Hyperglycaemia Enhances Nitric Oxide Production in Diabetes: A Study from South Indian Patients

Adela, Ramu; Nethi, Susheel Kumar; Bagul, Pankaj K.; Barui, Ayan Kumar; Mattapally, Saidulu; Kuncha, Madhusudan; Patra, Chitta Ranjan; Reddy, P. Naveen Chander; Banerjee, Sanjay K.

doi:10.1371/journal.pone.0125270

Cited by 107 publications

(74 citation statements)

References 46 publications

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“…In diabetes, elevated levels of glucose enhance the gene and protein expression of eNOS and iNOS thereby increased production of NO which leads to oxidative stress [33]. Likewise many of the biochemical pathways associated with hyperglycemia will increase the production of free radicals [34].…”

Section: Discussionmentioning

confidence: 99%

MD-1, a poly herbal formulation indicated in diabetes mellitus ameliorates glucose uptake and inhibits adipogenesis – an in vitro study

Telapolu

Kalachavedu

Punnoose³

et al. 2018

BMC Complement Altern Med

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BackgroundType 2 Diabetes (T2D) is a polygenic disease requiring a multipronged therapeutic approach. In the current scenario, the use of polyherbals is increasing among the diabetics. MD-1, a poly herbal formulation is constituted as a mixture of six popular anti diabetic herbs, used in the management of Diabetes mellitus (DM). The physicochemical, biochemical and in vitro efficacy studies have been carried out to ascertain the possible mechanisms underlying the anti-diabetic action of MD-1.MethodsMD-1 was evaluated for residual toxins as per Ayurvedic Pharmacoepia of India (API) procedures. The hydro alcoholic extract of the formulation (HAEF) was evaluated for anti oxidant activity against 2, 2-diphenyl-1-picrylhydrazil (DPPH) and nitric oxide radicals in vitro. The effect of HAEF on carbohydrate digestive enzymes α-glucosidase and α-amylase was studied using biochemical assays. HAEF was studied for its glucose lowering potential in L6 myotubes and 3T3L1 preadipocytes, using 2-deoxy-D-[1-3H] glucose (2-DG) uptake assay. Effect of MD-1 on adipogenesis was evaluated in 3T3L1 adipocytes using oil O red staining. The effect of HAEF on mRNA expression of peroxisome proliferator activated receptor gamma (PPARγ) and glucose transporter 4 (GLUT4) in 3T3L1 adiocytes was investigated by reverse transcriptase polymerase chain reaction (RT-PCR). Statistical analysis was performed by student t-test, ANOVA.ResultsResidual toxins present within the API limits and HAEF demonstrated strong antioxidant potential and significantly inhibited the α-glucosidase (IC50 63.6 ± 0.46 μg/mL) and α-amylase (IC50 242.81 ± 1.26 μg/mL) activity. HAEF significantly (p < 0.05) enhanced the insulin stimulated glucose uptake in both the cell lines studied. Unlike standard pioglitazone (PGZ), HAEF modulated the mRNA expression of PPARγ and GLUT4 (p < 0.0001) in 3T3L1 adipocytes, without inducing adipogenesis.ConclusionPhysicochemical parameters established in the study may serve as reference standards in regular quality control. Absence of residual toxins underpins the safety. The enhanced glucose uptake and favorable modulation of insulin sensitivity through a plausible weak PPARγ agonism is similar to the distinct PPARγ activation pattern of several reported natural compound agonists. The differential binding modes of such dynamic combinatorial ligands within the formulation unlike synthetic ligands like thiozolidinediones (TZD) can be linked to the safe mitigation of diabetic complications by MD-1.

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Section: Discussionmentioning

confidence: 99%

MD-1, a poly herbal formulation indicated in diabetes mellitus ameliorates glucose uptake and inhibits adipogenesis – an in vitro study

Telapolu

Kalachavedu

Punnoose³

et al. 2018

BMC Complement Altern Med

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“…Given the complex nature of in vivo NO radical detection, surrogate markers for free NO levels have oftentimes been utilized as a readout, including plasma NOx levels, nitrate, nitrosothiols or nitrosylated heme. In this context, we note that previous reports of enhanced NO production in diabetes [8] were based on the quantification of downstream metabolites of NO, such as NOx or nitrate. Furthermore, previous reports on decreased renal NO production in rat 7–10 days after induction of diabetes are based on decreased urinary nitrite/nitrate excretion [35, 36] or decreased plasma nitrite/nitrate levels at 8 weeks after induction of diabetes [15].…”

Section: Discussionmentioning

confidence: 99%

Direct Observation of Enhanced Nitric Oxide in a Murine Model of Diabetic Nephropathy

et al. 2017

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Uncoupling of nitric oxide synthase (NOS) secondary to redox signaling is a central mechanism in endothelial and macrophage activation. To date studies on the production of nitric oxide (NO) during the development of diabetic complications show paradoxical results. We previously showed that recoupling eNOS by increasing the eNOS cofactor tetrahydrobiopterin (BH4) could restore endothelial function and prevent kidney injury in experimental kidney transplantation. Here, we employed a diabetic mouse model to investigate the effects of diabetes on renal tissue NO bioavailability. For this, we used in vivo NO trapping, followed by electron paramagnetic resonance spectroscopy. In addition, we investigated whether coupling of NOS by supplying the cofactor BH4 could restore glomerular endothelial barrier function. Our data show that overall NO availability at the tissue level is not reduced sixteen weeks after the induction of diabetes in apoE knockout mice, despite the presence of factors that cause endothelial dysfunction, and the presence of the endogenous NOS inhibitor ADMA. Targeting uncoupled NOS with the BH4 precursor sepiapterin further increases NO availability, but did not modify renal glomerular injury. Notably, glomerular heparanase activity as a driver for loss of glomerular barrier function was not reduced, pointing towards NOS-independent mechanisms. This was confirmed by unaltered increased glomerular presence of cathepsin L, the protease that activates heparanase.

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“…Group 2 (T2DM) included subjects with HbA1c levels ≥ 6.5% as per American Diabetes Association (ADA) guidelines with proven history of T2DM but no other complications. Group 3 (CAD) included subjects with narrowing or blockage of one or more epicardial coronary artery with greater than 25% stenosis shown in coronary angiography and diagnosed by cardiologists3. This group had no prior history of T2DM.…”

Section: Methodsmentioning

confidence: 99%

“…This group had no prior history of T2DM. Group 4 (T2DM_CAD) included subjects with coronary artery disease as defined for group 3 but patient had HbA1c levels ≥6.5% and prior history of T2DM3. Exclusion criteria defined for this study were clinical or laboratory evidence of liver failure, renal failure (plasma creatinine levels >1.5 mg/dl), type 1 diabetes, cancer, thyroid disease and pregnancy; and subjects on vitamin D treatment therapy were also excluded in this study.…”

Section: Methodsmentioning

confidence: 99%

“…Hyperglycemic condition and insulin resistance in adults increases the risk of heart attack, stroke, angina, and coronary artery disease. Cardiovascular risk is two to four fold higher in diabetic subjects as compared to non-diabetic subjects234. Several factors like obesity, hyperglycemia, hypertension, inflammation, endothelial dysfunction and oxidative stress are responsible for the increased risk of cardiovascular complication among diabetic patients.…”

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confidence: 97%

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Lower Vitamin D Metabolites Levels Were Associated With Increased Coronary Artery Diseases in Type 2 Diabetes Patients in India

Adela

Borkar

Bhandi

et al. 2016

Sci Rep

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The purpose of the present study was to measure six vitamin D metabolites and to find the association between vitamin D deficiency and coronary artery diseases in diabetes (T2DM_CAD). Four groups [control (n = 50), type 2 diabetes (T2DM, n = 71), coronary artery diseases (CAD, n = 28), T2DM_CAD (n = 38)] of total 187 subjects were included in the study. Six vitamin D metabolites (D2, D3, 25(OH)D2, 25(OH)D3, 1,25(OH)2D2, 1,25(OH)2D3), total 25(OH)D and total 1,25(OH)2D were measured by UPLC/APCI/HRMS method in these subjects. Although all the vitamin D metabolites were significantly decreased in T2DM_CAD as compared to both control and T2DM subjects (p < 0.05), only two metabolites i.e., 25(OH)D3 and total 25(OH)D were significantly (p < 0.05) decreased in the T2DM subjects as compared with the control subjects (p < 0.05). Vitamin D3, 1,25(OH)2D2, 25(OH)D, and 1,25(OH)2D levels were significantly decreased in T2DM_CAD subjects as compared with CAD subjects (p < 0.05). Further, multiple logistic regression analysis revealed that total 25(OH)D and total 1,25(OH)2D can be used to predict T2DM (OR 0.82.95% CI 0.68–0.99; p = 0.0208) and T2DM with CAD (OR 0.460, 95% CI 0.242–0.874; p = 0.0177), respectively. Our data concludes that lower concentration of 1,25(OH)2D is associated with type 2 diabetes coexisting with coronary artery diseases in South Indian subjects.

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Hyperglycaemia Enhances Nitric Oxide Production in Diabetes: A Study from South Indian Patients

Cited by 107 publications

References 46 publications

MD-1, a poly herbal formulation indicated in diabetes mellitus ameliorates glucose uptake and inhibits adipogenesis – an in vitro study

MD-1, a poly herbal formulation indicated in diabetes mellitus ameliorates glucose uptake and inhibits adipogenesis – an in vitro study

Direct Observation of Enhanced Nitric Oxide in a Murine Model of Diabetic Nephropathy

Lower Vitamin D Metabolites Levels Were Associated With Increased Coronary Artery Diseases in Type 2 Diabetes Patients in India

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