Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

Abstract

Hydrogen sulfide (H 2 S) has been traditionally known for its toxic effects on living organisms. The role of H 2 S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H 2 S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H 2 S production and insulin release were also assayed. It was found that H 2 S was generated in rat pancreas islets, catalyzed predominantly by cystathionine g-lyase (CSE). Pancreatic CSE expression and H 2 S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H 2 S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level (Po0.05). Although in ZF rats it also reduced pancreatic H 2 S production and serum H 2 S level, PPG treatment did not alter serum insulin and glucose level. Finally, H 2 S significantly increased K ATP channel activity in freshly isolated rat pancreatic b-cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H 2 S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H 2 S production from pancreas. KEYWORDS: diabetes; hydrogen sulfide; insulin release; K ATP channel; pancreas; type 2 diabetes mellitus Known as a swamp gas or 'rotten egg' gas, hydrogen sulfide (H 2 S) has yielded a public image of air pollutant for centuries. Physiological importance of H 2 S as a gasotransmitter has been realized for less than a decade. Endogenous production of H 2 S from L-cysteine is catalyzed by cystathionine b-synthase (CBS) and/or cystathionine g-lyase (CSE) with ammonium and pyruvate as co-products. 1 This process occurs in different organs and tissues, such as neuronal, vascular, and intestinal tissues. 2 Physiological concentrations of circulating H 2 S have been reported in the range of 45-300 mM. 1 At this physiological range, exogenous H 2 S has been shown to relax different vascular tissues, including isolated rat aortae and perfused mesenteric artery bed. 3-5 Altered cell proliferation or apoptosis induced by H 2 S has also been widely reported. [6][7][8][9][10] Endogenous production and physiological function of H 2 S in pancreas have been studied with identification of both CBS and CSE in rat pancreatic tissues or cloned rat pancreatic b-cell line. 11,12 In recent years, pathophysiological implications of the CSE/H 2 S system in diabetes have been reported. 12 CSE mRNA expression and H 2 S formation in rat pancreas was significantly increased after diabetes induction by streptozotocin injection. 12 CBS expression was reported in pancreatic acinar cells. 13 Y...

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

“…Additionally, Kaneko et al suggested that elevation of the H 2 S levels as a result of L-cysteine metabolism may inhibit insulin release from isolated mouse islets and the mouse ␤-cell line MIN6 under diabetic conditions (11). In ZDF rats, abnormally high pancreatic production of H 2 S has been reported to suppress insulin release (101). These findings indicate that high concentrations of H 2 S in pancreas could have deleterious effects on the development of diabetes and that new therapeutic measures for diabetes may involve inhibiting endogenous H 2 S production from pancreas.…”

Significance of Hydrogen Sulfide Production in the Pancreatic β-Cell

“…Increases in CBS and CSE expression and H 2 S production in these diabetic tissues are reversed by insulin treatment, suggesting that this may be a secondary result from hyperglycemia or hypoinsulinemia. In Zucker diabetic fatty (ZDF) rats, which are a diabetic model with obesity and hyperinsulinemia, CSE expression is elevated in the islets (22). Intraperitoneal administration of PPG, but not of aminooxyacetate, a putative selective inhibitor of CBS, improves glycemic control in vivo in ZDF rats (22).…”

“…In Zucker diabetic fatty (ZDF) rats, which are a diabetic model with obesity and hyperinsulinemia, CSE expression is elevated in the islets (22). Intraperitoneal administration of PPG, but not of aminooxyacetate, a putative selective inhibitor of CBS, improves glycemic control in vivo in ZDF rats (22). However, non-obesediabetic (NOD) mice, another model of type 1 diabetes that results from an autoimmune disorder, show a progressive reduction of plasma H 2 S levels (29).…”

Rat pancreatic level of cystathionine γ-lyase is regulated by glucose level via specificity protein 1 (SP1) phosphorylation

“…H 2 S is produced in various types of cells via the enzymatic function of two enzymes: cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) [1]. CSE has been shown to be the predominant H 2 S-generating enzyme in pancreatic beta cells [2] and freshly isolated rat islets [3].…”