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

<a>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.</a>