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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 331-339

Association of circulatory adiponectin with the parameters of Madras Diabetes Research Foundation-Indian Diabetes Risk Score


1 Department of Biochemistry, Integral Institute of Medical Sciences and Research (IIMS&R), Integral University, Lucknow, India; Department of Biochemistry, United Institute of Medical Sciences, Rawatpur, Prayagraj, India
2 Department of Biochemistry, King George’s Medical University (KGMU), Lucknow, India
3 Department of Biochemistry, Integral Institute of Medical Sciences and Research (IIMS&R), Integral University, Lucknow, India
4 Department of Biochemistry, United Institute of Medical Sciences, Rawatpur, Prayagraj, India
5 Department of Biochemistry, Integral Institute of Medical Sciences and Research (IIMS&R), Integral University, Lucknow, India; Department of Basic Medical Sciences, Integral Institute of Allied Health Sciences and Research (IIAHSR), Integral University, Lucknow, Uttar Pradesh, India

Date of Submission09-Aug-2022
Date of Decision07-Sep-2022
Date of Acceptance12-Sep-2022
Date of Web Publication21-Dec-2022

Correspondence Address:
Dr. Mohammad M Khan
Department of Basic Medical Sciences, Integral Institute of Allied Health Sciences and Research (IIAHSR), Integral University, Lucknow, Uttar Pradesh 226026
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_86_22

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  Abstract 

Introduction: Adiponectin (APN) is an adipose-derived protein. It has shown a variety of functions such as anti-inflammatory, anti-atherogenic, antidiabetic, and insulin-sensitizing and lipid-oxidation-enhancing activities. The APN levels have shown a significant relationship with the risk factors for type 2 diabetes mellitus (T2DM). As per the Madras Diabetes Research Foundation-Indian Diabetes Risk Score (MDRF-IDRS), Asian Indians have high risk factors for T2DM and its complications. APN levels influence the risk factors for T2DM and its complications. Its circulatory level also varied with the age, family history of T2DM, waist circumference, and level of physical activity. Aim: The purpose of this narrative review is to find the association of circulatory APN with the parameters of MDRS-IDRS. Materials and Methods: Articles were searched by various databases such as PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar. Abstract, free full-text, and full-text articles were searched from the year 2003 to 2022. For this review, observational study, original articles, narrative review, systematic review, and meta-analysis articles published in the English language were included. It is needed to establish the association between the APN levels and the parameters of MDRF-IDRS. The modifiable risk factors of MDRF-IDRS may play a significant role to regulate the level of APN. The non-modifiable risk factors of MDRF-IDRS may help in the better management of APN levels and reduce the prevalence of T2DM. It is needed to clear that the APN levels influence the disease severities or not. It is also needed to improve the physical activity to regulate the APN level and to reduce the systemic inflammation and insulin resistance in Asian Indian population. Conclusion: Improvement in modifiable risk factors of MDRF-IDRS and level of APN may play a significant role in the therapeutic approach to prevent and/or delay the development of T2DM and its complications.

Keywords: Adiponectin, Indian Diabetes Risk Score, MDRF-IDRS, modifiable risk factors, non-modifiable risk factors, type 2 diabetes mellitus


How to cite this article:
Khan MD, Ahmad MK, Alam R, Khan S, Jaiswal G, Khan MM. Association of circulatory adiponectin with the parameters of Madras Diabetes Research Foundation-Indian Diabetes Risk Score. J Diabetol 2022;13:331-9

How to cite this URL:
Khan MD, Ahmad MK, Alam R, Khan S, Jaiswal G, Khan MM. Association of circulatory adiponectin with the parameters of Madras Diabetes Research Foundation-Indian Diabetes Risk Score. J Diabetol [serial online] 2022 [cited 2023 Jan 28];13:331-9. Available from: https://www.journalofdiabetology.org/text.asp?2022/13/4/331/364638




  Introduction Top


South Asian Indians have shown the high incidence of type 2 diabetes mellitus (T2DM) and faster development of T2DM from pre-T2DM. Dysfunction of pancreatic beta-cells and insulin resistance (IR) play a significant role in the pathophysiology of T2DM in South Asians. The study further suggested that the epidemic of T2DM is also spreading to rural areas of South Asia.[1],[2] It was further suggested that the increasing burden of T2DM is due to the high prevalence of overweight/obesity in India.[3] The inter-ethnic disparities were reported in the progression and development of T2DM and its associated complications. It is further suggested that ethnicity-specific biomarkers are required to develop the screening and diagnosis strategies to reduce the prognosis of T2DM and its associated complications.[4]

Adiponectin (APN) is a 30 kDa protein (244 amino acids) that consists of a signal peptide, a collagen-like domain, and a globular domain from N-terminus to the C-terminus. APN circulates as three multiple isoforms from low to medium to high molecular weight (LMW to MMW to HMW, respectively). The HMW is the most insulin-sensitizing isoform and abundantly present in plasma.[5],[6]

The circulating APN level in plasma has shown a very high range (2–30 µg/mL).[7] The circulating APN accounts 0.01% of the plasma proteins in adult individuals. The circulating level of APN varies with ethnicity. It is reported that the level of circulatory APN is low in Asian Indian population.[8],[9] The level of circulatory APN varies with gender and ethnicity.[10],[11]

There is a need to find a simple and cost-effective tool and a potential prognostic biomarker for screening of T2DM and cardiovascular disease (CVD), because genetic predisposition, dietary habits, and sedentary lifestyles are exponentially increasing the risk factors for obesity, hypertension, dyslipidemia, T2DM, and CVD in the Asian Indian population.

Aim

The purpose of this narrative review is to find the association of circulatory APN with the parameters of MDRS-IDRS.


  Materials and Methods Top


Article extraction source

Articles were searched by various databases such as PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar.

Eligibility criteria for including the articles

Abstract, free full-text, and full-text articles were searched from the year 2003 to 2022. For this review, observational study, original articles, narrative review, systematic review, and meta-analysis articles published in the English language were included. Articles were included based on the research questions.

Research question

Is there any association between circulatory APN and the parameters of MDRF-IDRS?

The following keywords were used to search the articles: “Circulatory adiponectin + Age,” “Circulatory adiponectin + Waist Circumference,” “Circulatory adiponectin + Family History of T2DM,” “Circulatory adiponectin + Physical Activity,” “Adiponectin + IDRS,” “Adiponectin + Asian Indian Population,” “Modifiable Risk factors for Diabetes,” and “Non-Modifiable Risk factors for Diabetes.”


  Structure and Mechanism of Adiponectin Top


APN interacts with two different transmembrane receptors: (1) APN receptor 1 (AdipoR1) is expressed all over and at a high level in skeletal muscle and (2) APN receptor 2 (AdipoR2) is expressed mainly in the liver.[12],[13] APN receptors are also expressed in pancreatic β-cells, and their expression is increased by exposure to free fatty acids. It is suggested that APN and its receptors are also contributing in the insulin secretion and function.[14],[15] The AdipoR1 activates 5′-adenosine monophosphate-activated protein kinase (AMPK) and glucose transporter-4 (GLUT4) to increase the uptake of glucose in muscle cells.[16] It also inhibits the phosphoenolpyruvate carboxylase (PEPC) hepatic enzyme and blocks gluconeogenesis, stimulates fatty acids oxidation, and further inhibits the fatty acids synthesis.[12],[17] Moreover, APN also increases burning of fatty acid and energy utilization via activation of AdipoR2 through peroxisome proliferator-activated receptor-α (PPAR-α) and PPAR-γ activation. AdipoR2 activation increases the uptake of glucose and decreases the triglyceride (TG) in the liver and skeletal muscle, and it further increases the insulin sensitivity in vivo.[15],[17]

APN activates downstream actions via the cell surface receptors. In skeletal muscle, LMW and HMW isoforms of APN up-regulate PPAR-α and activate AMPK through the AdipoR1. In the liver, only the HMW and full-length APN can act through the AdipoR2.[13],[18] It is illustrated in [Figure 1].
Figure 1: Diagrammatic illustration of the APN action through its receptors on insulin sensitivity and energy expenditure.[12],[13] AdipoR1 and AdipoR2 = adiponectin receptor 1 and 2, AMPK = 5′-adenosine monophosphate-activated protein kinase, FFA = free fatty acid, LMW = low-molecular weight, HMW = high-molecular weight, PPAR-α = peroxisome proliferator-activated receptor-α (created by Biorender.com)

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  Circulatory Adiponectin Influencing Factors Top


APN is an adipose-derived protein, with multivalent functions including anti-inflammatory, antidiabetic, anti-atherogenic, insulin-sensitizing, and lipid-oxidation-enhancing activities.[19],[20] Several studies suggested that the high circulating APN level reduces the risk for obesity, IR, T2DM and its complications such as atherosclerosis and CVD.[21],[22] Circulating APN level has shown a significant negative association with adiposity.[23] Zhang et al.[24] stated that low levels of APN were found in persistent obesity in children also. Circulating APN and weight regain have a significant inverse relationship in therapy dropout obese children.[25] It might be possible that visceral fat accumulation produces inhibiting factors for the synthesis or secretion of APN, such as tumor necrosis factor-α (TNF-α).[23] It has been predicted that between 30% and 70% variability in the circulating level of APN is determined by genetic factors.[26] Adiponectin gene (ADIPOQ) variants were significantly linked with hypoadiponectinemia, obesity, metabolic syndrome (MetS), and T2DM and its complications.[27],[28],[29],[30] Some rare mutations in the ADIPOQ gene are disturbing the multimerization process of proteins that consequently affect the biological activity of proteins. The mutations in the ADIPOQ gene disturbed the assembling of trimeric and HMW multimeric forms of proteins that lead the clinical symptoms of hypoadiponectinemia. Low levels of HMW multimeric forms of proteins are strongly associated with diabetes and obesity. The gene was investigated for different variants that predispose to insulin sensitivity, metabolic disease, obesity, and T2DM and its complications such as coronary artery disease.[31],[32],[33] APN receptor T-cadherin is also associated with risk factor for CVD including atherosclerosis.[34],[35]


  Prevalence of T2DM Top


In India, it was estimated that more than 77 million people had diabetes in 2019 and it is projected to be over 134 million diabetes burden in India by 2045.[3] According to the International Diabetes Federation (IDF), the prevalence of diabetes is more than 10.4% in India. In addition, more than 57.9% of the people still have undiagnosed diabetes.[36] The prevalence of diabetes was found to be higher in urban (14.2%) than in rural (8.3%) population. However, the prevalence of prediabetes was equally distributed in urban (14.5%) and rural (14.7%) population.[37]


  Madras Diabetes Research Foundation-Indian Diabetes Risk Score (MDRF-IDRS) Top


Mohan et al.[38] suggested that Asian Indians have a specific phenotype and uniqueness in physical, biochemical, and clinical characteristics. Indians have higher waist circumference (WC) with lower body mass index (BMI) leading to greater abdominal adiposity, increased IR, higher high-sensitive C-reactive protein (hs-CRP), and lower circulating APN levels. Gupta et al.[39] reported that MDRF-IDRS was found to be the most sensitive and useful tool for the screening of T2DM and hypertension in rural India.

Previous studies suggested that there are two major kinds of risk factors for T2DM: (1) non-modifiable risk factors: age and family history of T2DM and (2) modifiable risk factors: abdominal obesity and physical activity. The MDRF-IDRS studies revealed that the individuals having an MDRF-IDRS score (≥60) are at high risk for T2DM and its complications. The MDRF-IDRS score was calculated by using parameters (age, waist circumference, physical activity, and family history of T2DM).[40],[41],[42],[43]


  Non-modifiable Risk Factors for T2DM Top


Age

A study suggested that neonates have “thin fat phenotype” that further persisted in childhood and might be responsible for the diabetogenic phenotype in adults.[44] A study reported a high prevalence of IR in post-pubertal children due to the presence of excess body fat accumulation and abdominal adiposity in the metropolitan city Delhi.[45] According to the MDRF-IDRS, it is reported that Asian Indians are at high risk for T2DM and its complications.[40],[41],[42],[43] Asian Indians appear to have a high prevalence of macrovascular complications such as CVD compilations, whereas the prevalence of microvascular complications such as retinopathy and nephropathy was lower than that in Europeans.[46],[47]

The levels of plasma APN have shown an inverse relationship with body weight, fasting insulin concentrations, and homeostatic model assessment-insulin resistance (HOMA-IR) index in boys (aged 15–18 years) and in girls (aged 11–14 years). It is observed that the level of circulating APN reduced during male puberty and correlated with an increase in the testosterone level in boys. Due to this, body fat decreases and the early puberty adiposity may be disappeared in late puberty in boys.[48] The HMW adiponectin levels were lower and hs-CRP levels were higher in boys than in girls in late puberty. Young boys have shown additional abdominal fat and proinflammatory profile of biomarkers than girls.[49]

The study suggested that the cut-off value of circulating APN (5.1 μg/mL) can play a significant role in differentiating between T1DM and T2DM among young Asian Indians.[50] This cut-off point may well differ in other ethnic groups because of differences in the fat mass distribution and body weight in Indians.

The Indian Council of Medical Research–India Diabetes Study (ICMR-INDIAB) reported that above 15.5% of old age population (>65 years) are diabetic in India.[37] The low level of APN is associated with adipose tissue dysfunction in old age adults.[51] The risk of developing heart failure is significantly greater in obese menopausal women when compared with low BMI and WC menopausal women (≥55 years).[52] Women and older patients should be given more attention regarding the achievement of normal metabolic, adipose tissue, and endothelial functions to prevent or delay the T2DM complications and CVD.

Family history of T2DM

The circulating APN level has shown a significant correlation with a family history of T2DM. The circulating APN levels have been found to be significantly low in healthy individuals with a family history of T2DM when compared with healthy individuals without a family history of T2DM.

The progression of MetS to T2DM strongly linked with increased vascular adipose tissue, increased ectopic fat accumulation, and decreased level of APN in obese Japanese children, who have a family history of T2DM.[53] Similarly, the circulating APN level has shown a significant negative correlation with HOMA-IR and a strong association in individuals with family history of T2DM.[54] Genetic predisposition and presence of ADIPOQ gene variants were significantly linked with hypoadiponectinemia, obesity, and T2DM and its complications.[27],[28],[29],[30] This indicates that carrier of ADIPOQ gene variants that lead to hypoadiponectinemia may increase the risk factors for T2DM and its complications in individuals.


  Modifiable Risk Factors for T2DM Top


Abdominal obesity

WC is considered for the measurement of abdominal obesity. Abdominal obesity is a direct risk factor for CVD, independent of BMI.[55]

A negative correlation found between BMI and circulating APN levels could be because obesity leads to adipose tissue dysfunction. Indians have a higher degree of adiposity and body fat percentage than their Caucasian counterparts. However, Indians have low BMI.[56] Asian Indians have above 2-folds high prevalence of low BMI in young-onset diabetes (YOD) when compared with white Europeans. Asian Indians with low BMI in YOD have shown low beta-cell function.[57]

When adipose tissue fat storage capacity exceeded, further any nutritional excess will result in metabolic disturbance such as inflammation and IR.[58]

The distribution of obesity profiles [BMI, WC, and waist-to-hip ratio (WHR)] was found to have significant differences between cases and controls. Central obesity and high BMI were observed to increase the risk of T2DM.[42],[59] In postmenopausal obese women, the BMI and WC independently associated with visceral adipose tissue (VAT), circulating APN mRNA, triglycerides, and high-density lipoprotein. This suggested that the circulating APN has a potential modulatory role in lipid metabolism.[21]

For Asian Indian adults, the normal cut-off values for BMI (23 kg/m2 for both sexes) and WHR (0.88 and 0.81, for men and women, respectively) were suggested.[8],[56] It was observed that the Aggarwals of Delhi have higher mean values for BMI and WHR than these cut-off values.[60] Despite common, culturally embedded risk-prone lifestyle practices for both cases and controls, WHR was still found to have a significant effect on T2DM.[8],[42],[59]

A study on survivors and non-survivors of diabetic patients reported that the mean BMI for all T2DM patients (survivors and non-survivors) was higher than that of long-term survivors.[61] The average T2DM patients were obese than the long-term survivors.[41] In addition, it was reported that the HMW APN concentrations found a negative correlation with BMI and HOMA-IR in the T2DM patients.[20],[62]

Physical activity

Physical exercise is linked with an increase in the plasma level of APN and a decrease in the level of leptin and interleukin-6 (IL-6) in obese children, reducing the systematic inflammation.[63] Plasma APN concentrations also demonstrated a significant inverse relationship with levels of physical activity.[64] The response exercise and level of APN are related with the amount of adipose tissue and type of exercise.[65] The aerobic exercise significantly increases the APN levels and reduces the leptin levels in pre-diabetic and diabetic adults.[66] It is further reported that the physical activity may change the level of different isoforms of APN, especially the HMW isoform. The ratio of APN multimer isoforms may be changed by physical activity, which further may increase the biologically active form of plasma APN.[67]

A meta-analysis study reported that the physical exercise increases the circulatory APN levels in childhood obese subjects.[62] Similarly, physical exercise, mainly, aerobic exercise, can also increase the APN levels in pre-diabetic and diabetic adults.[65] It was reported that replacing the sedentary time (60 min) with light-intensity physical activity (60 min) increases the HMW (13%) and total APN levels (9%) in men.[68]

Intake of refined grain and decreased physical activity are associated with increased risk factors of diabetes in Asian Indian ethnic groups.[40],[69] Recently, it has been reported that regular drinking of sugar-sweetened beverages (SSBs) significantly contributes to weight gain and increases high risk factors for abdominal obesity, T2DM, and CVD in high-to-low-income countries equally.[70]

Anjana et al.[71] reported that more than only around 10% of people of India are physically active. It was further reported that around 57% of people of India do not match the recommended level of physical activity regimen.[72] It is suggested that urgent action needs to be taken to encourage the physical activity and to reduce the intake of SSBs in general population to reduce the burden of abdominal obesity and T2DM and its complications such as CVD in India.


  Systemic Inflammation, Insulin Resistance (IR), APN, and the Parameters of MDRF-IDRS are Linked Together Top


Obese adipose tissue secretes inflammatory markers (IL-6, CRP, and TNF-α) that directly mediate systemic inflammation and contribute to IR, T2DM, and CVD.[58]

Systemic inflammation in adipose tissue is resulting in visceral adiposity. Several studies hypothesized that a strong correlation exists between inflammation in adipose tissue and IR. Adipocytes and macrophages of adipose tissue produce inflammatory markers that enhance excessive free fatty acid, increased resistin, decreased adiponectin, and accumulation of ceramide and ectopic fat in liver and skeletal muscle resulting in IR.[73] Macrophages of adipose tissue promote systemic inflammation that damages the β-cells of pancreas and enhances IR.[74]

IR plays a central role which is influenced by both modifiable and non-modifiable risk factors for T2DM [Figure 2]. Insulin sensitivity and IR are influenced by variable APN levels in different ethnicities. The study reported that the circulating APN level and adiposity have inverse association.[23]
Figure 2: Role of APN on modifiable risk factors for T2DM. CVD = cardiovascular disease, IL-6 = interleukin-6, MDRF-IDRS = Madras Diabetes Research Foundation-Indian Diabetes Risk Score, TNF-alpha = tumor necrosis factor-alpha, T2DM = type 2 diabetes mellitus (created by Biorender.com)

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South Asia has a high prevalence of T2DM and faster development from pre-diabetes to diabetes. Dysfunction of pancreatic beta-cell and IR play a significant role in the pathophysiology of T2DM in South Asians. The study further suggested that the epidemic of T2DM is also spreading to rural areas of South Asia.[1],[2] This may be due to the differences in overall abdominal fat and visceral fat deposition which may contribute to the high risk of abdominal obesity and T2DM in South Asians.[75] Most importantly, ethnicity variations were also reported between plasma HMW APN levels and HOMA-IR. South Asians have low plasma HMW APN levels, which cause a greater increase in HOMA-IR and increase the risk factor for T2DM.[4],[76],[77] Several studies have shown that South Asians (Asian-Indians) have higher levels of IR than Caucasians in the same level of BMI.[78]

It was reported that Asian Indian population has a high risk of T2DM microvascular complications such as retinopathy and chronic kidney disease due to the presence of insulin deficiency and IR in T2DM study groups.[79]

A follow-up of the original Chennai Urban Population Study cohort showed that the overall mortality rates are almost three times high in the diabetes group when compared with the non-diabetic group. The study showed significant high mortality due to CVD and renal disease in diabetic subjects than in non-diabetic subjects.[80]

In the Asian Indian population, Snehalatha et al.[8] found a low mean APN level in the diabetic group when compared with the non-diabetic group. In North Indian population, adjustment for age did not show any change in the mean APN levels but adjustment for sex did influence the mean values of APN levels.[81] It is further suggested that estrogen improves the regulation of APN in females and testosterone inhibits the production of APN in males.[82]


  Modifications in the Modifiable Risk Factors of MDRF-IDRS Regulate the Secretion and Function of APN Top


Modifiable risk factors of IDRS are abdominal obesity and physical activity. It was reported that the improvement in physical activity reduces the abdominal obesity by reducing the systemic inflammation.[83] Reduction in the systemic inflammation reduces the secretion of inflammatory markers such as TNF-α and hs-CRP.[84] Reduction in the inflammatory markers such as TNF-α and hs-CRP elevates the APN levels.[85] Elevated level of APN increases the insulin sensitivity and reduces IR.[86] Physical activity has shown a significant impact on abdominal obesity, systemic inflammation, and IR.[87]

WC and IR have shown a strong association.[88] In addition, a large sample size NHANES study reported that WC is a significant predictor of fasting glucose, HbA1c, and HOMA-IR when compared with BMI.[89] Long-term physical activity reduces the weight and WC and provides overall health benefits.[90] However, physical inactivity/sedentary lifestyle increases the risk factors of chronic diseases. However, physical activity reduces the risk of CVD by improving the muscle functions and regulating the metabolic activity and benefiting to overall health.[91] A systematic review and meta-analysis suggested that exercise intervention induces a significant physical function and alterations in biomarkers in old age hospitalized adults.[92]

Several studies reported that physical activity/exercise significantly improves the level of APN and reduces the risk of abdominal obesity, T2DM, cardiometabolic and endothelial dysfunctions, and immunological and chronic diseases.[51],[63]

An in-vitro study reported that APN significantly balances hyperglycemia at various molecular and cellular levels, thus reducing the pathophysiological impact and progression of diabetic retinopathy.[93] APN regulates various biological functions. More research is needed to develop the exercise therapy protocol to regulate the level and effect of APN to improve the overall metabolic health benefits.[63]

The inter-ethnic disparities were reported in the progression and development of T2DM and its associated complications. It is further suggested that ethnicity-specific biomarkers are required to develop the screening and diagnosis strategies to reduce the prognosis of T2DM and its associated complications.[4]

The ICMR-INDIAB study in India showed a positive response of ABC targets [good control of blood glucose (A), blood pressure (B), and low-density lipoprotein cholesterol (C)] in self-reported diabetes groups. The study further suggested that education and awareness of diabetes can be better ways to achieve ABC targets in Indian population.[94] In addition, the World Health Organization announced the formation of a Global Diabetes Compact to increase the awareness and achieve the ABC targets in individuals.[95]

It is reported that the newly diagnosed T2DM is at high risk of atherosclerotic CVD in India. The study further supported that an easy-to-use and cost-effective screening tool is required to screen the T2DM and its complications at a very early stage.[96] For this purpose, MDRF-IDRS and ethnic-specific biomarkers such as APN may play a significant role to reduce the incidence and progression of abdominal obesity and T2DM and its complications.

Strength and limitations

Mainly, Asian Indian population-based published articles were included for this current review. Systematic review and meta-analysis are required to establish the evidence-based association between circulatory APN levels and parameters of MDRF-IDRS.


  Conclusion Top


This review indicated that the circulatory APN level might play a key role in reducing the risk factors for T2DM and its complications in Asian Indians. This review emphasized that the APN level is significantly influenced by modifiable and non-modifiable risk factors of MDRF-IDRS. It is also needed to improve the physical activity to elevate the level of APN and to reduce the systemic inflammation and IR in Asian Indian population. Improvement in modifiable risk factors of MDRF-IDRS and level of APN may play a significant role in the therapeutic approach to prevent and/or delay the development of T2DM and its complications.

Acknowledgements

We are grateful to Dr. Gyanendra Kumar Sonkar, Professor, Department of Biochemistry, King George’s Medical University (KGMU), Lucknow, Uttar Pradesh, India. We also acknowledge Prof. (Dr.) Abha Chandra, Dean, Integral Institute of Medical Sciences and Research (IIMSR), Integral University, Lucknow, Uttar Pradesh, India for the invaluable help and suggestions to write this article without any hindrance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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