Researchers identify mechanism of diabetes-linked PAX4 R192H variant

A joint research team from Konkuk University Medical Center, KAIST, Seoul National University, and Seoul National University Hospital has identified the biological mechanism behind the PAX4 R192H genetic variant, which significantly increases the risk of type 2 diabetes in East Asians.

The PAX4 R192H variant is relatively common in East Asian populations, with a frequency of approximately 10%. Unlike many other common diabetes-related variants that only slightly increase risk, this specific mutation has a notably high impact. The study, published in the journal Genome Medicine, reveals that the variant impairs the identity and compensatory capacity of pancreatic beta cells when facing metabolic stress.

Using genetically modified mice, researchers found that while endocrine cell development appeared normal, high-fat diets led to a sharp decline in glucose processing and insulin secretion. In human subjects, a 14-year longitudinal study of 4,242 individuals showed that those with the PAX4 R192H variant experienced a 1.4 times faster decline in beta-cell function indicators compared to non-carriers. The risk of type 2 diabetes was found to increase even more significantly as body mass index (BMI) rose. This research provides critical insights into why East Asians may develop type 2 diabetes at lower BMIs compared to Western populations and could aid in developing personalized prevention strategies.