Role of Nitric Oxide in Insulin Secretion and Glucose Metabolism

NO is involved in carbohydrate metabolism and disrupted NO pathways (i.e., decreased cNOS-derived NO bioavailability or iNOS-induced overproduction of NO) leads to the development of T2DM. cNOS-derived NO improves insulin secretion and signaling, increases glucose uptake, and regulates hepatic glucose output. These physiological effects of NO are mainly mediated by the sGC–cGMP pathway. Cytokine-induced overactivity of iNOS leading to pathological levels of NO (micromolar) disturbs glucose and insulin homeostasis. NO-releasing drugs can restore disrupted NO signaling and improve carbohydrate metabolism in insulin resistance and T2DM. The clinical implications of NO donors encapsulated with common hypoglycemic agents like metformin might be considered as a future treatment for T2DM. Nitric oxide (NO) contributes to carbohydrate metabolism and decreased NO bioavailability is involved in the development of type 2 diabetes mellitus (T2DM). NO donors may improve insulin signaling and glucose homeostasis in T2DM and insulin resistance (IR), suggesting the potential clinical importance of NO-based interventions. In this review, site-specific roles of the NO synthase (NOS)–NO pathway in carbohydrate metabolism are discussed. In addition, the metabolic effects of physiological low levels of NO produced by constitutive NOS (cNOS) versus pathological high levels of NO produced by inducible NOS (iNOS) in pancreatic β-cells, adipocytes, hepatocytes, and skeletal muscle cells are summarized. A better understanding of the NOS–NO system in the regulation of glucose homeostasis can hopefully facilitate the development of new treatments for T2DM. Nitric oxide (NO) contributes to carbohydrate metabolism and decreased NO bioavailability is involved in the development of type 2 diabetes mellitus (T2DM). NO donors may improve insulin signaling and glucose homeostasis in T2DM and insulin resistance (IR), suggesting the potential clinical importance of NO-based interventions. In this review, site-specific roles of the NO synthase (NOS)–NO pathway in carbohydrate metabolism are discussed. In addition, the metabolic effects of physiological low levels of NO produced by constitutive NOS (cNOS) versus pathological high levels of NO produced by inducible NOS (iNOS) in pancreatic β-cells, adipocytes, hepatocytes, and skeletal muscle cells are summarized. A better understanding of the NOS–NO system in the regulation of glucose homeostasis can hopefully facilitate the development of new treatments for T2DM. an energy sensor that regulates cellular metabolism; it is activated by a deficit in nutrient status and stimulates glucose uptake and lipid oxidation to produce energy. a serine/threonine-specific protein kinase that is activated by cGMP. glucose-sensing neurons widely dispersed throughout the hypothalamus. GI neurons are activated in hypoglycemia via an interaction between AMPK and NO, which leads to chloride channel closure, membrane depolarization, and increased action potential frequency. GE neurons mainly utilize a glucose-sensing mechanism like that of the pancreatic β-cell, through KATP channels. an ATP-sensitive potassium channel and metabolic sensor that couples cellular metabolism to electrical activity. In pancreatic β-cells, the KATP channel regulates GSIS and is a target for sulfonylurea antidiabetic drugs. a matrix metallopeptidase predominantly expressed by tissue mature macrophages; positively regulates iNOS expression and activity. pharmacologically active substances that release NO in vivo or in vitro; the most common NO donors include sodium nitroprusside (SNP), S-nitroso-N-acetyl-penicillamine (SNAP), 2-(N,N-diethylamino)diazenolate-2-oxide (DEANO), 3-morpholinosydnonimine (SIN-1), 1,1-diethyl-2-hydroxy-2-nitrosohydrazine (NONOate), 1-hydroxy-2-oxo-3-[N-methyl-3-aminopropyl]-3-methyl-1-triazene (NOC-7), and S-nitrosoglutathione (GSNO). pharmacologically active substances that interfere with the toxic effects of excessive NO production while preserving some activity of NO that might be essential for normal biological function [e.g., 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO)]. pharmacologically active substances that inhibit NOS enzymes and therefore NO production. The most common NOS inhibitors are L-arginine analogs [e.g., NG-nitro-L-arginine methyl ester (L-NAME), L-NG-monomethyl L-arginine (L-NMMA), NG-methyl-L-arginine (L-NMA), nitro-L-arginine (L-NNA)], which are competitive and nonselective inhibitors. Some NOS inhibitors are selective; for example, 7-nitroindazole (7-NI), a specific nNOS inhibitor, and aminoguanidine, a selective iNOS inhibitor. produced by the reaction of NO with the superoxide anion (O2•−); a strong oxidant that reacts at a relatively slow rate with most biological molecules. The pathological effects of NO at toxic levels are partly attributed to peroxynitrite. refers specifically to chemical reactions involving the addition of a nitrosonium ion (NO+) to a nucleophilic group, such as an amine or thiolate. refers to the direct addition of NO to a reactant (e.g., cysteine residues of a protein); in chemistry, it is defined as the coordination of NO to a metal center to form a metal nitrosyl complex. a heterodimeric (α and β subunits) heme protein of molecular mass ∼150 kDa; known as the primary receptor of NO that responds to NO binding by increasing cyclase activity, producing guanosine 3′,5′-cGMP, and generating a signaling cascade.