Gene expression profiling of selected genes (TLR4, PPARy2, TCF7L2 and IRS1) in type 2 diabetes mellitus malay subjects and their first degree relatives

Type 2 Diabetes Mellitus (T2DM) is known as a metabolic disorder which characterized by high level of blood sugar due to dysfunction of pancreatic beta cells or insulin resistance in insulin target tissues. International Diabetes Federation (IDF) has predicted that the number of people who suffering from the disease in the world will increase from 382 million in 2013 to 552 million by 2030. According to the National Health Morbidity Survey (NHMS) IV, prevalence of T2DM in Malaysia was 15.2% in 2011, which increased from 14.9% in the third survey despite health campaigns and efforts. Environmental risk factors such as sedentary lifestyle, dietary factors, smoking, and lack of physical activity in combination with genetic factors play important role in progression of T2DM. First-degree relatives (FDR) of Type 2 diabetic patients are at risk of developing the disease. The risk in offspring rises by two to four-fold with having a parent with T2DM and up to six-fold when both parents are affected. Thus; early diagnosis and prevention programme may lead to decrease the risk of T2DM. Recently, human genetic studies have reported several candidate genes such as peroxisome proliferator-activated receptor γ (PPARγ) and transcription factor 7-like 2 (TCF7L2) which substantially develop the risk of T2DM. In addition, Insulin receptor substrate1(IRS1) as another candidate gene is involved in insulin-stimulated signalling pathway in T2DM. Toll-like receptors (TLRs) are innate immune receptors which have showed to play important role in pathogenesis of T2DM, particularly TLR4. The main objective of this study was to determine expression pattern of selected genes (TLR4, PPARγ2, TCF7L2 and IRS1) among Malay T2DM subjects and their first degree relatives. The candidate genes were selected based on their known role in glucose homeostasis. A total of 15 T2DM, 15 first degree relatives of Type 2 diabetic patients and 15 healthy subjects as control group were recruited. The RNA was extracted from whole blood specimen by using a commercial extraction kits. Quantitative Real-Time PCR was used to amplify the target cDNA copies of RNA. Statistical analysis was performed by t-test; crosstabs and general linear model (Anova) through the SPSS statistical software and P≤0.05 were considered as significant. The gene expression analysis and relative expression in real-time PCR was performed by using REST software. The anthropomorphic value and the blood biochemical factors were evaluated as supplementary information. The fasting plasma glucose (P=0.000), HA1c (P=0.000) and systolic blood pressure (P=0.003) were significantly different between T2DM and control. Also there was a significant difference between T2DM and healthy subjects in term of HDL (P=0.000) and TG (P=0.000). However, LDL and cholesterol level of T2DM subjects were under control and not significantly different (P=0.201 and P=0.90 respectively) in comparison with control group. Regarding to the relatives of T2DM patients, significant difference was observed in FPG (P=0.000) and SBP (P=0.008). Gene expression pattern was determined in T2DM patients and their first degree relatives. Compared to controls, TLR4 gene was significantly upregulated in T2DM patients, while it downregulated in their FDR. We also showed that expression of IRS1 was significantly deceased (down regulated) in patients with T2DM compared with controls whereas altered expression in PPARγ2 and TCF7L2 genes were not found among T2DM and FDR compared with healthy individuals. In conclusion, the result from this study demonstrated that TLR4 and IRS1 might be involved in pathogenesis of T2DM and also altered expression of TLR4 in first degree relative of Type 2 diabetes is an important marker showing genetic predisposition to T2DM, and hence could be used as diagnostic tool in the prediction of T2DM in Malay subjects.

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