Regulation of carbohydrate metabolism by nitric oxide and hydrogen sulfide: Implications in diabetes

Abstract

Nitric oxide (NO) and hydrogen sulfide (H₂S) are two gasotransmitters that are produced in the human body and have a key role in many of the physiological activities of the various organ systems. Decreased NO bioavailability and deficiency of H₂S are involved in the pathophysiology of type 2 diabetes and its complications. Restoration of NO levels have favorable metabolic effects in diabetes. The role of H₂S in pathophysiology of diabetes is however controversial; H₂S production is decreased during development of obesity, diabetes, and its complications, suggesting the potential therapeutic effects of H₂S. On the other hand, increased H₂S levels disturb the pancreatic β-cell function and decrease insulin secretion. In addition, there appear to be important interactions between NO and H₂S at the levels of both biosynthesis and signaling pathways, yet clear an insight into this relationship is lacking. H₂S potentiates the effects of NO in the cardiovascular system as well as NO release from its storage pools. Likewise, NO increases the activity and the expression of H₂S-generating enzymes. Inhibition of NO production leads to elimination/attenuation of the cardioprotective effects of H₂S. Regarding the increasing interest in the therapeutic applications of NO or H₂S-releasing molecules in a variety of diseases, particularly in the cardiovascular disorders, much is to be learned about their function in glucose/insulin metabolism, especially in diabetes. The aim of this review is to provide a better understanding of the individual and the interactive roles of NO and H₂S in carbohydrate metabolism.

Keywords: Carbohydrate metabolism; Diabetes; Hydrogen sulfide; Nitric oxide.

Figure 1.. Hydrogen sulfide and nitric oxide biosynthetic pathways.

Hydrogen sulfide (H₂S) and nitric oxide (NO) are produced by enzymatic and non-enzymatic pathways. Non-enzymatic production of H₂S is mediated through reducing elemental sulfur or organic polysulfides. Enzymatic production of H₂S is mediated by cystathionine γ-lyase (CSE), cystathionine-beta synthase (CBS), and 3-mercaptopyruvate sulfuretransferase (3-MST). NO is produced by nitrate/nitrite pathway which can be enzymatic or non-enzymatic. NO is also produced from L8 arginine by neuronal NO synthase (nNOS), inducible NO synthase (iNOS), and endothelial NO 9 synthase (eNOS).

Figure 2.. Mechanisms of nitric oxide-stimulated insulin secretion in pancreatic β-cell.

Glucose enters the pancreatic β-cells through glucose transporter type 2 (GLUT-2) (1). Glucose is phosphorylated by glucokinase (2) and increases cytoplasmic adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio (3); increased ATP/ADP ratio closes (ATP)15 dependent K⁺ (K_ATP) channels (4) and causes membrane depolarization (5) and the subsequent activation of L-type voltage-dependent Ca²⁺ channels (VDCC) (6). Elevation of cytosolic free Ca²⁺ concentration is followed by activation of synaptotagmin as a calcium sensor (7) and then exocytosis of insulin granules into the circulation (8). Nitric oxide (NO) causes mitochondrial depolarization, which induces calcium release from mitochondria. NO also facilitates glucose-stimulated insulin secretion by S-nitrosylation of glucokinase or syntaxin 4.

Figure 3.. Mechanisms of hydrogen sulfide-inhibited insulin secretion from pancreatic β-cell.

Hydrogen sulfide (H₂S) inhibits insulin secretion by opening of K_ATP channels via Ssulfhydration. Opening of K_ATP channels causes membrane hyperpolarization and therefore closing of VDCC. H₂S also inhibits VDCC directly via S-sulfhydration. H₂S inhibits glucose-induced mitochondrial membrane hyperpolarization and ATP production. G6P, Glucose 6-phosphate; SNAP 23/25, Synaptosome Associated Protein 23/25; VAMP, Vesicle Associated Membrane Protein.