Effects Of Hydrogen Sulfide On Lipid Metabolism In Type 2 Diabetes Mellitus And Its Mechanism

Hydrogen sulfide (H2S) is well known as a toxic gas with the characteristic smell of rotten eggs.Until1989, scientists detected in rat and human brain to the endogenous production of H2S which showe some physiological role.With in-depth study of H2S and found that endogenous H2S on the cardiovascular system, digestive system, nervous system and immune system are important physiologic function, such as it can lower blood pressure by adjusting the KATP channel in the vascular smooth muscle, it also play a cytoprotective role by antioxidant, anti-apoptosis, protecting mitochondrial. In vivo, cystathionine-β-synthase (cystathionine-β-synthase,CBS) and cystathionine-γ-lyase (cystathionine-γ-lyase, CSE) are the key enzyme which regulate the production of endogenous H2S, physiological concentrations have a clear functional and can be exogenous gas simulation.H2S is regarded as third gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO).Diabetes is one of the world’s higher incidence diseases.Dyslipidemia is very common in diabetes.Mainly in patients with diabetes die of cardiovascular disease which is caused by dyslipidemia, one of the most important risk factor, but its etiology is not very clear, the study of lipid metabolism disorders of diabetes is extremely important.The present study is shown in type2diabetes, obesity, non-obese diabetic (NOD) mice reduced H2S synthesis. In the pancreas of diabetic rats Zucker a large number of endogenous H2S production, low concentration of exogenous H2S by adjusting KATP channel opening inhibited pancreatic β-cell insulin release.But H2S in lipid metabolism of type2diabetes have not yet reported. Therefore, we research the role of exogenous H2S in lipid diorder of diabetes, more in-depth understanding of the new gaseous signal molecule.Firstly, the db/db diabetic mice as a model, the effect of exogenous H2S on glucose and lipid metabolism in type2diabetic mice the role is observed.Use the NaHS as the donor of H2S.Starting from8weeks of age (glucose and lipid metabolism are disorders), daily intraperitoneal injection of different concentrations of NaHS (10,50,100μmol/kg/d), for4weeks, and study the role of H2S in type2diabetic mice glucose and lipid metabolism.The results showed that1week after administration of high blood sugar began to be eased while further drop blood glucose at2weeks, no effect on body weight; After4weeks of administration, NaHS100μmol/kg/d mice increased the insulin sensitivity, had no effect on insulin secretion; Plasma C-reactive protein (CRP), low density lipoprotein (LDL), asparagine aminotransferase (AST) levels decreased.The results show that H2S have some regulatory role glucose and lipid metabolism disorder in type2diabetes.Sencondly, we stained by HE and Sudan III and oxidase test db/db diabetic mouse liver fat accumulation and triglyceride (TG) content, the results show, NaHS50μmol/kg/d and100μmol/kg/d treatment group Morphology of liver cells were normal, decreased accumulation of lipid droplets in liver cells, but the TG content was no significant difference among groups. By PAS staining and anthrone method to measure liver glycogen content, display NaHS100μmol/kg/d reduced the liver glycogen. These results indicate that H2S can be part of the improvement of liver damage in type2diabetes.Then, to clarify the mechanism of these phenomena, we further study in the db/db diabetic mice. The results showed that, NaHS50μmol/kg/d group of db/db diabetic mouse liver peroxisome proliferator-activated receptor y (peroxisome proliferator-activated receptor gamma, PPAR-y), peroxisome proliferator-activated Receptor a (peroxisome proliferator-activated receptor alpha, PPAR-α) mRNA levels decreased, but no change in its protein expression. NaHS10,50,100μmol/kg/d mice liver sterol regulatory element-1(sterol regulatory element-binding protein-1c, SREBP-lc), HMG coenzyme A reductase (3-hydroxy-3-methylglutary coenzyme A reductase, HMGCoA reductase), peroxisome proliferators activated receptor co activator (peroxisome proliferative activated receptor coactivator1, PGC-1, PGC-1α, or PPARGC1) mRNA levels decreased. NaHS100μmol/kg/d mice liver AMP-activated protein kinase (AMP-activated protein kinase, AMPK) and acetyl coenzyme A carboxylase (acetyl-CoA carboxylase, ACC) phosphorylation levels increase, NaHS50μmol/kg/d group of ACC mRNA levels decrease. The results indicate H2S improve type2diabetes by the AMPK/ACC, PPAR-y, PPAR-a.The above results show that H2S can improve the lipid disorder of diabetes by AMPK/ACC, PPAR to decrease the damage of liver.In order to further reseach the mechanism of H2S improving the lipid disorder of diabetes in db/db mice, the normal hepatocytes are separated and primary cultured to study the H2S on glucose and lipid metabolism of hepatocytes under high glucose medium, and thus research the effect of H2S improve the mechanism of glucose and lipid disorders. The results show that given NaHS50μmol/L can promote the glucose consumption of liver cells, lower the TG level of the hepatocytes, and further found that H2S can be time and concentration-dependent manner to promote intracellular signaling molecule phosphorylation of AMPK and ACC, the time-dependent manner to promote cytoplasmic and nuclear PPAR-y, PPAR-a protein expression, increased cell PPAR-y, PPAR-a, GCK mRNA levels, reduce FAS, ACC mRNA levels of SREBP-lc mRNA levels were not affected. H2S improve the role of lipid metabolism may be associated with AMPK/ACC, PPAR-y, PPAR-a, SREBP-lc, HMGCoA reductase, PGC-la. H2S is passed AMPK affect PPAR-y, PPAR-a expression, but also future experiments to prove it.In summary, the paper observed in the overall level of exogenous H2S can improve lipid metabolism in type2diabetes, thus helping to prevent the occurrence of damage liver. H2S was observed at the cellular level to improve the role of lipid metabolism may be associated with AMPK/ACC, PPAR-y, PPAR-a, SREBP-lc, HMGCoA reductase, PGC-1α.As hydrogen sulfide and its derivatives used in glucose and lipid metabolism in type2diabetes prevention and treatment of disorders provide experimental clues.