Low-Frequency Genetic Variant in the Hepatic Glucokinase Gene Is Associated With Type 2 Diabetes and Insulin Resistance in Chinese Population

Abstract

Glucokinase (GCK) regulates insulin secretion and hepatic glucose metabolism, and its inactivating variants could cause diabetes. We aimed to evaluate the association of a low-frequency variant of GCK (rs13306393) with type 2 diabetes (T2D), prediabetes, or both (impaired glucose regulation [IGR]) in a Chinese population. An association study was first conducted in a random cluster sampling population (sample 1: 537 T2D, 768 prediabetes, and 1,912 control), and then another independent population (sample 2: 3,896 T2D, 2,301 prediabetes, and 868 control) was used to confirm the findings in sample 1. The A allele of rs13306393 was associated with T2D (odds ratio 3.08 [95% CI 1.77–5.36], P = 0.00007) in sample 1; rs13306393 was also associated with prediabetes (1.67 [1.05–2.65], P = 0.03) in sample 2. In a pooled analysis of the two samples, the A allele increased the risk of T2D (1.57 [1.15–2.15], P = 0.005), prediabetes (1.83 [1.33–2.54], P = 0.0003) or IGR (1.68 [1.26–2.25], P = 0.0004), insulin resistance estimated by HOMA (β = 0.043, P = 0.001), HbA_1c (β = 0.029, P = 0.029), and urinary albumin excretion (β = 0.033, P = 0.025), irrespective of age, sex, and BMI. Thus, the Chinese-specific low-frequency variant increased the risk of T2D through reducing insulin sensitivity rather than islet β-cell function, which should be considered in the clinical use of GCK activators in the future.