Pharmacogenomics of Sulfonylureas Response in Relation to rs7754840 Polymorphisms in Cyclin-Dependent Kinase 5 Regulatory Subunit-associated Protein 1-like (CDKAL1) Gene in Iranian Type 2 Diabetes Patients

Document Type : Original Article


1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Tehran, Iran

2 Iranian Blood Transfusion Organization Research Centre, Tehran, Iran

3 Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Sulfonylureas are important drugs of choice for treatment of type 2 diabetes mellitus (T2DM). It is suggested that differential response to sulfonylureas from T2DM patients is under influence of single nucleotide polymorphisms in some of the target genes. In spite of favorable therapeutic effects, sulfonylureas are associated with some adverse side effects such as microvascular complications and stroke, especially in older patients. Therefore, for T2DM patients who are getting less benefit, sulfonylureas should be avoided. Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like (CDKAL1) gene variation is reported to be associated with sulfonylureas effectiveness. Due to the inconsistency of available data regarding association of rs7754840 in CDKAL1 gene with sulfonylureas response in T2DM patients, the present study is conducted. Materials and Methods: Fifty-one diabetic patients sensitive to sulfonylureas and 51 patients resistant to sulfonylureas treatment were recruited to this study. After extraction of DNA from patients' peripheral blood samples, rs7754840 single-nucleotide polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism assay using MaeII (Tail) restriction enzyme. Results: Frequency of G allele in resistant group was more than sensitive group (71, 6% vs. 57, 8%). Regression analysis was shown significant association between GG genotype and higher risk of resistance to sulfonylureas treatment (odds ratio = 2.250 [95% confidential intervals: 1.010–5.012]; P = 0.046). Conclusion: Our data confirmed that genotypes of rs7754840 are significantly associated with sulfonylureas treatment response. rs7754840 in CDKAL1 gene in combination with other clinicopathological findings would help to move towards personalized therapy of T2DM patients.


Kong AP, Luk AO, Chan JC. Detecting people at high risk of type 2 diabetes- how do we find them and who should be treated? Best Pract Res Clin Endocrinol Metab 2016;30:345-55.  Back to cited text no. 1
Bain SC, Feher M, Russell-Jones D, Khunti K. Management of type 2 diabetes: The current situation and key opportunities to improve care in the UK. Diabetes Obes Metab 2016;18:1157-66.  Back to cited text no. 2
Yang Y, Wang Y, Zhou K, Hong A. Constructing regulatory networks to identify biomarkers for insulin resistance. Gene 2014;539:68-74.  Back to cited text no. 3
Wheeler E, Barroso I. Genome-wide association studies and type 2 diabetes. Brief Funct Genomics 2011;10:52-60.  Back to cited text no. 4
Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: The last ten years. Cell 2012;148:1160-71.  Back to cited text no. 5
Cefalu WT. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: Rationale and specific agents. Clin Pharmacol Ther 2007;81:636-49.  Back to cited text no. 6
El-Sisi AE, Hegazy SK, Metwally SS, Wafa AM, Dawood NA. Effect of genetic polymorphisms on the development of secondary failure to sulfonylurea in Egyptian patients with type 2 diabetes. Ther Adv Endocrinol Metab 2011;2:155-64.  Back to cited text no. 7
McTaggart JS, Clark RH, Ashcroft FM. The role of the KATP channel in glucose homeostasis in health and disease: More than meets the islet. J Physiol 2010;588:3201-9.  Back to cited text no. 8
Holden SE, Currie CJ. Mortality risk with sulphonylureas compared to metformin. Diabetes Obes Metab 2014;16:885-90.  Back to cited text no. 9
Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: Systematic review and meta-analysis. Diabet Med 2013;30:1160-71.  Back to cited text no. 10
Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: A meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:938-53.  Back to cited text no. 11
Miller M, Knatterud G, Hawkins BS. A study of the effects of hypoglycemic agents on vascular complications in patients with adult onset diabetes. VI. Supplementary report on nonfatal events in patients treated with tolbutamide. Diabetes 1976;25:1129-53.  Back to cited text no. 12
Schroner Z, Javorský M, Halušková J, Klimčáková L, Babjaková E, Fabianová M, et al. Variation in CDKAL1 gene is associated with therapeutic response to sulphonylureas. Physiol Res 2012;61:177-83.  Back to cited text no. 13
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-6.  Back to cited text no. 14
Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. Agenome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007;316:1341-5.  Back to cited text no. 15
Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, et al. Avariant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007;39:770-5.  Back to cited text no. 16
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007;316:1336-41.  Back to cited text no. 17
Takeuchi F, Serizawa M, Yamamoto K, Fujisawa T, Nakashima E, Ohnaka K, et al. Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 2009;58:1690-9.  Back to cited text no. 18
Ohara-Imaizumi M, Yoshida M, Aoyagi K, Saito T, Okamura T, Takenaka H, et al. Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. PLoS One 2010;5:e15553.  Back to cited text no. 19
Dehwah MA, Wang M, Huang QY. CDKAL1 and type 2 diabetes: A global meta-analysis. Genet Mol Res 2010;9:1109-20.  Back to cited text no. 20
Ubeda M, Rukstalis JM, Habener JF. Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J Biol Chem 2006;281:28858-64.  Back to cited text no. 21
Lew J, Huang QQ, Qi Z, Winkfein RJ, Aebersold R, Hunt T, et al. Abrain-specific activator of cyclin-dependent kinase 5. Nature 1994;371:423-6.  Back to cited text no. 22
Sim X, Ong RT, Suo C, Tay WT, Liu J, Ng DP, et al. Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia. PLoS Genet 2011;7:e1001363.  Back to cited text no. 23
Tuerxunyiming M, Mohemaiti P, Wufuer H, Tuheti A. Association of rs7754840 G/C polymorphisms in CDKAL1 with type 2 diabetes: A meta-analysis of 70141 subjects. Int J Clin Exp Med 2015;8:17392-405.  Back to cited text no. 24
Groenewoud MJ, Dekker JM, Fritsche A, Reiling E, Nijpels G, Heine RJ, et al. Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Diabetologia 2008;51:1659-63.  Back to cited text no. 25
Stancáková A, Pihlajamäki J, Kuusisto J, Stefan N, Fritsche A, Häring H, et al. Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance. J Clin Endocrinol Metab 2008;93:1924-30.  Back to cited text no. 26
Kirchhoff K, Machicao F, Haupt A, Schäfer SA, Tschritter O, Staiger H, et al. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 2008;51:597-601.  Back to cited text no. 27
Palmer ND, Goodarzi MO, Langefeld CD, Ziegler J, Norris JM, Haffner SM, et al. Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. Diabetes 2008;57:1093-100.  Back to cited text no. 28
Mansoori Y, Daraei A, Naghizadeh MM, Salehi R. Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population. Adv Biomed Res 2015;4:45.  Back to cited text no. 29
[PUBMED]  [Full text]  
Chistiakov DA, Potapov VA, Smetanina SA, Bel'chikova LN, Suplotova LA, Nosikov VV, et al. The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. Acta Diabetol 2011;48:227-35.  Back to cited text no. 30
Ren Q, Han X, Tang Y, Zhang X, Zou X, Cai X, et al. Search for genetic determinants of sulfonylurea efficacy in type 2 diabetic patients from China. Diabetologia 2014;57:746-53.  Back to cited text no. 31
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK prospective diabetes study (UKPDS) group. Lancet 1998;352:837-53.  Back to cited text no. 32
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.  Back to cited text no. 33
Reitman ML, Schadt EE. Pharmacogenetics of metformin response: A step in the path toward personalized medicine. J Clin Invest 2007;117:1226-9.  Back to cited text no. 34
Loganadan NK, Huri HZ, Vethakkan SR, Hussein Z. Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: Current evidence and challenges for clinical implementation. Pharmacogenomics J 2016;16:209-19.  Back to cited text no. 35
Sehra D, Sehra S, Sehra ST. Sulfonylureas: Do we need to introspect safety again? Expert Opin Drug Saf 2011;10:851-61.  Back to cited text no. 36
Nordin C. The case for hypoglycaemia as a proarrhythmic event: Basic and clinical evidence. Diabetologia 2010;53:1552-61.  Back to cited text no. 37
Holstein A, Egberts EH. Risk of hypoglycaemia with oral antidiabetic agents in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 2003;111:405-14.  Back to cited text no. 38
Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410-8.  Back to cited text no. 39
Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000;49:1751-60.  Back to cited text no. 40
Shimajiri Y, Yamana A, Morita S, Furuta H, Furuta M, Sanke T, et al. Kir6.2 E23K polymorphism is related to secondary failure of sulfonylureas in non-obese patients with type 2 diabetes. J Diabetes Investig 2013;4:445-9.  Back to cited text no. 41
Osada UN, Sunagawa H, Terauchi Y, Ueda S. A common susceptibility gene for type 2 diabetes is associated with drug response to a DPP-4 inhibitor: Pharmacogenomic cohort in Okinawa Japan. PLoS One 2016;11:e0154821.  Back to cited text no. 42