ObjectiveType 2 diabetes mellitus (T2DM) is a chronic disorder characterized by pancreatic beta-cell dysfunction and insulin resistance because of unsettled hyperglycemia. The present study was designed to understand the association of genetic variations in SLC30A8 and GLIS3 genes with T2DM. MethodA total of 600 samples were taken with 400 T2DM cases (240 males and 160 females; mean age 42.4 ± 9.3) and 200 control cases (130 males and 70 females; mean age 40.7 ± 8.2) in the study from regions across North India. A genetic study was conducted by PCR-RFLP methods. P parametric and non-parametric tests were used to analyze the data based on the qualitative and quantitative data. ResultsSignificant difference was found in biochemical parameters and sedentary lifestyle compared between T2DM patients and healthy controls such as triglycerides, HbA1c, T-cholesterol, LDL-C, BMI, systolic and diastolic BP, PPG, FPG, weight loss, fatigue, slow wound healing, blur vision, urination, appetite, urination, consumption of alcohol, non-veg, fast food and sugary drink, excessive consumption of calorie, normal and brisk (20 min) walk, prolonged sitting 3 h work, leisure sitting (3 h) and standing work (3 h) while no significant differences were observed in parameters such as HDLC, WHR, family history, household chores and exercise among T2DM patients and controls. In SLC30A8 rs13266634 variant, it was observed that TC and CC genotypes frequencies were significantly higher in T2DM cases as compared to healthy controls (OR- 2.88; 95%CI- 1.93–4.31; p < 0.0001 and OR- 5.6; 95%CI- 2.33–13.55; p = 0.0001). C allele frequency was higher as compared to healthy controls. For the GLIS3 rs7034200 variant, no significant difference was found in allelic frequency in cases and controls (p-0.434). We did not find any significant association of T2DM with GLIS3 gene variant under dominant as well as recessive models. ConclusionPresent study concludes that the association of genetic variations between T2DM cases and control was found to have a significant difference and play a vital role in T2DM risk based on odds ratio. However, the difference in frequency of alleles in the GLIS3 variant was non-significant among T2DM patients and healthy controls.