Diabetes mellitus (DM) is one of the most frequently occurring endocrine disorders characterized by the common phenotype of hyperglycemia. It is a growing health care problem worldwide and is characterized by metabolic abnormalities such as diabetic ketoacidosis and non-ketotic hyperosmolar coma and leads to complications involving the eyes, kidney, nerves, blood vessels and the gastrointestinal tract. ^[1]

Diabetic individuals are highly prone to coronary artery diseases (CAD) and hence it is necessary to search for advanced markers to assess the CAD risk. Diabetes Mellitus being a chronic disorder results from various factors in which a complete or partial deficiency or impaired function of insulin occurs. The most frequent grievous disorder that effects type 2 diabetic individuals is cardiovascular disease. ^[2] Among diabetic subjects the risk for cardiovascular disease is 2-4 folds greater in comparison to normal subjects. ^[3]

Diabetes mellitus is one of the major risk factor for the progression of atherosclerosis, which is two to three folds more common as compared to that of normal population. Elevated concentrations of serum Homocysteine (Hcy) is expected to enhance the production of oxidation products such as Hcydisulfides and Hcythiolactone, leading to endothelial cell damage by extravagant sulfation of collagen which in turn aggravates the progression of thrombosis and arteriosclerosis. ^[4]  Plasma homocysteine levels are elevated in both viz; type 2 diabetic patients as well as in pre-diabetic individuals with insulin resistance. In such individuals, plasma Hcy concentrations is influenced by the insulin concentrations and anti-diabetic therapy such as metformin, glitazones or insulin that can either elevate or reduce the plasma Hcy concentrations. ^[5]

Hyperhomocysteinemia is increased in insulin resistant and hyperinsulinemic patients, and also in T2DM patients with intact pancreatic β-cell function.4 But when these patients lose pancreatic β-cells, they might then show a fall in plasma Hcy concentrations. ^[5] Non-diabetic i.e. normal individuals who are having insulin-resistance syndrome also show higher plasma Hcy concentrations which proves the association between elevated plasma Hcy concentrations and increased plasma insulin concentrations. ^[6]

As diabetic individuals are at higher risk of vascular disease, therefore it is required to look for reliable markers that can help in predicting prognosis and diagnosis of the disease.This study aims at finding a reliable correlation between serum homocysteine levels and insulin levels which shall indicate the degree of insulin resistance in patients with Type 2 Diabetes Mellitus, and hence predict their risk for atherosclerosis and cardiovascular disease. ^[7]

This is a prospective study was conducted in the Department of General Medicine, Mahavir Institute of Medical Sciences.

Inclusion Criteria: The inclusion criteria are as follows: 1) Hospitalized T2DM patients in the Medicine Department of the Hospital; 2) aged 30 years or older; 3) with complete clinical data required for the study.

Exclusion Criteria: 1) Patients with special disease states, such as diabetic ketosis or ketoacidosis, hyperosmolar hyperglycemic state, infection, pregnancy, shock; 2) with primary kidney disease and/or renal artery stenosis; 3) with a duration of hypertension longer than that of diabetes mellitus; 4) with abnormal folic acid and vitamin B12 levels or those taking folic acid, vitamin B12, and vitamin B6 that may affect the Hcy level; 5) with only 1 record of UACR of ≥30 mg/g and/or eGFR of <60 mL/min/1.73 m² or those with an interval between 2 abnormal results of less than 3 months.

Biochemical detection: Fasting blood was collected. Serum total Hcy was measured with cycling enzymatic method. Serum total Hcy concentration of <15 mol/L was considered normal. Serum folic acid and vitamin B12 were detected with electrochemiluminescence immunoassay. Glucose was determined enzymatically. Glycosylated haemoglobin (HbA1c) was measured using high performance liquid chromatography. Serum total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were measured by enzymatic clearance assay. Triglyceride (TG) was measured by TG LiquiColor Test. Serum creatinine was measured using standard technique. Estimate glomerular filtration rate (eGFR) was calculated with MDRD method.

Statistical analysis

Continuous data were expressed as mean and standard deviation (SD), and categorical data as percentages. Hcy distribution was tested for normality. Categorical data were compared using chi-square test. Among different age groups, comparisons were done with one way analysis of variance (ANOVA). A value of 2-tailed P<0.05 was considered for statistical significance. Statistical analysis was performed using SPSS version 17 for windows (SPSS Inc., Chicago, Illinois).

A total of 160 type 2 diabetic patients were included in the study. The mean age of the participants was 55.4 ± 9.8 years, with 88 males (55%) and 72 females (45%).

Table 1 Age Distribution of Patients

Table 2 Baseline Characteristics of the Study Population

Correlation Analysis

Pearson correlation analysis was performed to assess the relationship between serum homocysteine levels and HbA1c, serum creatinine, and estimated glomerular filtration rate (eGFR).

Table 3 Correlation of Serum Homocysteine with HbA1c and Kidney Function

A significant positive correlation was observed between serum homocysteine and HbA1c (r = 0.41, p < 0.001), suggesting that higher homocysteine levels are associated with poor glycemic control Serum homocysteine also showed a strong positive correlation with serum creatinine (r = 0.55, p < 0.001), indicating an association with declining kidney function An inverse correlation was found between serum homocysteine and eGFR (r = -0.48, p < 0.001), suggesting that higher homocysteine levels correspond to lower renal function.

To further evaluate the impact of homocysteine on renal function, patients were categorized into tertiles based on homocysteine levels:

Table 4 Kidney Function Across Homocysteine Tertiles

Patients in the highest tertile of homocysteine levels exhibited significantly lower eGFR and higher serum creatinine levels compared to those in the lowest tertile (p < 0.001 for trend).

The strong correlation between homocysteine and serum creatinine, along with the inverse correlation with eGFR, indicates that higher homocysteine levels are associated with reduced renal function. These findings are consistent with previous studies that have reported elevated homocysteine as a risk factor for diabetic nephropathy. The progressive decline in eGFR across homocysteine tertiles further supports the role of homocysteine as a potential biomarker for kidney dysfunction in diabetic patients.^[8]

Possible mechanisms underlying these associations include impaired renal clearance of homocysteine, endothelial dysfunction, and increased oxidative stress, all of which contribute to kidney damage and diabetic complications. Additionally, elevated homocysteine may promote vascular damage through increased inflammation and thrombogenesis, further exacerbating microvascular complications in diabetes. ^[9]

From a clinical perspective, these findings highlight the importance of monitoring homocysteine levels in diabetic patients, particularly those with poor glycemic control and declining renal function. Future research should explore whether interventions aimed at reducing homocysteine levels, such as B-vitamin supplementation or lifestyle modifications, can help mitigate the risk of diabetic nephropathy and improve overall outcomes in this population. ^[10]

Uric acid may be used as a screening tool for glycemic control and insulin secretion. In diabetology clinics, uric acid should be required in addition to baseline studies to determine insulin secretion. In type-2 diabetic patients, the proposed regression models can be used as a guide to estimate insulin secretion and -cell function. In healthy people, serum uric acid is linked to blood glucose levels. However, this link is not consistent between healthy and diabetic people, as the hyperglycemic state is associated with a low uric acid level in the blood. It’s unclear whether elevated serum uric acid predicts the risk of type 2 diabetes because most people have a period of impaired glucose tolerance before developing diabetes. ^[11]

The Rotterdam Study, a comprehensive population-based, prospective cohort study of subjects, looked into the link between serum uric acid and diabetes risk. We have shown the risk of developing type 2 diabetes is higher in the subjects with high serum levels of uric acid. Furthermore, one quarter of cases of diabetes can be attributed to high serum uric acid. Our results are consistent with previous studies. ^[12]

Uric acid association with the risk of diabetes (Herman and Goldbourt, 1982). Recently it has been shown that serum levels of uric acid are significantly linked to the risk of diabetes in mid-aged men (Nakanishi et al. 2003). However, after controlling for BMI, alcohol consumption, smoking, physical activity, fasting blood glucose, and parental diabetes history, another study in middle-aged men found that the link was not significant. This research could lessen the chances of an independent effect by the fact that the scope of the research consists mainly only of people.^[12]

In our research, we discovered that, while not statistically significant, the link between men and women was weaker in men than in women. Since hyperuricemia was thought to be a result of insulin resistance rather than its precursor, recognition of high serum uric acid as a risk factor for diabetes has been a point of contention for a few decades. Recent research suggests, however, that uric acid may be related to the creation of diabetes. Serum uric acid has proven to be linked to oxidative damage (Butler et al., 2000) and tumor necrosis factor output (Butler et al., 2000) linked to both diabetes development.^[13]

A latest study in rats also found a pathogenic role for fructose-induced hyperuricaemia in metabolic syndrome (Mehmetet al., 2016). ^[14] These research results are a prerequisite for type 2 diabetes, high serum uric acid. Presently, only negative effects for hyperuricemia are gout and renal disorders. The serum uric acid as a potentially risk factor for hypertension, stroke and cardiovascular diseases has been presented recently (Johnson et al., 2003). ^[15] Our results indicate a further effect of hyperuricemia is type 2 diabetes. In view of the fact that a reduction in the serum uric acid in the highest-quartile subject may decrease diabetes incidence by 24 per cent when this is causative, the importance of this finding is even more obvious. High serum uric acid can therefore have a greater public health impact than currently expected.

However, uric acid does not serum hyperuricemia or a risk marker for treatment in clinical practices, but serum uric acid methods are widely used and cheap. In addition, xanthan oxidase inhibitors are safe and inexpensive, and are currently used to decrease serum uric acid. Along with the number of past writings, our results suggest that lowering uric acid can be a novel thermal focus for diabetes control and justify a future randomized testing of the potential benefits of serum uric acid evaluation and reduction in seamless access of serious illness. ^[16]

The correlation is shown at serum uric acid and diabetes age levels, showing that the patient’s age rises in serum uric acid. In Type II diabetic patients serum UA levels were increased, which appeared to be deeper in male diabetic patients compared with female. The hyperuricemia in men and the increased levels of serum uric acid in postmenopausal women were observed because an estrogen promotes uric acid excretion. Through the mechanisms and elevated serum uric acid (SUA), the glomerulus and the tubulo interstitium, associated with increased remodelling and fibrosis of the kidney, lead to endothelial dysfunction.^[17] The gouty nephropathy has produced similar histological changes. Reducing allopurinol SUA composition attenuated these histological and functional changes but may partially have an oxidative stress reduction (Hayden and Tyagi, 2004). ^[18].

The findings indicate that elevated serum homocysteine levels are significantly associated with poor glycemic control and declining kidney function in type 2 diabetic patients. Monitoring homocysteine levels may provide additional insight into the risk of diabetic nephropathy and vascular complications. Further studies are needed to establish causality and potential therapeutic targets for homocysteine reduction in this population.

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