Adenosine deaminase activity in type 2 diabetes mellitus: does it have any role?

Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia [1]. There is an estimated 143 million people worldwide suffering from diabetes [2], almost five times more than the estimates ten years ago. This number may probably double by the year 2030 [3]. Data in Southeast Asia highlights that more than 436,000 people have been affected by Type 2 diabetes Mellitus (T2DM) and there is a definite probability for the number rising to 1,328,000 by 2030 [4]. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels. Autoimmune destruction of theβcells of the pancreas with consequent insulin deficiency and abnormalities that result in insulin resistance are the processes involved in the development of diabetes [5]. Also, T2DM has been always pigeon-holed as an intricate metabolic syndrome with multifactorial etiologies. The disease has been characterized by an atypical metabolism of all biomolecules i.e. carbohydrates, fats and proteins. Thus, collectively leading to an increased levels of blood glucose and lipid levels within the blood [6, 7].

Insulin resistance is associated with low-grade tissue specific inflammatory responses induced by various pro-inflammatory with oxidative stress mediators notably pro-inflammatory cytokines such as Interleukin-1 beta, Interleukin-6, Tumor Necrosis Factors- alpha along with numerous adipocytokines and chemokines, epigenetic factors and other transcriptional and metabolic pathways. Moreover, chronic exposure of pro-inflammatory mediators stimulates the activation of cytokine signaling proteins which ultimately block the activation of insulin signaling receptors in β-cells of pancreatic islets [7‐9]. Adenosine deaminase (ADA) is a polymorphic enzyme that catalyzes the irreversible deamination of adenosine to inosine and has an important role in regulating adenosine concentration. Inosine and 2′-deoxyinosine are converted to the metabolic products i.e. hypoxanthine, xanthine and consequently to uric acid [10]. ADA is still considered as a marker for the assessment of cell mediated immunity [11]. ADA is suggested to be an important enzyme for modulating the bioactivity of insulin [12], but its clinical significance in T2DM has not yet been proven. In cases of oxidative stress and cell membrane damage, serum ADA is increased [13].

Previously, ADA has been reported to be a marker for insulin function [10], [13]. But, the correlation between ADA in diabetic patients has not been studied extensively in our country. Even though there are some reports available on ADA levels in diabetic subjects, these are all inconclusive and controversial. Since a relationship exists between ADA and cell mediated immunity [14]. This study was undertaken as a preliminary study to determine its serum activity and highlight its importance in the immuno-pathogenesis of T2DM. Thus, the present study was conducted to estimate the Serum ADA activity, glycated Haemoglobin (HbA1c), fasting and postprandial glucose level in patients with T2DM and to correlate the serum level of ADA with glycated Hemoglobin (HbA1c), fasting and postprandial glucose level in T2DM.

The study population comprised of total of 204 participants diagnosed of T2DM and 102 healthy controls. Demographic data has been depicted in Table 1. Biochemical parameters showed that Mean serum ADA was significantly higher in Diabetic patients compared to healthy controls as illustrated in Table 2. Further, ADA levels was significantly higher in Uncontrolled T2DM than in controlled T2DM as shown in Table 3 respectively. Spearman’s Correlation of FPG, PPG, and HbA1c with serum ADA showed a significant positive correlation with all of the three glycemic parameters. This suggests the use of ADA as an alternative marker of Glycemic control in Diabetic patients. Serum ADA showed a significant positive correlation with HbA1c which is considered as a good marker for long term glycemic control. Hence, it highlights the role of ADA as a potential marker for glycemic control as depicted in Table 4.

T2DM is the predominant form of diabetes worldwide, accounting for 90% of cases globally [17]. It is a multifactorial systemic disease with hereditary and environmental causes being the major attributable factor. These lead to insulin resistance and defective secretion of insulin by pancreatic beta-cell. Immunological disturbances of cell-mediated origin are believed to initiate from T-lymphocyte dysfunction. Invitro studies have shown that in T2DM, inappropriate immune responses may result from the defects in the action of insulin that is required for the function of T-lymphocytes [18]. ADA plays a crucial role in lymphocyte proliferation and differentiation and shows its highest activity in T- lymphocytes [17, 18]. The present study shows a significant elevation in the ADA levels (U/L) in uncontrolled diabetic subjects (49.24 ± 16.89) compared to controlled population (35.74 ± 16.78). The high plasma ADA activity might be due to abnormal T-lymphocyte responses or proliferation; may point towards a mechanism that involves its release into the circulation [19, 20]. Hence, we suggest that increased ADA activity in diabetic individuals could be due to altered insulin related T-lymphocyte function or due to increased immunological dysfunction. Previously, Chang and Shaio, have demonstrated that impaired cell mediated immunity was associated with abnormal lymphocyte proliferation [21].

This study shows that ADA is raised in patients with diabetes mellitus, with values increasing in uncontrolled compared to controlled T2DM. Thus, the altered serum ADA levels may help in predicting immunological dysfunction in diabetic individuals. The present study depicts that there is a significant positive correlation between Serum ADA levels and Hba1c, which suggests that Serum ADA level can also be used as a biomarker in predicting glycemic control in diabetic patients. Studies have shown that there is a direct correlation with the expression and activity of ADA with the extent of severity of inflammation, as T2DM is associated with chronic hyperglycemia and an ongoing low-grade systemic inflammation [22]. The role of ADA in the cellular immunity was first identified in patients with severe combined immune-deficiency (SCID) [23, 24]. The high activity of this enzyme was considered to be a reflection of immunological disturbances observed in tuberculosis [25] infectious mononucleosis [26], jaundice [27], leukemia [28] and other conditions ( [29‐31]).

Assessment of Serum ADA level is cost-effective and the efficient use of this biomarker may help in establishing this enzyme as a good marker for assessing cell-mediated immunity in diabetic individuals. Thus, we conclude that elevated ADA activity may be an important indicator in the immuno-pathogenesis of T2DM and can also be implicated as a biomarker for predicting glycemic control in diabetic individuals.