Background: CDKAL1 gene encodes the cyclin-dependent kinase 5, an enzyme which inhibits the Ca2+ efflux from the pancreatic beta cell and facilitates insulin secretion. The rs7756992 polymorphism of this gene has been associated with variability in sulphonylurea response. Aim: In this study, we investigated the association between CDKAL1 rs7756992 gene polymorphism and secondary sulphonylurea failure in Malaysian Type 2 Diabetes population. Method: This cross-sectional study conducted at seven outpatient clinics across Malaysia from September 2014 to March 2016 recruited 128 patients receiving maximal doses of sulphonylurea in combination with metformin for more than a year. Their demographic and clinical information was obtained from medical records while the glycemic parameters were measured using fasting blood samples. Blood samples were also taken to extract their DNA for genotyping which was performed using Taqman genotyping assay (Applied Biosystems, U.S). Homeostatic model assessment of insulin secretion (HOMA2B) and insulin resistance (HOMA2IR) was also calculated. Secondary sulphonylurea failure was defined as HbA1c > 7.0%. Results: A total of 31 (24.2%) of the recruited subjects were wildtype homozygotes (AA) while 66 (51.6%) and 31 (24.2%) subjects were AG heterozygotes and GG homozygotes respectively. The population was in Hardy-Weinberg Equilibrium (HWE) (X2 = 0.125, p = 0.7237). They consisted of 53 males (41.4%) and 75 females (58.6%) with a mean age of 60.2 ± 8.7 years and a mean diabetes duration of 8.7 ± 2.5 years. The subjects showed poorly controlled diabetes with a mean fasting plasma glucose (FPG) of 9.0 ± 3.5 mmol/L and mean HbA1c of 8.7 ± 1.9% (71.6 ± 15.6 mmol/mol). Their mean fasting plasma insulin was 11.0 ± 7.1 mU/L and mean fasting c-peptide was 2.7 ± 1.4 ng/mL. They also had about a half of pancreatic beta cell function with a mean HOMA2B of 49.6 ± 43.5% and a mean HOMA2IR of 1.7 ± 1.3. Carriers of the risk allele, G had about 2.5 times significantly increased odds for poor glycemic control (HbA1c > 7.0%) than A-allele carriers (OR = 2.448, 95% CI: 1.336 – 4.387, p = 0.004). Discussion: Previous studies have associated sulphonylurea response with rs7756992 polymorphism as the sulphonylurea mechanism of insulin secretion also involves Ca2+ influx in which the CDKAL1 gene plays an important role. The finding of our study is in agreement with a study in Caucasians which showed that the AG and GG heterozygotes for the risk allele, G had a significantly higher mean FPG indicating poor glycemic control. In conclusion, it is evident that harbouring the risk allele, G for the CDKAL1 rs7756992 gene polymorphism increases the risk of secondary sulphonylurea failure in Malaysian Type 2 Diabetes patients.

CDKAL1 rs7756992 gene polymorphism increases risk of sulphonylurea failure in Malaysian type 2 diabetes patients