Diabetes 2013 Aug-7

Serum nitric oxide metabolites and high sensitivity C-reactive protein are important biomarkers in non obese, Indian type 2 Diabetic males

Int Diabetes Dev Ctries.2012 Sep;32(3):163-168.

Rajlaxmi Sarangi, Somanath Padhi, Srikrushna Mahapatra, Nateshan Bhumika

Abstract

Inflammation, endothelial dysfunction, and oxidative stress are postulated to be the principal events in the pathogenesis of type 2 diabetes mellitus and its vascular complications. Serum Nitric Oxide metabolites (NOX) and high sensitivity C-reactive protein (hs-CRP) were measured in eighty non-obese, type 2 diabetic males (40 to 65 years) without (group B, N = 40) and with vascular disease [16 retinopathy (group C), 24 hypertension (group D)]; and compared with forty healthy, age and sex matched control subjects (group A). The mean age of diabetic patients and healthy controls was 49.5 ± 5.80 vs. 51.0 ± 7.15 years, respectively (P = 0.212). Diabetic group had higher Fasting Plasma Glucose (FPG), hs-CRP, and NOX levels than control group (135.3 ± 28.69 vs. 96.7 ± 10.46; 5.1 ± 2.59 vs. 1.7 ± 0.54; 61.1 ± 15.67 vs. 37.1 ± 3.69, respectively, P = 0.001). When compared with diabetics without complication (53.7 ± 10.37), levels of NOX were significantly higher (P = 0.001) both in retinopathy (74.5 ± 19.39) and hypertension (64.4 ± 13.60) group, whereas that of hs-CRP (4.4 ± 2.85 vs.6.5 ± 2.93, P = 0.015) differed only in retinopathy group. There was no difference between retinopathy and hypertension group. There was significant (P < 0.05) positive correlation between age, duration of diabetes, hs-CRP, and NOX; hs-CRP and NOX among group B and C. A negative correlation was noted between hs-CRP and NOX (r = −0.068, P = 0.752) among hypertensives. By multivariate regression analysis, FPG, hs-CRP and NOX were found to be independent indicators of complications after adjustment for age and duration of diabetes. This study reveals that NOX and hs-CRP are important biomarkers in type 2 diabetes mellitus and its associated vascular complications.

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Endothelial dysfunction is regarded as a major cardiovascular risk factor in patients with type 2 diabetes mellitus (DM). Among the number of factors involved in the maintaining proper vascular homeostasis, nitric oxide (NO) plays a pivotal role in guaranteeing physiological endothelial function. It is still a matter of controversy whether and in which way imbalance in glucose metabolism might affect NO synthesis and bioavailability. Our study on type 2 diabetic males, clearly demonstrates that increased NO metabolites (NOX) [a measure of nitrosative stress] and high sensitivity C-reactive protein (hs-CRP) is linked to hyperglycemia and its associated vascular complications.

In accordance with our observation, recent studies have also documented significant positive association between NOX, dysglycemia, and vasculopathy in patients with type 2 DM. A recent large population based study (ref.1) from Iran recruited 2769 subjects (1124 males, 1645 females) (20-87 years) and observed a weak but significant positive correlation between the serum NOX levels and serum fasting glucose in both men (r =0.092, p =0.002) and women (r =0.112, p=0.001). However, after multivariable adjustment, this incremental trend still remained in men (p= 0.006) but disappeared in women (p= 0.436).

The vicious circle of hyperglycemia, NO, and adenosine; and the underlying molecular mechanism are now fully elucidated (Figure-1).(ref.2)

 

Somanath Padhi-second

Figure-1: Vicious circle of hyperglycemia-nitric oxide (NO)-adenosine, and the ALANO pathway.

Primary cultures of human umbilical vein endothelial cells (HUVEC) obtained from gestational diabetic (GDM) pregnancies, as well as HUVEC cultured in high glucose, exhibit increased synthesis of NO and reduced uptake of the endogenous nucleoside vasodilator, adenosine by the activation of adenosine/L-arginine/NO (ALANO) pathway. These findings have been explained by a reduced expression and activity of human equilibrative nucleoside transporter type 1 (hENT1), the main mediator of adenosine uptake, which might be down regulated by NO-dependent reduced SLC29A1 transcription. NO dependent down regulation of SLC29A1 expression is postulated to be brought about by the transcription factor hCHOP (C/EBP homologous protein 10)–C/EBPα complex in fetal endothelial cells from GDM. Notably, hCHOP expression is up-regulated in cultured HUVEC by high glucose as well as in diabetic patients. Therefore, it may be proposed that in gestational diabetes, increased NO release by HUVEC could occur via activation of ALANO pathway. Decreased activity of hENT1 leads to extracellular accumulation of adenosine, which results in increased transport of L-arginine via human cationic amino acid transporters (hCATs) and enhanced NO synthesis by increased eNOS (endothelial nitric oxide synthase) activity. A recent pioneer study by Yang et al (ref.3) on diabetic embryopathy have found that hyperglycemia, both in vitro and in vivo, resulted in activation of c-Jun N-terminal kinases (JNK) 1/2 ;which in turn, caused increase expression of inducible NOS (iNOS) gene and iNOS mRNA levels. This led to increased nitrosative stress in diabetic embryopathy, and JNK2 inhibitors (SP600125) abolished this effect.

Hence the earlier notion of ‘reduced NO in endothelial dysfunction, especially in dysglycemia’ needs to be reviewed more intensely in future prospective studies.

References:

  1. Ghasemi A, Zahediasl S, Azimzadeh I, Azizi F. Increased serum nitric oxide metabolites in dysglycaemia. Ann Human Biol 2011; DOI: 10.3109/03014460.2011.575384.
  2. Pandolfi A, Di Pietro N. High glucose, nitric oxide, and adenosine: a vicious circle in chronic hyperglycaemia? Cardiovasc Res 2010; 86:9–11. DOI:10.1093/cvr/cvq055.
  3. Yang P, Cao Y, Li H. Hyperglycemia induces inducible nitric oxide synthase gene expression and consequent nitrosative stress via c-Jun N-terminal kinase activation. Am J Obstet Gynecol 2010; 203:185.e5-11.
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