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

Diabetes. 2021 Mar;70(3):809-816. doi: 10.2337/db20-0564. Epub 2020 Dec 9.

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), HbA1c (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / metabolism
  • China
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Exons / genetics
  • Genetic Variation / genetics
  • Genetic Variation / physiology
  • Glucokinase / metabolism
  • Glucose Tolerance Test
  • Humans
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Insulin Secretion / genetics
  • Insulin Secretion / physiology
  • Liver / metabolism*
  • Middle Aged
  • Plasmids / genetics
  • Prediabetic State / genetics
  • Promoter Regions, Genetic / genetics

Substances

  • Blood Glucose
  • Glucokinase

Associated data

  • figshare/10.2337/figshare.13344425