Glucose‐induced production of hydrogen sulfide may protect the pancreatic beta‐cells from apoptotic cell death by high glucose

Abstract

a b s t r a c tWe examined the expression of the major H 2 S-producing enzymes, cystathionine-b-synthase (CBS) and cystathionine-c-lyase (CSE). CBS was ubiquitously distributed in the mouse pancreas, but CSE was found only in the exocrine. Freshly isolated islets expressed CBS, while CSE was faint. However, high glucose increased the CSE expression in the beta-cells. L-Cysteine or NaHS suppressed islet cell apoptosis with high glucose, and increased glutathione content in MIN6 beta-cells. Pretreatment with L-cysteine improved the secretory responsiveness following stimulation with glucose. The CSE inhibitor DL-propargylglycine antagonized these L-cysteine effects. We suggest H 2 S may function as an 'intrinsic brake' which protects beta-cells from glucotoxicity.

Significance of Hydrogen Sulfide Production in the Pancreatic β-Cell

“…We also found that CSE and CBS mRNAs are expressed in mouse pancreatic islets (18,19). Further analyses revealed that expression of CSE, but not CBS, dramatically increases in the islets following glucose stimulation (19). This finding was the first to indicate that expression of H 2 S-producing enzymes can be induced by a physiological stimulus.…”

“…We measured H 2 S content as acid-labile sulfur in the mouse insulin-secreting cell line MIN6 (18), and we found that H 2 S levels in this β-cell line were comparable with those in brain homogenates (5, 9 -11). We also found that CSE and CBS mRNAs are expressed in mouse pancreatic islets (18,19). Further analyses revealed that expression of CSE, but not CBS, dramatically increases in the islets following glucose stimulation (19).…”

“…In contrast, we have recently reported that H 2 S may act as a cytoprotectant for intact mouse islets and MIN6 cells. NaHS or L-cysteine reduced apoptotic cell death of mouse islets or MIN6 cells exposed to high glucose, fatty acids, or a mixture of cytotoxic cytokines (19,24). Moreover, concomitant incubation of mouse islets with L-cysteine restored the secretory activity of islets subjected to chronic exposure to high glucose (19).…”

“…NaHS or L-cysteine reduced apoptotic cell death of mouse islets or MIN6 cells exposed to high glucose, fatty acids, or a mixture of cytotoxic cytokines (19,24). Moreover, concomitant incubation of mouse islets with L-cysteine restored the secretory activity of islets subjected to chronic exposure to high glucose (19). Because the L-cysteine effect was inhibited by the CSE inhibitor, DL-propargylglycine (PPG), H 2 S production by CSE seems to be important to β-cell protection.…”

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

“…38 We observed that % tail DNA significantly increased in hyperglycemia treated 1.1B4 cells, which is similar to observations with RINm5F, INS-1E cells, and isolated mouse islets. [39][40][41][42] Execution of apoptosis was evident from a slight increase in caspase 3/7 activity after 72 h exposure which has also been observed in hyperglycemia treated INS-1 cells and isolated human islets. 43,44 In conclusion, this study has demonstrated multiple effects of glucotoxicity on gene expression and insulin secretory function in 1.1B4 cells, suggesting that this novel human-derived pancreatic β-cell line is useful for further investigations of β-cell dysfunction and its correction with novel therapeutic agents.…”