaBP-9k KO mice to hypoxic conditions for 10 days.

Results: Hypoxia induced endoplasmic reticulum (ER) stress, increasing both insulin signaling and insulin resistance. By exposing hypoxia, CaBP-9k KO mice showed an increased level of ER stress marker protein relative to wild type mice. Without hypoxic conditions, CaBP-9K ablation regulates calcium channels and causes ER stress in a CaBP-9K specific manner. Ablation of CaBP-9k also showed decreased levels of sulfonylurea receptor1 (SUR1) and inward-rectifier potassium ion channel 6.2 (Kir6.2), which are insulin secretion marker genes. Overall, the results of the present study demonstrated that CaBP-9k regulates synthesis of insulin and is part of the insulin-secreting calcium signaling. Therefore, impaired CaBP-9K signaling may be linked with diabetes mellitus and CaBP-9K protein is as a potential candidate for gene therapy of type 1 diabetes.