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Background: Growth differentiation factor-15 (GDF-15) is involved in insulin resistance and diabetes. In this study, we determine the associations of GDF-15 with miR-181b-5p, miR-330-3p, mothers against decapentaplegic homolog 7 (SMAD7), and insulin resistance in visceral adipose tissue (VAT) and peripheral blood mononuclear cells (PBMCs) in type 2 diabetes mellitus (T2DM) patients. Methods: Sixty patients, equally divided into those with T2DM and non-diabetic controls, were recruited for gene expression analysis. Protein-protein interaction (STRING), target prediction (miRNet), and functional enrichment were conducted accordingly. Results: Our study showed that VAT and PBMCs had similar expression profiles, where GDF-15 and miR-181b-5p were upregulated, whereas SMAD7 and miR-330-3p were downregulated. Serum GDF-15 could differentiate between T2DM and non-diabetic patients (P<0.001). Target prediction revealed a microRNA (miRNA)-messenger RNA regulatory network, transcription factors, and functional enrichment for the miRNA that suggested involvement in T2DM pathogenesis. Conclusion: VAT GDF-15 is associated with insulin resistance and is possibly regulated by miR-181b-5p, miR-330-3p, and SMAD7 in T2DM.
RESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM) is an ever-growing epidemic in India and poses significant morbidity, mortality, and socioeconomic burden. INTRODUCTION: Growth differentiation factor-15 (GDF15) is a stress-responsive cytokine, increased in T2DM patients compared to control subjects without the disease. We aimed to assess whether serum GDF15 and adipose tissue GDF15 expression can differentiate between obese pre-diabetes and T2DM and control populations. METHODOLOGY: We recruited 156 individuals including 73 type 2 diabetes, 30 pre-diabetes, and 53 healthy controls. Clinical history, anthropometric measurements and biochemical profiling were taken. Insulin resistance indices were calculated following HOMA models. Serum GDF15 was measured by sandwich ELISA. Visceral adipose tissue (VAT) expression of GDF15 was observed in 17 T2DM patients and 29 controls using SYBR Green chemistry in RT-PCR using GAPDH as the housekeeping gene. The data were analyzed on R programming platform using RStudio. RESULTS: Serum GDF15 was significantly higher (p<0.001) in T2DM subjects (median 1445.47 pg/mL) compared to pre-diabetes (627.85 pg/mL) and healthy controls (609.01 pg/mL). Using the ΔΔCt method, the VAT GDF15 expression was 1.54 fold and 1.57 fold upregulated in T2DM (n=17) compared to control subjects (n=29), and obese (n=12) compared to non-obese (n=34)subjects, respectively. The optimal cut-off point following Youden's index method was found to be 868.09 pg/mL. ROC curve analysis revealed that serum GDF15 had a sensitivity, specificity, and area under the curve (AUC) of 90.41%, 79.52%, and 0.892 respectively. GDF15 levels were significantly associated with age, BMI, HbA1c, fasting blood sugar, and insulin resistance indices. CONCLUSION: Hence, serum GDF15 is a biomarker for T2DM patients in our study population from Western India. However, larger prospective cohorts are necessary to validate this claim.
