Abstract
Oxidative and nitrosative stress plays a pivotal role in the incidence of metabolic disorders. Studies from this lab and others in iNOS-/- mice have demonstrated occurrence of insulin resistance (IR), hyperglycemia and dyslipidemia highlighting the importance of optimal redox balance. The present study evaluates role of nitrite, L-arginine, antidiabetics (metformin, pioglitazone) and antibiotics (ampicillin-neomycin combination, metronidazole) on metabolic perturbations observed in iNOS-/- mice. The animals were monitored for glucose tolerance (IPGTT), IR (insulin, HOMA-IR, QUICKI), circulating lipids and serum metabolomics (LC-MS). Hyperglycemia, hyperinsulinemia and IR were rescued by nitrite, antidiabetics, and antibiotics treatments in iNOS-/- mice. Glucose intolerance was improved with nitrite, metformin and pioglitazone treatment, while ampicillin-neomycin combination normalised the glucose utilization in iNOS-/- mice. Increased serum phosphatidylethanolamine lipids in iNOS-/- mice were reversed by metformin, pioglitazone and ampicillin-neomycin; dyslipidemia was however marginally improved by nitrite treatment. The metabolic improvements were associated with changes in selected serum metabolites-purines, ceramide, 10-hydroxydecanoate, glucosaminate, diosmetin, sebacic acid, 3-nitrotyrosine and cysteamine. Bacterial metabolites-hippurate, indole-3-ethanol; IR marker-aminoadipate and oxidative stress marker-ophthalmate were reduced by pioglitazone and ampicillin-neomycin, but not by nitrite and metformin treatment. Results obtained in the present study suggest a crucial role of gut microbiota in the metabolic perturbations observed in iNOS-/- mice.
Highlights
Type 2 diabetes is a cardio-metabolic disorder commonly associated with insulin resistance (IR) and dyslipidemia [1]
Circulating non-esterified fatty acids (NEFA), total cholesterol, triglycerides and low density lipoproteins (LDL) content were significantly enhanced in Inducible nitric oxide synthase (iNOS)-/- mice, while high density lipoproteins (HDL) levels were comparable to WT (Figure S1D)
These results suggest that nitrite treatment partially improved the glucose intolerance and dyslipidemia in iNOS-/- mice with reversal in nitric oxide (NO) availability
Summary
Type 2 diabetes is a cardio-metabolic disorder commonly associated with insulin resistance (IR) and dyslipidemia [1]. Inducible nitric oxide synthase (iNOS), a calcium independent enzyme, was initially recognised as an inflammatory mediator but has been identified for its importance in the regulation of metabolism [7,8,9,10] Studies from this lab [11,12,13] and others [14,15] have demonstrated metabolic perturbations in the obese, insulin resistant and dyslipidemic iNOS-/- mice, which improved partially after nitrite supplementation [13]. INOS-/- mice displayed gut microbiota dysbiosis and altered metabolic profile which were reversed by the vancomycin induced depletion of gram-positive bacteria [16] It suggests the crucial role of optimal redox balance in maintaining the host metabolic homeostasis, and gut microbes composition
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