Development and and Analysis of Novel Therapeutic Targets to Improve Pancreatic β-Cell Function in Type 2 Diabetes

Pancreatic beta-cell dysfunction is a major feature of type 2 diabetes. Therefore maintenance of beta-cell function is essential to preventing the onset and progression of type 2 diabetes. To elucidate the mechanisms underlying the regulation of insulin secretion and beta-cell survival, we particularly focused on the roles of gasotransmitters in pancreatic beta-cells. Nitric oxide (NO) and hydrogen sulfide (H2S) are recognized as toxic gases. However, they are also vital physiological and pathophysiological mediators in various cell types. NO, generated from L-arginine by reactions catalyzed by NO synthases, is a well-known neurotransmitter and smooth muscle relaxation factor. In pancreatic beta-cells, induction of nitric oxide synthase 2 (NOS2) by inflammatory cytokines generates a large amount of NO, which contributes to the impairment of beta-cell function and induction of beta-cell apoptosis, which are, in turn, involved in the development of type 1 diabetes. In contrast, a physiological level of NO, generated by constitutive NOS (cNOS), acts as a positive or negative regulator of insulin secretion and beta-cell survival, depending on concentration. H2S generated from L-cysteine has been shown to play a role of neuromodulator, and this gas possesses cytoprotective properties. In pancreatic beta-cells, H2S functions as a potent suppressor of insulin secretion. Furthermore, chronic exposure to high glucose induces H2S production by increasing the expression of a H2S-producing enzyme, cystathionine gamma-lyase (CSE). H2S generated by CSE prevents beta-cell apoptosis via an antioxidant mechanism. Here, we describe the current understanding of the function of gasotransmitters in regulating insulin secretion and pancreatic beta-cell survival.