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

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], = 0.00007) in sample 1; rs13306393 was also associated with prediabetes (1.67 [1.05-2.65], = 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], = 0.005), prediabetes (1.83 [1.33-2.54], = 0.0003) or IGR (1.68 [1.26-2.25], = 0.0004), insulin resistance estimated by HOMA (β = 0.043, = 0.001), HbA (β = 0.029, = 0.029), and urinary albumin excretion (β = 0.033, = 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.