STK11 rs2075604 Polymorphism Is Associated with Metformin Efficacy in Chinese Type 2 Diabetes Mellitus

Qingchu Li, Cuilin Li, Haoyun Li, Liu Zeng, Zhiqiang Kang, Yu Mao, Xinyue Tang, Panpan Zheng, Li He, Fang Luo, Zhi Li, Qingchu Li, Cuilin Li, Haoyun Li, Liu Zeng, Zhiqiang Kang, Yu Mao, Xinyue Tang, Panpan Zheng, Li He, Fang Luo, Zhi Li

Abstract

Metformin is a classical oral antidiabetic drug, often recommended to be the first-choice treatment of type 2 diabetes mellitus (T2DM). Based on the previous research on STK11 and diabetes, we aimed to investigate the distributive characteristic of STK11 rs2075604 polymorphism and the potential influence of STK11 rs2075604 polymorphism on metformin efficacy among Chinese T2DM patients. There was no significant difference between T2DM patients (G = 64.8%, T = 35.2%) and healthy subjects (G = 62.7%, T = 37.2%) in STK11 rs2075604 genotype and allele frequencies. After 12 weeks of treatment, 62 patients were defined as the responders and 32 patients as nonresponders according to the decrease of HbA1c level. And the GT + TT genotype in STK11 rs2075604 can decrease HbA1c level more significantly than the GG genotype. Furthermore, the allele frequency of T in the STK11 rs2075604 was higher in the responders than the nonresponders (43.55% versus 26.56%). The T allele in the STK11 rs2075604 had a 2.133 times great chance of responding to metformin treatment. In conclusion, this study suggested that the STK11 rs2075604 genetic polymorphism was significantly associated with metformin efficacy in Chinese T2DM patients and the carriers of the T allele may gain a better therapeutic metformin efficacy compared with the G allele. This trial is registered with clinical study registration number NCT03155087.

Figures

Figure 1
Figure 1
The decreased level of HbA1c in T2DM patients with different STK11 rs2075604 genotypes after metformin treatment. Data are shown as mean ± SD. ∗P < 0.05 compared with the GG genotype group (n = 94).
Figure 2
Figure 2
The decreased level of FBG in T2DM patients with different STK11 rs2075604 genotypes after metformin treatment. Data are shown as mean ± SD. ∗P < 0.05 compared with the GG genotype group (n = 94).

References

    1. Graham G. G., Punt J., Arora M., et al. Clinical pharmacokinetics of metformin. Clinical Pharmacokinetics. 2011;50:81–98.
    1. Zhou G., Myers R., Li Y., et al. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of Clinical Investigation. 2001;108:1167–1174.
    1. Duca F. A., Cote C. D., Rasmussen B. A., et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nature Medicine. 2015;21:506–511.
    1. U.P.D.S. Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet. 1998;352:854–865.
    1. Tarasova L., Kalnina I., Geldnere K., et al. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenetics and Genomics. 2012;22:659–666.
    1. Xiao D., Guo Y., Li X., et al. The impacts of SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms on metformin therapeutic efficacy in Chinese type 2 diabetes patients. International Journal of Endocrinology. 2016;2016:7.4350712
    1. Umamaheswaran G., Praveen R. G., Damodaran S. E., Das A. K., Adithan C. Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients. Clinical and Experimental Medicine. 2015;15:511–517.
    1. Mahrooz A., Parsanasab H., Hashemi-Soteh M. B., et al. The role of clinical response to metformin in patients newly diagnosed with type 2 diabetes: a monotherapy study. Clinical and Experimental Medicine. 2015;15:159–165.
    1. Xiao D., Zhang S., Li X., et al. IL-1B rs1143623 and EEF1A1P11-RPL7P9 rs10783050 polymorphisms affect the glucose-lowing efficacy of metformin in Chinese overweight or obese type 2 diabetes mellitus patients. Pharmacogenomics. 2015;16:1621–1629.
    1. Woods A., Johnstone S. R., Dickerson K., et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Current Biology. 2003;13:2004–2008.
    1. Legro R. S., Barnhart H. X., Schlaff W. D., et al. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. The Journal of Clinical Endocrinology and Metabolism. 2008;93:792–800.
    1. Bassols J., Megia A., Soriano-Rodriguez P., et al. A common gene variant in STK11 is associated with metabolic risk markers and diabetes during gestation. Fertility and Sterility. 2013;100:788–792.
    1. Shaw R. J., Lamia K. A., Vasquez D., et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–1646.
    1. Bennett P. H. Impact of the new WHO classification and diagnostic criteria. Diabetes, Obesity & Metabolism. 1999;1(Supplement 2):S1–S6.
    1. WHO. Global Report on Diabetes. Switzerland: WHO Press; 2016.
    1. Weng J. Evolution in the Chinese diabetes society standards of care for type 2 diabetes. Diabetes/Metabolism Research and Reviews. 2016;32:440–441.
    1. Chamberlain J. J., Rhinehart A. S., Shaefer C. J., Neuman A. Diagnosis and management of diabetes: synopsis of the 2016 American Diabetes Association Standards of Medical Care in Diabetes. Annals of Internal Medicine. 2016;164:542–552.
    1. Kone M., Pullen T. J., Sun G., et al. LKB1 and AMPK differentially regulate pancreatic beta-cell identity. The FASEB Journal. 2014;28:4972–4985.
    1. Bang S., Chen Y., Ahima R. S., Kim S. F. Convergence of IPMK and LKB1-AMPK signaling pathways on metformin action. Molecular Endocrinology. 2014;28:1186–1193.
    1. Shan T., Zhang P., Bi P., Kuang S. Lkb1 deletion promotes ectopic lipid accumulation in muscle progenitor cells and mature muscles. Journal of Cellular Physiology. 2015;230:1033–1041.
    1. Hardie D. G., Alessi D. R. LKB1 and AMPK and the cancer-metabolism link - ten years after. BMC Biology. 2013;11:p. 36.
    1. Russo G. L., Russo M., Ungaro P. AMP-activated protein kinase: a target for old drugs against diabetes and cancer. Biochemical Pharmacology. 2013;86:339–350.
    1. Lopez-Bermejo A., Diaz M., Moran E., Zegher F., Ibáñez L. A single nucleotide polymorphism in STK11 influences insulin sensitivity and metformin efficacy in hyperinsulinemic girls with androgen excess. Diabetes Care. 2010;33:1544–1548.

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