Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes.
Chronic exposure to high glucose induces the expression of cystathionine gamma-lyase (CSE), a hydrogen sulfide-producing enzyme, in pancreatic beta-cells, thereby suppressing apoptosis. The aim of this study was to examine the effects of hydrogen sulfide on the onset and development of type 2 diabetes. Middle-aged (6-month-old) wild-type (WT) and CSE knockout (CSE-KO) mice were fed a high-fat diet (HFD) for 8weeks. We determined the effects of CSE knockout on beta-cell function and mass in islets from these mice. We also analyzed changes in gene expression in the islets. After 8weeks of HFD, blood glucose levels were markedly increased in middle-aged CSE-KO mice, insulin responses were significantly reduced, and DNA fragmentation of the islet cells was increased. Moreover, expression of thioredoxin binding protein-2 (TBP-2, also known as Txnip) was increased. Administration of NaHS, a hydrogen sulfide donor, reduced TBP-2 gene levels in isolated islets from CSE-KO mice. Gene levels were elevated when islets were treated with the CSE inhibitor dl-propargylglycine (PPG). These results provide evidence that CSE-produced hydrogen sulfide protects beta-cells from glucotoxicity via regulation of TBP-2 expression levels and thus prevents the onset/development of type 2 diabetes.
Department of Pharmacology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan.
Mitsuhiro
M
Okamoto
Mami
M
Yamaoka
Masahiro
M
Takei
Tomomi
T
Ando
Shigeki
S
Taniguchi
Isao
I
Ishii
Kazuo
K
Tohya
Toshimasa
T
Ishizaki
Ichiro
I
Niki
Toshihide
T
Kimura
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000235:genetics; D019610:Cytoprotection; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006862:Hydrogen Sulfide / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D013879:Thioredoxins / Q000235:genetics
D002352:Carrier Proteins; C445672:Txnip protein, mouse; D013879:Thioredoxins; D003542:Cystathionine gamma-Lyase; D005947:Glucose; D006862:Hydrogen Sulfide
ATP-sensitive K(+); CAT; CBS; CO; CSE; Cell protection; ChREBP; DAO; HFD; Hydrogen sulfide; K(ATP); NO; PPG; Pancreatic beta-cells; STZ; TBP-2; Type 2 diabetes mellitus; carbohydrate response element-binding protein; carbon monoxide; cystathionine beta-synthase; cystathionine gamma-lyase; cysteine aminotransferase; d-amino acid oxidase; dl-propargylglycine; high-fat diet; nitric oxide; streptozotocin; thioredoxin binding protein-2