title: Development and Analysis of Novel Therapeutic Targets to Improve Pancreatic β-Cell Function in Type 2 Diabetes.
abstract: Pancreatic β-cell dysfunction is a major feature of type 2 diabetes. Therefore maintenance of β-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 β-cell survival, we particularly focused on the roles of gasotransmitters in pancreatic β-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 β-cells, induction of nitric oxide synthase 2 (NOS2) by inflammatory cytokines generates a large amount of NO, which contributes to the impairment of β-cell function and induction of β-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 β-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 β-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 γ-lyase (CSE). H2S generated by CSE prevents β-cell apoptosis via an antioxidant mechanism. Here, we describe the current understanding of the function of gasotransmitters in regulating insulin secretion and pancreatic β-cell survival.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Kaneko
mesh_terms: D000975:Antioxidants; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D002384:Catalysis; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology
chemical_list: D000975:Antioxidants; D007328:Insulin; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide