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Clinical utility of estimated glucose disposal rate as a surrogate marker of insulin resistance in patients with type 2 diabetes mellitus
, Rajarshi Kar1, Shanmuga Priya Kirubalenin1
* Corresponding author: Dr. Mohit Mehndiratta, Department of Biochemistry, University College of Medical Sciences & Guru Teg Bahadur Hospital, University of Delhi, Delhi, India. drmohitucms@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Almeida EA, Mehndiratta M, Madhu SV, Kar R, Kirubalenin SP. Clinical utility of estimated glucose disposal rate as a surrogate marker of insulin resistance in patients with type 2 diabetes mellitus. Ann Natl Acad Med Sci (India). doi: 10.25259/ANAMS_27_2025
Abstract
Objectives
To calculate estimated glucose disposal rate (eGDR) in newly diagnosed treatment naive patients with type 2 diabetes mellitus (T2DM) and correlate it with homeostatic model assessment of insulin resistance (HOMA-IR) and clinical/ biochemical parameters.
Material and Methods
eGDR was calculated using a formula based on waist circumference (WC) and body mass index (BMI) in 60 patients newly diagnosed with T2DM. HOMA-IR was calculated using fasting values of plasma glucose and insulin. Serum fasting insulin and serum total antioxidant status (TAS) were estimated using commercially available kits.
Results
Mean age of the participants was 48+/-10.1 years (range:29-60 years). HOMA1-IR values were in the range of 1.2-34.4 while eGDR values were in the range of 4.9-12.5 mg/Kg/min. A significant negative association between HOMA1-IR and eGDR/eGDRBMI was noted.
Conclusion
The use of eGDR as a surrogate marker instead of HOMA-IR needs to be validated, and necessary modifications should be made before its application in patients with T2DM.
Keywords
Estimated glucose disposal rate
Homeostatic model assessment of insulin resistance
Insulin resistance
surrogate marker
Type 2 Diabetes Mellitus
INTRODUCTION
Diabetes Mellitus (DM) is defined as “a group of metabolic diseases characterized by hyperglycemia, resulting from defects in insulin secretion and/or insulin action.” Although broadly classified into four categories; type 2 diabetes mellitus (T2DM) is the most prevalent form of the disease. The etiopathogenesis of T2DM involves a variable degree of insulin resistance (IR) leading to relative insulin deficiency along with impaired secretion of insulin and impaired cellular use of glucose, resulting in hyperglycemia. IR is defined as “a decrease in the metabolic response of insulin-responsive cells to insulin or, at a systemic level, an impaired/lower response to circulating insulin by blood glucose levels.”1 IR in most patients of T2DM can be attributed to obesity; however, IR has also been reported in non-obese individuals and patients with T1DM (Double diabetes).2
Measurement of IR is not only useful in examining the pathogenesis of hyperglycemia but also guides patient management. The hyperinsulinemic-euglycemic clamp method is the gold standard method3 for the measurement of IR. However, it has limited utility in a clinical setting, mainly because it is a complex and costly process.4 This lead to the development of surrogate markers for IR, the most widely used being homeostatic model assessment of insulin resistance (HOMA-IR). It is calculated using a formula with fasting serum insulin levels and fasting blood glucose levels. Although widely used as a marker of IR, it suffers from drawbacks. The major drawback of the HOMA model is that it makes no distinction between hepatic insulin sensitivity and peripheral insulin sensitivity,5 which was corrected in the updated HOMA2 model.6
Estimated glucose disposal rate (eGDR) is a well-established marker of IR in individuals with T1DM.7 It is calculated using a formula that incorporates clinical examination findings like waist-hip ratio/waist circumference (WC)/BMI, HbA1c, and presence of hypertension. It has shown good correlation with IR measured by the euglycemic-hyperinsulinemic clamp7-9 in patients with T1DM. Although extensively studied in T1DM, there is only one study10 that has compared eGDR against the clamp technique in T2DM patients and noted a highly significant correlation. We conducted this study to calculate eGDR/eGDRBMI in newly diagnosed patients of T2DM and study it’s association with clinical/biochemical parameters.
MATERIAL AND METHODS
The study was designed and carried out in the Biochemistry and Endocrinology unit of a tertiary care hospital, Delhi, India, after ethical approval. The study was carried out in accordance with the Declaration of Helsinki. A detailed literature search did not yield any study assessing eGDR in newly diagnosed patients of T2DM. The data on eGDR were generated as secondary data from preexisting data collected for another project, which was a pilot study. No fresh participant recruitment was done, and data from 60 participants were analyzed.
Participant selection
Participants included newly diagnosed treatment naive patients of T2DM belonging to the age group of 20-65 years except those with normal BMI (18.51-24.99 kg/m2). World Health Organization (WHO) criteria were used for the diagnosis of T2DM.11 Presence of thyroid disorders, smoking, chronic alcoholism, renal and hepatic disorders, and severe comorbid illnesses resulted in exclusion of participants. Pregnant and lactating women were also excluded from the study. Anthropometric measurements were taken as per standard guidelines.12
Plasma glucose and routine biochemical parameters were estimated on the RX Imola Autoanalyzer (RANDOX, UK). D-10 analyzer (BIO-RAD, USA) was used for estimation of HbA1C levels. Fasting serum insulin was estimated by ELISA (DRG International, USA), following the manufacturer’s protocol (sensitivity: 1.76 IU/mL).
Calculation of eGDR and HOMA-IR
eGDR was calculated using the formula incorporating WC as follows7
Seeing a good correlation between WC and BMI, the formula was adapted to include BMI instead of WC. eGDRBMI was calculated as
The presence of hypertension (0=no, 1=yes) was defined as the actual blood pressures ≥140/90 mm Hg or current use of any anti-hypertensive agents.
HOMA1-IR in the subjects was calculated using the using the formula:13 HOMA-IR = fasting plasma glucose (mmol/L) x fasting serum insulin (µIU/mL)/22.5.
HOMA2-IR was calculated using HOMA Calculator version 2.2, as described by Wallace et al.14 (2004) (available on www.OCDEM.ox.ac.uk)
Calculation of the Atherogenic Index of Plasma (AIP)
AIP = Log [Triglyceride/High Density Lipoprotein-Cholesterol].15
Total antioxidant status (TAS) estimation
Commercially available kit (Cayman Chemical, USA) was used for the estimation of TAS following the manufacturer’s protocol and reported as µM Trolox Equivalents.
Statistical analysis
Statistical analysis was carried out using SPSS v 26.0 (IBM Corporation, USA) software. Spearman’s rho correlation test was used to assess the association between parameters. A p-value <0.05 was considered statistically significant.
RESULTS
A total of 60 participants were recruited. Out of the 60 participants recruited, 16 belonged to the female sex, and hypertension was noted to be present in six participants. The average age of the study participants was 48.8 ± 10.1 years. (range 29-60 years). Physical and biochemical variables have been reported as a range (minimum value-maximum value) in Table 1. Correlation coefficients (r) between eGDR/eGDRBMI and other parameters have been mentioned in Table 2. A significant negative correlation was noted between HOMA-1R and eGDR/eGDRBMI. A negative correlation was noted between eGDR/eGDRBMI with FBS, HbA1c, BMI, and PBF. To study the correlation between IR and complications associated with T2DM (atherogenicity and oxidative stress), we also documented the levels of AIP and TAS in these individuals. eGDR/eGDRBMI had a non-significant negative association with AIP and TAS.
| Variables | Range (Min-Max)* |
|---|---|
| Waist circumference (cm) | 62-118 |
| Percentage body fat (%) | 15.4-53.5 |
| Systolic blood pressure (mm Hg) | 100-148 |
| Diastolic blood pressure (mm Hg) | 60-96 |
| Fasting plasma glucose (mg/dL) | 128 -376 |
| 2-hour post prandial plasma glucose (mg/dL) | 174-514 |
| HbA1C (%) | 6.8 -16.4 |
| Fasting serum insulin (µIU/mL) | 4.1-37.6 |
| HOMA1-IR | 1.2-34.4 |
| HOMA2-IR | 1.6-37.5 |
| eGDR (mg/kg/min) | 4.9-12.5 |
| eGDRBMI (mg/kg/min) | 3.2-12.7 |
| TAS (µM trolox equivalents) | 1.3-7.5 |
| AIP | 0.28 -1.18 |
*does not include data of participants with normal BMI (18.51 to 24.99 kg/m2) HbA1c: Glycated hemoglobin, HOMA-IR: Homeostasis model assessment of insulin resistance, TAS: Total antioxidant status, AIP: Atherogenic index of plasma, eGDR: Estimated glucose disposal rate, BMI: Body mass index, T2DM: Type 2 diabetes mellitus.
| Variable | eGDR (n=60) | eGDRBMI (n=60) | ||
|---|---|---|---|---|
| R | p value | r | p value | |
| HOMA-IR | -0.289 | 0.023 | -0.163 | 0.021 |
| WC | -0.356 | 0.054 | -0.161 | 0.22 |
| BMI | -0.42 | 0.001 | -0.319 | 0.013 |
| PBF | -0.391 | 0.002 | -0.336 | 0.009 |
| FBS | -0.003 | 0.98 | -0.486 | <0.0001 |
| HbA1c | -0.18 | 0.161 | -0.701 | <0.0001 |
| FSI | -0.408 | 0.001 | -0.279 | 0.031 |
| TAS | -0.245 | 0.168 | -0.006 | 0.961 |
| AIP | -0.152 | 0.258 | -0.013 | 0.924 |
HOMA-IR: Homeostasis model assessment of insulin resistance, WC: waist circumference, BMI: Body mass index, PBF: Percentage body fat, FBS: Fasting blood sugar, HbA1c: Glycated hemoglobin, FSI: Fasting serum insulin, TAS: Total antioxidant status, AIP: Atherogenic index of plasma, eGDR: Estimated glucose disposal rate, T2DM: Type 2 diabetes mellitus. p-value <0.05 was considered statistically significant.
DISCUSSION
IR has long been linked with DM and has been documented to precede the development of clinical signs and symptoms of T2DM.6 Studies have also demonstrated the presence of IR in patients with T1DM, a phenomenon known as double diabetes.2 There are numerous physical and biochemical surrogate markers to assess IR in clinical practice. The presence of acanthosis, C-peptide levels, and HOMA-IR are the most commonly used surrogate clinical markers of IR in T2DM patients, while eGDR is an established marker of IR in T1DM patients. eGDR has also been shown to have a strong link to the development of complications in T1DM patients.16 A study17 has reported increased morbidity and mortality risk associated with low eGDR in patients of T2DM; however, the validity of its use in patients of T2DM is yet to be ascertained.
Although HOMA-IR suffers from various drawbacks (as listed below), since it is the most widely used surrogate marker of IR, we performed a correlational analysis between HOMA1-IR and eGDR/eGDRBMI. We report a significant negative correlation between HOMA-1R and eGDR/eGDRBMI. Correlation analysis also revealed a negative correlation between eGDR/eGDRBMI and FBS, HbA1c, BMI, and PBF. This reinforces the presence of higher IR associated with hyperglycemia and obesity. eGDR/eGDRBMI also had a non-significant negative association with AIP and TAS, signifying that higher IR is associated with increased cardiovascular risk and oxidative stress, both linked to T2DM complications.
HOMA1-IR is the most widely used surrogate marker of IR in routine clinical practice, as it is calculated using a single value of fasting serum insulin and fasting plasma glucose. However, it suffers from certain drawbacks, which are frequently overlooked. First and foremost, the original model was computed using the mean of three samples taken at an interval of 5 minutes because both blood insulin and glucose values are known to change over short time periods.13 Preanalytical factors, such as the presence of hemolysis, lipemia, and inappropriate storage conditions, can affect insulin levels, thus resulting in false values.18 The HOMA1 model was designed on insulin levels assayed via the radioimmunoassay technique. Currently, insulin levels are primarily measured via immunoassay. Insulin levels can also be estimated via ELISA, the type of assay to be used while computing HOMA-IR values, which results in inter-assay variation19 in results obtained (based on the method of estimation) while comparing patient reports.
eGDR, on the other hand, takes into account both physical and biochemical parameters for which standard guidelines exist. The international standardization of the HbA1c assay makes eGDR free of the drawbacks of the HOMA-IR model with respect to insulin level estimation. In addition, the use of HbA1c negates the effect of preanalytical factors and the need for repeated sampling (glucose & insulin) as is required for HOMA-IR.
A study20 has cautioned against the use of HOMA-IR in the presence of factors influencing insulin sensitivity (increased resting metabolic rate, total lean body mass) and secretion (low beta cell mass), as these are also known to affect HOMA-IR values. Another study21 has questioned the validity of the use of HOMA-IR in patients with high values of plasma glucose (uncontrolled diabetes) or insulin secretory defects. Therefore, if we calculate IR in lean patients of T2DM using the HOMA-IR model, it may not reflect the true level of IR. eGDR, on the other hand, has been standardized in patients with T1DM who tend to have a low BMI with the presence of insulin secretory defects and, therefore, is relatively free of these factors compared to HOMA-IR.
HOMA-IR is also not a good predictor of IR compared to the clamp method in older patients suffering from T2DM and in those with impaired glucose tolerance.22,23 This has been attributed to declining glucose tolerance with advancing age.24-26 eGDR, on the other hand, has been shown to be a reliable marker in these patients.
Another limitation is the absence of accurate thresholds or cut-off points of HOMA-IR.27-29 A universal cut-off is not feasible due to the presence of ethnic and sex variations27, and an increase in HOMA-IR values with sexual maturity.30 eGDR may suffer from the same problem and needs to be validated.
Another disadvantage of HOMA-IR is that its use in those receiving exogenous insulin and oral hypoglycemic agents is not advised due to a lack of validation studies.14 eGDR has been standardized in patients of T1DM who are on exogenous inulin and, therefore, eGDR could serve as a marker of IR in this set of patients.
eGDR was tailor-made to measure IR in patients with T1DM. These patients tend to be on the leaner side and devoid of complications associated with obesity. Therefore, the parameters might require modification before being applied to patients with T2DM. For example, eGDR/eGDRBMI is calculated using the WC/BMI of an individual and the presence/absence of hypertension alongside a few numerical adjustment factors. The majority of patients with T2DM tend to be obese and suffer from metabolic syndrome. Therefore, it would be scientifically unsound to apply the formula adapted for lean patients to these patients, as it would overestimate these variables. This calls for the further exploration of eGDR in these individuals and the modification of the formula to address the possible confounders.
Limitations of the study
The present study was done with a limited sample size and did not include healthy euglycemic controls. In all subjects, the HOMA-IR score was calculated based on a single value of blood glucose and insulin level collected at the same time point. True IR via the clamp method was not checked. Also, the study did not include patients of T2DM with normal BMI (18.51-24.99 Kg/m2) and therefore data on IR in this group is missing. The formula for eGDR was formulated using parameters signifying IR in T1DM, and these parameters may not signify IR in T2DM patients. Therefore, the formula may have to be modified when used in T2DM patients.
Clinical implication and future prospects
This is the first study done comparing IR using eGDR in newly diagnosed patients of T2DM prior to initiation of therapy. eGDR is a promising marker of IR in T2DM and needs to be explored further
CONCLUSION
Although our study reports a significant negative correlation between eGDR and HOMA-IR, the use of eGDR as a surrogate marker instead of HOMA-IR needs to be validated, and necessary modifications need to be made prior to its use in patients with T2DM.
Authors’ contributions
EAA: Concept, design, definition of intellectual content, literature search, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation and editing; MM: Concept, design, definition of intellectual content, literature search, clinical studies, data acquisition, data analysis, statistical analysis, manuscript review and editing; SVM: Concept, design, definition of intellectual content, literature search, clinical studies, data acquisition, data analysis, statistical and manuscript review; RK: Concept, design, definition of intellectual content, clinical studies, data acquisition, data analysis, statistical analysis, manuscript editing and review; SPK: Literature search, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation and editing.
Ethical approval
The research/study was approved by the Institutional Ethical Committee-Human Research of University College of Medical Sciences, number IEC-HR/2019/41/25, dated 16th October 2019.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent.
Financial support and sponsorship
Nil.
Conflicts of interest
Dr. Rajarshi Kar is on the Editorial Board of the journal.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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