The utility of adiponectin and nitric oxide metabolites as biomarkers for prediction and follow-up of vascular complications in children with type 1 diabetes mellitus Al Saeed M

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ORIGINAL ARTICLE

Year : 2013 | Volume : 2 | Issue : 3 | Page : 156-160

The utility of adiponectin and nitric oxide metabolites as biomarkers for prediction and follow-up of vascular complications in children with type 1 diabetes mellitus

Mohamed Al Saeed
Department of Surgery, College of Medicine, Taif University, Taif, Saudi Arabia

Date of Web Publication

14-Feb-2014

Correspondence Address:
Mohamed Al Saeed
Department of Surgery, College of Medicine, Taif University, PO Box 888, Taif-21947
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2278-0521.127044

Abstract

Background and Aim: Adiponectin is an adipocytokine secreted from adipose tissue, and plays an important role in type 2 diabetes, obesity, and cardiovascular disease. This study aimed to estimate the concentration of serum adiponectin in type 1 diabetic children and to establish its association with vascular complications of the disease. Materials and Methods: A total of 25 children with type 1 diabetes were enrolled in the study. Another group of 20 healthy children with matched gender and age served as control. The diabetic patients were classified into pre-pubertal and pubertal groups, and according to gender, into male and female groups. Results: The results obtained showed a significant elevation in the serum adiponectin value in diabetic children compared to control. Serum adiponectin level showed a highly significant increase in patients with diabetic nephropathy and neuropathy than those without the complications. On the other hand, no significant increase in serum adiponectin was observed in patients with retinopathy compared to those without retinopathy. Serum nitric acid metabolites showed a significant reduction in type 1 diabetes children compared to the control group. A negative significant correlation was found between serum adiponectin and serum nitric acid metabolites levels, and a positive significant correlation was detected between serum adiponectin and random blood glucose, HbA1C, urinary microalbuminuria, blood urea nitrogen, creatinine, total cholesterol, and LDL in the same patients. Conclusion: In type 1 diabetes, regular estimation of adiponectin with nitric oxide metabolite may be a useful biomarker for early prediction and follow-up of diabetic vascular complications.

Keywords: Adiponectin, Saudi Arabia, Taif, type 1 diabetes, vascular complications

How to cite this article:
Al Saeed M. The utility of adiponectin and nitric oxide metabolites as biomarkers for prediction and follow-up of vascular complications in children with type 1 diabetes mellitus. Saudi J Health Sci 2013;2:156-60

How to cite this URL:
Al Saeed M. The utility of adiponectin and nitric oxide metabolites as biomarkers for prediction and follow-up of vascular complications in children with type 1 diabetes mellitus. Saudi J Health Sci [serial online] 2013 [cited 2023 Mar 22];2:156-60. Available from: https://www.saudijhealthsci.org/text.asp?2013/2/3/156/127044

Introduction

Diabetes mellitus is the most common metabolic disease worldwide and represents a major health problem in Saudi Arabia, affecting about 30% of the population. ^[1] Type 1 diabetes accounts for 5-10% of all cases of diabetes and its incidence is increasing. ^[1],[2] Adiponectin is an insulin-sensitizing hormone that belongs to a family known as adipokines, which are expressed mostly by adipocytes. ^[3] It is an important regulator of lipid and glucose metabolism with anti-inflammatory and anti-atherogenic properties. ^[3],[4] Many authors have reported that an elevated adiponectin level represents a beneficial counter regulatory mechanism, reducing the risk of coronary and other vascular complications among patients with type 2 diabetes. ^[4],[5],[6] In children with type 1 diabetes, the relationship between adiponectin and the presence of vascular complications is controversial. ^[7] Microvascular and macrovascular changes are long-term complications affecting small and large vessels and result in retinopathy, neuropathy, and nephropathy, which can be readily assessed clinically and biochemically. ^[8] However, for early atherosclerotic changes, we can assess the endothelial function. ^[8],[9] Nitric oxide (NO) is the main molecule derived from the endothelium, and it is considered by many investigators to be one of the best biomarkers of endothelial dysfunction. ^{[10],[11],[12],[13]} Serum nitric oxide metabolite (NOx) is the sum of nitrate and nitrite levels and can be measured to reflect the bioactivity of the endothelial NO as it has a short half-life. ^[13],[14] This study aimed to measure the serum adiponectin level and its relationship with vascular complications in children and adolescents with type 1 diabetes.

Materials and Methods

This prospective study was carried out at King Abdul Aziz Specialist Hospital, from July 2011 to July 2012, in Taif, Saudi Arabia; the study was approved by the ethics committee. The study included all patients who met the criteria of type 1 diabetes, ^[2] with age of 18 years or less, and the parents of such patients accepted the participation in the study through written consents. We excluded from the study patients with type 1 diabetes who were receiving any medications other than insulin and those with the duration of diabetes less than one year; this was because serum adiponectin level is not elevated in children with type 1 diabetes except after more than 6 months. ^[7] All patients and controls were subjected to careful history, which included diabetic duration, treatment, history of hypoglycemic or hyperglycemic attack, and history suggestive of chronic diabetic complications such as ocular manifestations, peripheral neuropathy manifestations, cardiovascular, and/or peripheral vascular manifestations. The examination included neurological (motor and sensory) and fundus examination in addition to a complete cardiac and peripheral vascular examination. Laboratory investigations included random blood glucose, measurement of mean HbA1c percentage (HbA1c%) using quantitative calorimetric determination of glycohemoglobin in whole blood, measurement of blood urea nitrogen and serum creatinine, quantitative determination of urinary microalbuminuria using morning urine samples, serum total cholesterol, high-density lipoprotein (HDL - Cholesterol), and low-density lipoprotein (LDL - Cholesterol) were also measured in addition to NOx. Serum adiponectin was assayed using mouse ADPN enzyme-linked immunosorbent assay.

Statistical analysis

Results were expressed as mean ± standard deviation (SD). For comparison between two variables, Student's t-test was applied. P < 0.05 was considered as statistically significant. Pearson and Spearman's correlation test were used to correlate each parameter with different variants in the same group to differentiate between positive and negative correlations and to find significant difference. Comparison of clinical characteristics of the groups was done using Analysis of Variance (ANOVA) test.

Results

Demographic data and laboratory biomarkers (mean ± SD) of type 1 diabetic children and controls are shown in [Table 1]. The data reveal that random blood glucose level, HBA1c percentage, lipid profiles, serum adiponectin, and urinary microalbumin displayed highly significant increase (P < 0.001) in diabetic children than controls, while the nitric oxide metabolite level showed a significant decrease in the type 1 diabetic children versus the healthy controls. [Table 2] shows a significant variation with regard to age of onset of diabetes, duration, and daily insulin dose between pre-pubertal and pubertal diabetic patients, but no significant discrepancy was found (P > 0.05) in total cholesterol, HDL, LDL, and serum adiponectin levels between the two groups. At the same time, the random blood glucose, HbA1c%, and microalbuminuria levels were significantly higher in pubertal diabetic patients, while NOx was significantly lower in this patient group. [Table 3] shows significant difference between male and female diabetic children with regard to total cholesterol level, HDL, LDL, microalbuminuria levels, NOx, and serum adiponectin (P < 0.05). According to [Table 4], no significant difference was noticed between diabetic children with and without retinopathy with regard to serum adiponectin levels. However, a significant reduction was noted in NOx in patients with neuropathy, and nephropathy than those without these complications (P < 0.05). Meanwhile, serum adiponectin levels show a highly significant increase in diabetic children with microalbuminuria, neuropathy, and endothelial dysfunction (those with low NOx levels) than those without any complications.

Table 1: Demographic data and laboratory biomarkers (mean±SD) of type 1 diabetic children and controls

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Table 2: Comparison of demographic data and laboratory biomarkers (mean�SD) between pre-pubertal and pubertal type 1 diabetic children

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Table 3: Comparison of demographic data and laboratory biomarkers (mean±SD) between male and female type 1 diabetic children

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Table 4: Comparison between diabetic children with or without complication according to their mean level of adiponectin

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Discussion

Hypo-adiponectinemia has been shown in diet-induced obesity, coronary artery diseases, and peripheral arterial diseases, and this phenomenon has been suggested to contribute to the pathogenesis of these diseases. ^[5] Previous studies demonstrate that total serum adiponectin concentrations were higher in type 1 diabetic children than healthy controls. ^{[6],[7],[15],[16]}

The present study proved that serum adiponectin level was significantly higher in diabetic patients than healthy controls. This result could be explained by variation in adiponectin concentration by the differences in fat distribution and function between diabetic and non-diabetic individuals. ^[7] In addition, exogenous insulin delivery in type 1 diabetic patients could play a role in elevated adiponectin levels through induction of adipose tissue hyperplasia. ^[17]

The present study revealed lower adiponectin levels in diabetic boys compared to diabetic girls. Bottner and Mantzoros ^[18] agreed with this finding, adding that adiponectin levels decrease significantly in boys than girls in healthy children and adolescents, and also at the end of puberty. Moreover, Galler et al. ^[19] detected a decline in serum adiponectin concentration during puberty in males, but no change in females; they explained this phenomenon by the inhibitory effects of androgens in males and the stimulatory effect of estrogen on adiponectin secretion in females. Another explanation of Fujita et al. ^[20] about the difference between males and females was that males have a tendency to accumulate more visceral and relatively less subcutaneous fat than females, thus determining this sex difference. Jeffery et al. ^[16] added that testosterone administration to hypogonadal males had been shown to suppress adiponectin levels.

In the current study, I found significant increase in serum adiponectin in type 1 diabetic children with nephropathy, neuropathy, and those with endothelial dysfunction than without complications, but no significant difference in serum adiponectin levels were observed between diabetic children with or without retinopathy. These findings are in accordance with those of other studies. ^{[3],[4],[5],[6],[16],[17],[19],[20],[21],[22]} A previous study by Li and Wen ^[5] showed that total adiponectin levels were higher in type 1 diabetic patients with microvascular complications than those without complications. This study declared a significant reduction in NOx in patients with neuropathy, and nephropathy than those without these complications (P < 0.05). In agreement with these findings, various studies approved that numerous mechanisms are involved in the development of microvascular problems in patients with diabetes, which can lead to endothelial dysfunction as, decreasing the production of endogenous vasodilators such as nitric oxide (NO), with subsequent reduction in NOx in addition to the release of endogenous vasoconstrictors such as endothelin-1 or angiotensin II. ^[4],[8] Moreover, the release of growth factors such as vascular endothelial growth factor by endothelial cells and production of proinflammatory cytokines by macrophages play a role in the production of microangiopathy. ^[8] Habeeb et al. ^[23] found that adiponectin elevation in diabetic patients may be a physiological response to avoid renal tubular injury and to prevent the infiltration of inflammatory cell into the tubulointerstitial area, which is a hallmark of diabetic nephropathy that may be developed if further complications occur. Galαn et al. ^[24] revealed that impaired renal function in type 1 diabetes could explain another cause of elevated serum concentration of adiponectin. The study performed by Chudek et al. ^[25] demonstrated that high serum adiponectin levels decreased after renal transplantation, suggesting that renal insufficiency could either have an effect on the clearance of adiponectin and/or have a stimulatory effect on adiponectin production. The present study supported the previous results where we found a significant increase in microalbuminuria in diabetic patients compared to control and in pubertal diabetic patients compared to prepubertal patients, which may be explained by the constant hyperglycemia and long duration of the disease that lead to microvascular problems.

The diabetic patients in the present study had hyperglycemia and increased HbA1c%, which, as some authors have found, alter the action of insulin on adiponectin; this may lead to an increase in adiponectin as blood glucose rises. ^[26] Ferdinando and Michael ^[27] declared that exposure of adipocytes to hyperglycemia results in altered post-translational modifications, leading to altered adiponectin actions, which may be a compensatory mechanism to reduce hepatic glucose output in the hyperglycemic milieu of type 1 diabetes. Saraheimo et al., ^[28] in a univariate analysis, found a positive correlation between adiponectin, creatinine, systolic blood pressure, and HbA1c (P < 0.05).

The present study shows that there was a positive correlation between adiponectin level and total serum cholesterol, LDL, and HDL. These findings were similar to the results of Fujita et al. ^[20] and Leth et al. ^[29]

This study verified significantly lower NOx levels reflecting the reduced bioactivity of endothelial nitric oxide synthase (eNOS) and NO in diabetic children compared to that in the control group, with lower levels in females than males and in pubertal than pre-pubertal patients. This was in accordance with the findings of other investigators, who correlated low NOx levels with endothelial dysfunction and suggested it to be a common link of all cardiovascular risk factors. ^{[10],[11],[12],[13],[17],[21],[22],[30],[31]} The development of endothelial dysfunction unless properly managed would eventually progress to premature atherosclerosis; moreover, low nitric oxide plasma level is suggested to be one of the earliest biomarkers of atherosclerosis, before sonographic or angiographic evidence of atherosclerotic plaque formation. ^[11],[13] In this study, I verified a negative correlation between NOx and serum adiponectin levels. As adiponectin possesses anti-inflammatory effects, the increase in its levels in diabetic children with endothelial dysfunction may serve as a modulator for macrophage foam cell formation in addition to the suppression of the adherence of monocytes to human endothelial cells, which seems to act as an endogenous regulator for endothelial cells in response to inflammatory diseases to counteract the development of microangiopathy and macroangiopathy. ^[4],[21] In vivo studies revealed increased proliferation of vascular smooth muscle cells with severe neointimal thickening, with atherosclerotic changes in apolipoprotein E-deficient mice; however, supplementation of adiponectin in this mouse model attenuated the neointimal proliferation. ^[32] Cheng et al., ^[21] in their study, declared that protective effect of adiponectin on the vascular system is achieved through stimulation of endothelial NO production and endothelium-dependent vasodilatation. Dekker et al. ^[33] found that elevated adiponectin levels were associated with 28% reduced risk of cardiovascular diseases and lower adiponectin levels were associated with lower ankle-brachial index and reduced exercise performance, indicating more severe diseases. In conclusion, in type 1 diabetes, adiponectin may be enhanced and acts as a physiological counter regulatory response to diminish endothelial and vascular damage and reduction in serum NOx was verified to be correlated with endothelial dysfunction and vascular complications. Thus, regular estimation of adiponectin with NOx may be a useful biomarker for early prediction and follow-up of diabetic vascular complications. However, the disease-specific association of adiponectin with macrovascular complications as coronary artery diseases and peripheral artery disease in type 1 diabetic patients has to be evaluated with more studies.

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