salvianolic-acid-B and Diabetes-Mellitus--Type-2

Impaired insulin sensitivity of insulin-sensitive tissues plays a major role in the pathogenesis of type 2 diabetes, salvianolic acid B (SalB), a natural antioxidant usually treated various cardiovascular diseases was also reported potential utility on diabetes and dyslipidemia. Based on these, we aimed to explored whether the antioxidant effect of SalB play a pivotal role in the molecular mechanisms leading to insulin resistance. We found that SalB improved glucose tolerance and insulin sensitivity, decreased serum ALT, AST and ALP levels of ob/ob mice. Also, transcription of Bip and CHOP, phosphorylation of PERK and IRE1 for endoplasmic reticulum stress (ER) and phosphorylation of IRS-1 for insulin sensitivity in the liver of ob/ob mice were relieved by SalB. Further, SalB decreased phosphorylation of PERK, IRE1 and IRS1 and transcription of Bip and CHOP stimulated by palmitate of hepatic cells HL7702, but did not reversed phosphorylation of JNK and IRS1 and transcription of Bip and CHOP when ER stress was stimulated by tunicamycin. These data shows that SalB improved insulin resistance of ob/ob mice through suppression of hepatic ER stress.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hepatocytes; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Membrane Proteins; Mice; Palmitates; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factor CHOP; Tunicamycin

Salvia miltiorrhiza Bge. (Labiatae) has been widely used for treating diabetes for centuries. Salvianolic acid B (SalB) is the main bioactive component in Salvia miltiorrhiza; however, its antidiabetic activity and possible mechanism are not yet clear.. To investigate the effects of SalB on glycometabolism, lipid metabolism, insulin resistance, oxidative stress, and glycogen synthesis in type 2 diabetic rat model.. High-fat diet (HFD) and streptozotocin-induced diabetic rats were randomly divided into model group, SalB subgroups (50, 100, and 200 mg/kg), and rosiglitazone group.. Compared with the model group, SalB (100 and 200 mg/kg) significantly decreased blood glucose (by 23.8 and 21.7%; p < 0.05 and p < 0.01) and insulin (by 31.3 and 26.6%; p < 0.05), and increased insulin sensitivity index (by 10.9 and 9.3%; p < 0.05). They also significantly decreased total cholesterol (by 24.9 and 27.9%; p < 0.01), low-density lipoprotein cholesterol (by 56.2 and 64.6%; p < 0.01), non-esterified fatty acids (by 32.1 and 37.9%; p < 0.01), hepatic glycogen (by 41.3 and 60.5%; p < 0.01), and muscle glycogen (by 33.2 and 38.6%; p < 0.05), and increased high-density lipoprotein cholesterol (by 50.0 and 61.4%; p < 0.05 and p < 0.01), which were originally altered by HFD and streptozotocin. In addition, SalB (200 mg/kg) markedly decreased triglyceride and malondialdehyde (by 31.5 and 29.0%; p < 0.05 and p < 0.01), and increased superoxide dismutase (by 56.6%; p < 0.01), which were originally altered by HFD and streptozotocin.. The results indicate that SalB can inhibit symptoms of diabetes mellitus in rats and these effects may partially be correlated with its insulin sensitivity, glycogen synthesis and antioxidant activities.

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Diet, High-Fat; Drugs, Chinese Herbal; Male; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Streptozocin

The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of type 2 diabetes mellitus (T2DM). Salvia miltiorrhiza (Danshen), one of the most commonly used of traditional Chinese medicines, is often used in Compound Recipes for treating diabetes, however with unclear mechanisms. Since salvianolic acid B (SalB) is the most abundant bioactive ingredient of salvia miltiorrhiza water-extract. In this study, we tested whether SalB has any effect on the amyloidogenicity of hIAPP. Our results clearly suggest that SalB can significantly inhibit the formation of hIAPP amyloid and disaggregate hIAPP fibrils. Furthermore, photo-crosslinking based oligomerization studies suggest SalB significantly suppresses the toxic oligomerization of hIAPP monomers. Cytotoxicity protection effects on pancreatic INS-1 cells by SalB were also observed using MTT-based assays, potentially due to the inhibition on the membrane disruption effects and attenuated mitochondria impairment induced by hIAPP. These results provide evidence that SalB may further be studied on the possible pharmacological treatment for T2DM.

Topics: Amino Acid Sequence; Amyloid; Benzofurans; Cell Line; Cell Survival; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Erythrocytes; Hemolysis; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Mitochondria; Molecular Sequence Data; Protein Structure, Secondary; Salvia miltiorrhiza

Lithospermic acid B (LAB) has been reported to protect OLETF rats, an established type 2 diabetic animal model, from the development of diabetes-related vascular complications. We investigated whether magnesium lithospermate B (LAB) has a protective role under cytokine-induced apoptosis in INS-1 cells in vitro and whether it slows the development of diabetes in OLETF rats in vivo. Pretreatment with 50 μM LAB significantly reduced the 1000 U/mL INF-γ and 100 U/mL IL-1β-induced INS-1 cell death. LAB significantly alleviated cytokine-induced phosphorylations of p38 and JNK in accordance with a decrease in cleaved caspase-3 activity in beta-cells. LAB also protected against the cytokine-induced caspase-3 apoptotic pathway via significant activation of Nrf2-HO (heme-oxygenase)-1 and Sirt1 expression. OLETF rats treated with 40 mg/kg/day LAB showed a significant improvement in glucose tolerance compared to untreated OLETF control rats in vivo. Our results suggest that the cytoprotective effects of LAB on pancreatic β-cells are related with both alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2-HO-1 and Sirt1.

Topics: Animals; Apoptosis; Benzofurans; Cells, Cultured; Cytokines; Depsides; Diabetes Mellitus, Type 2; Heme Oxygenase (Decyclizing); Insulin-Secreting Cells; Male; NF-E2-Related Factor 2; Protective Agents; Random Allocation; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Signal Transduction; Sirtuin 1

Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes.

Topics: Administration, Oral; Aldehyde Reductase; Animals; Benzofurans; Blood Glucose; Blood Pressure; Chemokine CCL2; Depsides; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression Regulation; Male; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Salvia miltiorrhiza