Ashish Purohit

Manuscript received: 4th Aug 2013, Reviewed: 16th Dec Aug
Author Corrected; 29th Aug 2013, Accepted for Publication: 25th Sep 2014

Introduction

Type-2 diabetes mellitus is a heterogeneous disorder characterized by chronic hyperglycemia due to dynamic interactions between varying defects of insulin secretion and insulin resistance. Either of these defects may be the predominant feature in a particular case [1]. 29.1 million people or 9.3% of US populations have diabetics in which diagnosed is 21.0 million and undiagnosed is 8.1 million people [2]. In adults type 2 DM accounts for about 90-95% of all diagnosed cases of diabetes. It usually begins with insulin resistance, a disorder in which the cells primarily with in the muscles, liver, and fat tissue do not use insulin properly [2]. Type 2 diabetics have achieved pandemic proportions and it arises because insulin production is inadequate relation to demand of the body [3]. The hemostasis model assessment- estimated insulin resistance (HOMA-IR) developed by Matthews et al has widely used for the estimation of insulin resistance in the research [4]. Martins et al [5] established that insulin resistance precedes and strongly predicts the development of type 2 diabetes mellitus among whites in the United States. There is paucity of such studies in India. At present there is no exact cut off value of insulin resistance by HOMA in various studies among Indians. In the absence of local reference data for HOMA-IR score, we studied the insulin resistance in 50 patients of type-2 diabetes mellitus and normal healthy controls, to find out the insulin resistance value in type-2 diabetes mellitus patients and controls in Gwalior Region. Thus, estimation of insulin resistance was helpful in detection of early complications and selecting the treatment options. Hence the present study was planned.

Material and Methods

The present study was a prospective case control study conducted in the Department of Medicine, G.R. Medical College and J.A. Group of Hospitals, Gwalior. Fifty newly diagnosed type 2 diabetes mellitus patients and 50 healthy controls were studied.

Inclusion criteria: American Diabetes Association criteria have been used for selecting the newly diagnosed type-2 diabetes mellitus patients [6].

Exclusion criteria: Patients receiving drugs that alter the insulin sensitivity

Oral hypoglycemic agents (Insulin,  agonist, Prazosin, Diuretics, Steroids, OCP's), Condition associated with insulin resistance (PCOD, Thyrotoxicosis, Congestive cardiac failure, Chronic renal failure, Cirrhosis, Pregnancy), Hypertension (JNC – 7 stage I hypertension and stage II hypertension). The volunteer study subjects, who satisfied the inclusion and exclusion criteria, were educated regarding the study, its aims ad objectives. If they were willing to participate in the study, an informed consent was obtained and the subject taken into the study.

Controls: 50 healthy age and sex matched volunteers who had no personal or family history of diabetes mellitus, hypertension were recruited to serve as controls. Exclusion criteria were clinical evidence of any illness, personal or family history of Diabetes Mellitus, hypertension, current use of any form of medication.

Collection of data: All patients and controls were subjected to detailed history and physical examination and investigations. Information on age, sex and anthropometrics waist circumference, waist hip ratio, height, weight, BMI [wt. (kg)/ ht (mtr2)] and ABI (was calculated using mercury sphygmomanometer in both case and control) measures were obtained from all cases and control subjects.

Patients were subjected to fundus examination to find out any diabetic retinal abnormalities.
Fasting (overnight 8 hrs) and postprandial (2 hrs) venous plasma glucose was determined by glucose oxidase method using glucose auto analyzer. Concentrations of total cholesterol, triglyceride HDL, LDL and cholesterol were determined by enzymatic kinetic method using an auto analyzer. Renal function test viz. blood urea & serum creatinine were done. Urine routine & microscopy and urine for microalbumin were also determined.

The serum plasma was stored at 20oC until assayed. Corresponding specific insulin concentration was determined by radioimmunoassay (RIA) using a human specific antibody RIA kit ECG was done..

Calculation of insulin resistance by HOMA
The HOMA method developed in 1985 by Matthews and co-workers was used in this study as it is simple and appropriate to developing countries where dynamic studies like the euglycemic glucose clamp technique [7], though the gold standard may not be feasible due to the degree of sophistication and cost of equipment necessary. Recently resistance in diabetic patients has been the focus of much attention [7,8,9,]. A significant correlation has been reported between the insulin resistance index calculated by HOMA and the hyperinsulinemic-euglycemic clamp (clamp IR ) [7,10].

HOMA-IR was calculated using formula: HOMA IR) =

       Fasting plasma glucose (mg/dl)
                 __________________________________________ × Fasting plasma insulin
   ______________________________18________________________________________________
                       22.5

The figure 22.5 in equation brings the insulin resistance values to one (Insulin sensitivity of 100%) of normal subject.

Statistical Analysis
Statistical analysis was done by calculation of range, median, mean, standard deviation, percentage, odds ratio, chi square test and p value.

Statistical software:
The statistical software SPSS 10.0 was used for the analysis of the data and Microsoft word and excel have been used to generate graphs, tables etc.

Results

Table No. 1
Age wise distribution of cases

Above table shows that most of the patients had albumin creatinine ratio <30mg/g. Out of 39 patients, 17 patients had HOMA IR >3.31.

11 patients had albumin creatinine ratio >30mg/g, of which 5 patients had HOMA IR >3.31.

Discussion

The HOMA method developed by Mathew’s & co-workers (1985)[11] was used in the present study for estimation of Insulin resistance as it is simple and appropriate. The HOMA method has been re-validated as a reliable method to asses insulin resistance in clinical practice as the HOMA IR score is shown to closely mirror the insulin resistance obtained by euglycemic clamp technique in assesment of insulin resistance (BONORA E et-al 2000)[7]. At present there is no exact cut off value of HOMA available in India. The present study was undertaken to find out insulin resistance value in T2 DM patients and age & sex matched healthy controls.

Complications
In the present study, most common complications in type 2 DM were retinopathy & neuropathy (26% each) followed by nephropathy in 22% cases, CAD in10% cases and risk of PVD in 12%. Fasting plasma glucose, Fasting plasma Insulin and Insulin resistance. Mean value of fasting plasma insulin in cases was found to be 10.53±9.42µU/ml while in controls 7.43±2.26µU/ml with p value (0.025) which is statistically significant as shown in table no.12. Adamu G Bakari et al. (2005)[12] study found mean FPI 4.20±1.78 µU/ml in 40 T2 DM patients, Vijay Vishwanathan et al (2010)[13] found mean FPI 46.1±2.5 µU/ml in controls in their study. In the present study, mean FPI in cases was found to be higher than other studies i.e. may be marker of Insulin resistance. Mean Fasting plasma Glucose in cases was 164.12±54.43 mg/dl while in controls it was 110.6±7.07 mg/dl with P value 0.000 and this difference is statistically significant. Mean HOMA IR Score in studied cases was 4.15±3.56 & mean HOMA IR score in controls was 2.03±0.64 with P value 0.000072 which was statistically highly significant. It means that Insulin resistance was found in type 2 DM patients.

HOMA IR in cases found to be mean 4.15±3.56. Adamu G et al (2005)[12] found mean HOMA-IR 1.73 in diabetic patients, Akira et al (2001)[14] found mean HOMA IR 2.04±1.56 in 55 type 2 DM patients. Bonora et al (2000)[7] found mean HOMA-IR of 2.06±0.14 in non diabetic normal population. Enzo Bonora et al (2007)[15] reported HOMA-IR of 2.5 in normal subjects. Hui- Qi Qu, et al (2011)[16] study showed that the best cut off of HOMA-IR for identifying those with insulin resistance is 3.80. HOMA-IR score in present study was higher than previous studies it indicates that IR was higher in Patient of T2 DM in Gwalior Chambal zone as compared to other countries.

It is interesting that equation given by Mathew & co-workers [11] in 1985 shows that HOMA-IR 1 is equivalent to insulin sensitivity of 100% but in present study it was found that the mean value of HOMA IR score in cases was 4.15±3.56 while in healthy controls it was 2.03±0.64 so normal cut off value for HOMA-IR in healthy controls is difficult to specify. Mathew & co-workers (1985)[11] said that normal value of HOMA-IR in healthy controls should be 1 but the present study shows that the mean value of HOMA-IR in healthy control was 2.03 & by adding two standard deviation the normal cut off value should be 2.03±2x0.64 equal to 3.31. It indicates that the normal cut off value of HOMA-IR in healthy persons in present study was 3.31. Previously HOMA-IR was calculated in healthy controls in various studies which are summarized in table from given below.

Table 5: Showing comparison between various studies

Total 13 patients had diabetic retinopathy in studied group. Out of 13 patients, 7 patients of diabetic retinopathy had HOMA-IR score more than 3.31 while 6 patients had HOMA-IR less than cut off value with p value of 0.0051, so higher insulin resistance was statistically significant factor in the development of diabetic retinopathy. In the present study total 11 patients had diabetic nephropathy, of which 5 patients with diabetic nephropathy had HOMA-IR >3.31 while 6 patients of diabetic nephropathy have HOMA-IR ≤3.31 with P Value (0.00349) which was statistically significant factor. Thus, insulin resistance is associated with development of diabetic nephropathy. Vijay Vishwnathan et al (2010)[13] also found high Insulin resistance in T2 DM patients associated with diabetic neuropathy they found that mean HOMA-IR significantly increases with progression of renal disease. In the present study total 5 patients had CAD, of which 3 patients had HOMA-IR >3.31 while 2 patients had HOMA-IR ≤3.31 with p Value (0.01) which statistically significant thus insulin resistance was a significant factor in development of CAD. In the present study 13 patients had neuropathy, of which 8 patients had HOMA-IR >3.31 while 5 patients had HOMA-IR≤3.31 with p value 0.002467 which is statistically significant factor in development of neuropathy. In the present study total 6 patients had PVD; of which 4 patients had HOMA-IR score more than 3.31 & 2 patients had HOMA ≤3.31 which is statistically significant. Thus insulin resistance was significant factor in development of PVD.

Diabetic Nephropathy
Mean blood urea in cases was 31.96±10.84mg/dl and in controls 29.76±6.56mg/dl mean serum creatinine value was 0.89±0.17mg/dl in cases and 0.87±0.113mg/dl in controls (p value 0.49). Albumin creatinine ratio is important indicator of nephropathy. Vijay Vishwanathan et al (2010)[13] studied insulin resistance in different stages of diabetic renal dysfunction. They found that insulin resistance increases with worsening of renal function. In present study, 39 patients had normal albumin/creatinine ratio (<30mg/dl) while 11 patients showed albumin/creatinine ratio >30mg/dl. Out of 39 patients having normal albumin/creatinine ratio, 17 patients had HOMA-IR >3.31 while out of 11 patients having disturbed albumin/creatinine ratio, 5 patients had insulin resistance.

Conclusions

• Mean value of HOMA-IR was significantly high in cases as compared to controls.
•  In present study the normal cut off value for HOMA IR was 3.31
•  44% type 2 DM patients had insulin resistance (HOMA IR >3.31) while 4% controls had insulin resistance (HOMA IR>3.31).

In day to day practice clinicians must think about insulin resistance in diabetic patients. As insulin resistance is an independent risk factor in diabetic patients in addition to all well established risk factors i.e. CAD, Hypertension, and Obesity. It should be measured in all the diabetic patients because it is cheap and easily measurable from FPI and fasting blood sugar level. Its measurement will help to prevent the development of various complications of diabetes at early stages.

Funding: Nil, Conflict of interest: Nil
Permission from IRB: Yes

References

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Age (in years)	No. of Cases	%
31-40	09	18%
41-50	18	36%
51-60	20	40%
>61	03	06%
Total	50	100