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A Low Frequency Genetic Variant in the Hepatic Glucokinase Gene is Associated with Type 2 Diabetes and Insulin Resistance in Chinese Population

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posted on 2020-12-10, 18:10 authored by Ada AdminAda Admin, Yumin Ma, Yingying Luo, Siqian Gong, Xianghai Zhou, Yufeng Li, Wei Liu, Simin Zhang, Xiaoling Cai, Qian Ren, Lingli Zhou, Xiuying Zhang, Yanai Wang, Xiuting Huang, Xueying Gao, Mengdie Hu, Xueyao Han, Linong Ji

Glucokinase (GCK) regulates insulin secretion and hepatic glucose metabolism, its inactivating variants could cause diabetes. We aimed to evaluate the association of a low-frequency variant of GCK (rs13306393) with type 2 diabetes (T2DM), prediabetes or both (IGR) in Chinese population. An association study was firstly conducted in a random cluster sampling population (Samples 1, 537 T2DM, 768 prediabetes and 1912 controls), then another independent Samples 2 (3896 T2DM, 2301 prediabetes and 868 controls) was used to confirm the findings in Samples 1. A-allele of rs13306393 was associated with T2DM [OR 3.08 (95%CI 1.77-5.36), p=0.00007] in Samples 1. Rs13306393 was also associated with prediabetes [OR 1.67 (95%CI 1.05-2.65), p=0.03] in Samples 2. In pooled analysis of two samples, A-allele increased the risk of T2DM [OR1.57 (95%CI 1.15-2.15), p=0.005], prediabetes [OR 1.83 (95%CI 1.33-2.54), p=0.0003) or IGR [OR 1.68 (95% CI 1.26-2.25), p=0.0004], insulin resistance estimated by homeostasis model assessment (beta=0.043, p=0.001), HbA1c (beta=0.029, P=0.029) and urinary albumin excretion (beta=0.033, p=0.025) irrespective of age, gender and BMI. Thus, the Chinese specific low-frequency variant increased the risk of T2DM through reducing insulin sensitivity rather than islet beta cell function, which should be considered in clinical use of GCK activators in the future.