sodium-nitrite and Diabetes-Mellitus--Type-2

A deficiency in hydrogen sulfide (H. T2D was induced using a high fat diet combined with low-dose of streptozotocin (30 mg/kg). Rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite (50 mg/L) and NaSH (0.28 mg/kg) were administered for 9 weeks. Intraperitoneal pyruvate tolerance test (PTT) was performed at the end of the ninth week and mRNA expressions of PI3K, Akt, eNOS, PEPCK, G6Pase, and FBPase were measured in the liver.. Co-administration of nitrite and NaSH decreased elevated serum glucose concentrations during PTT. Compared to T2D + nitrite, co-administration of nitrite and NaSH resulted in significant increases in mRNA expression of PI3K, Akt, and eNOS and significant decreases in mRNA expression of G6Pase and FBPase but had no effect on PEPCK expression.. Long-term NaSH administration at low-dose, potentiated the inhibitory effects of nitrite on mRNA expression of key liver gluconeogenic enzymes in rats with T2D. This inhibitory effect of nitrite and NaSH co-administration on gluconeogenesis were associated with increased gene expression of PI3K, Akt, and eNOS in the liver.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gluconeogenesis; Insulin; Liver; Male; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Signal Transduction; Sodium Nitrite; Sulfides

Impaired skin nitric oxide production contributes to delayed wound healing in type 2 diabetes (T2D). This study aims to determine improved wound healing mechanisms by acidified nitrite (AN) in rats with T2D. Wistar rats were assigned to four subgroups: Untreated control, AN-treated control, untreated diabetes, and AN-treated diabetes. AN was applied daily from day 3 to day 28 after wounding. On days 3, 7, 14, 21, and 28, the wound levels of vascular endothelial growth factor (VEGF) were measured, and histological and stereological evaluations were performed. AN in diabetic rats increased the numerical density of basal cells (1070 ± 15.2 vs. 936.6 ± 37.5/mm

Topics: Animals; Citric Acid; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Male; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Rats, Wistar; Skin; Skin Cream; Sodium Nitrite; Vascular Endothelial Growth Factor A; Wound Healing

Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D.. T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study.. Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D.. The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gluconeogenesis; Kidney; Male; Rats; Rats, Wistar; Sodium Nitrite; Sulfides

We tested the hypothesis that short-term oral sodium nitrite supplementation would improve vascular dysfunction in obese, diabetic mice.. Vascular function was determined in control mice and in db/db mice receiving drinking water with or without sodium nitrite (50 mg/L) for 5 weeks. Nitrite supplementation increased plasma nitrite concentrations in db/db mice (0.19±0.02 µM vs 0.80±0.26 µM; p < 0.05). Db/db mice had lower endothelium-dependent dilation (EDD) in response to increasing doses of acetylcholine versus heterozygous control mice (71.2% ± 14.3% vs 93% ± 7.0%; p < 0.05), and sodium nitrite supplementation restored endothelium-dependent dilation to control levels (92.9% ± 2.3% vs 93% ± 7.0%; p < 0.05). The improvement in endothelial function was accompanied by a reduction in intrinsic stiffness, but not by alterations in plasma or vascular markers of inflammation.. These data suggest that sodium nitrite may be a novel therapy for treating diabetes-related vascular dysfunction; however, the mechanisms of improvement are unknown.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Heterozygote; Homozygote; Mice, Inbred C57BL; Mice, Mutant Strains; Point Mutation; Receptors, Leptin; Sodium Nitrite; Vascular Stiffness; Vasodilation; Vasodilator Agents

Nitrite anion has been demonstrated to be a prodrug of nitric oxide (NO) with positive effects on tissue ischemia/reperfusion injury, cytoprotection, and vasodilation. However, effects of nitrite anion therapy for ischemic tissue vascular remodeling during diabetes remain unknown. We examined whether sodium nitrite therapy altered ischemic revascularization in BKS-Lepr(db/db) mice subjected to permanent unilateral femoral artery ligation. Sodium nitrite therapy completely restored ischemic hind limb blood flow compared with nitrate or PBS therapy. Importantly, delayed nitrite therapy 5 days after ischemia restored ischemic limb blood flow in aged diabetic mice. Restoration of blood flow was associated with increases in ischemic tissue angiogenesis activity and cell proliferation. Moreover, nitrite but not nitrate therapy significantly prevented ischemia-mediated tissue necrosis in aged mice. Nitrite therapy significantly increased ischemic tissue vascular endothelial growth factor (VEGF) protein expression that was essential for nitrite-mediated reperfusion of ischemic hind limbs. Nitrite significantly increased ischemic tissue NO bioavailability along with concomitant reduction of superoxide formation. Lastly, nitrite treatment also significantly stimulated hypoxic endothelial cell proliferation and migration in the presence of high glucose in an NO/VEGF-dependent manner. These results demonstrate that nitrite therapy effectively stimulates ischemic tissue vascular remodeling in the setting of metabolic dysfunction that may be clinically useful.

Topics: Animals; Diabetes Mellitus, Type 2; Femoral Artery; Hindlimb; Ischemia; Mice; Neovascularization, Pathologic; Nitrates; Nitric Oxide; Sodium Nitrite; Time Factors; Vascular Endothelial Growth Factor A

Diabetes mellitus type 2 is a syndrome of disordered metabolism with inappropriate hyperglycemia owing to a reduction in the biological effectiveness of insulin. Type 2 diabetes is associated with an impaired nitric oxide (NO) pathway that probably serves as the key link between metabolic disorders and cardiovascular disease. Insulin-mediated translocation of GLUT4 involves the PI3K/Akt kinase signal cascade that results in activation of endothelial NO synthase (eNOS). eNOS is dysfunctional during diabetes. We hypothesize that loss of eNOS-derived NO terminates the signaling cascade and therefore cannot activate GLUT4 translocation and that dietary nitrite may repair this pathway. In this study, we administered 50mg/L sodium nitrite to db/db diabetic mice for 4 weeks. After 4 weeks treatment, the db/db mice experienced less weight gain, improved fasting glucose levels, and reduced insulin levels. Cell culture experiments using CHO-HIRc-myc-GLUT4eGFP cell lines stably expressing insulin receptor and myc-GLUT4eGFP protein, as well as L6 skeletal muscle cells stably expressing rat GLUT4 with a Myc epitope (L6-GLUT4myc), showed that NO, nitrite, and GSNO stimulate GLUT4 translocation independent of insulin, which is inhibited by NEM. Collectively our data suggest that nitrite improves insulin signaling through restoration of NO-dependent nitrosation of GLUT4 signaling translocation. These data suggest that NO-mediated nitrosation of GLUT4 by nitrite or other nitrosating agents is necessary and sufficient for GLUT4 translocation in target tissue. Description of this pathway may justify a high-nitrate/nitrite diet along with the glycemic index to provide a safe and nutritional regimen for the management and treatment of diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Ethylmaleimide; Gene Expression Regulation; Glucose Transporter Type 4; Humans; Male; Mice; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Transport; Proto-Oncogene Proteins c-myc; Rats; Receptor, Insulin; Signal Transduction; Sodium Nitrite

Topics: Animals; Diabetes Mellitus, Type 2; Ischemia; Neovascularization, Pathologic; Nitric Oxide; Sodium Nitrite; Vascular Endothelial Growth Factor A

Numerous factors may influence the incidence of diabetes in the population. The production of reactive oxygen species (ROS) is elevated in diabetes patients. Based on the reported involvement of reactive species and nitrate/nitrite in diabetes, this present study has examined in the alkaline Comet assay, the effect of different levels of NaNO(2) in the presence of the oxygen radical generating agent, hydrogen peroxide (H(2)O(2)). Peripheral lymphocytes from diabetic and non-diabetic Caucasians and Asians of both sexes were studied in vitro. Endogenous factors (e.g., sex, age, body mass index-BMI) and exogenous factors (lifestyle factors e.g., smoking and drinking habits, diet) were taken into account. A preliminary study in two individuals showed that DNA damage remained constant over a wide dose range of NaNO(2) (1-75mM), but when H(2)O(2) was added at a constant concentration of 50microM per dose of NaNO(2), there was an increase in DNA damage corresponding with the varying levels of NaNO(2) investigated. This was also seen with the 44 individuals (non-diabetic, n=24; type 1 diabetic, n=11; type 2 diabetic, n=9) investigated. NaNO(2) was capable of inducing a significant level of DNA damage in lymphocytes (p<0.001), but only with the addition of H(2)O(2). When levels of DNA damage were analysed in terms of the different variables there were few significant differences in damage between diabetic and non-diabetic subjects, or other sub-population groups, and no statistically significant differences in susceptibility were observed between subject covariates using regression techniques.

Topics: Adolescent; Adult; Aged; Asian People; Comet Assay; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; DNA Damage; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Hydrogen Peroxide; In Vitro Techniques; Lymphocytes; Male; Middle Aged; Reactive Oxygen Species; Sodium Nitrite; United Kingdom; White People

Topics: Acetaminophen; Aged; Analgesics, Non-Narcotic; Arthritis, Rheumatoid; Diabetes Mellitus, Type 2; Drug Combinations; Female; Food Preservatives; Humans; Methemoglobin; Methemoglobinemia; Sodium Nitrite