Konkuk University Medical Center Research Team Identifies Mechanism of Genetic Variant Increasing Diabetes Risk

14-Year Follow-Up of 4,242 Koreans

Researchers in Korea have identified the mechanism of action behind a genetic variant that is relatively common among East Asians, including Koreans, and significantly increases the risk of type 2 diabetes.

A joint research team from Konkuk University Medical Center, KAIST, Seoul National University, and Seoul National University Hospital announced on the 24th that they have confirmed the PAX4 R192H variant increases the risk of type 2 diabetes by impairing pancreatic beta cell identity and their ability to compensate for metabolic stress. PAX4 R192H is a variant that, to date, has only been observed in East Asian populations and is present in more than 10% of individuals from this group, including Koreans.

Kyungsoo Park, Professor of Endocrinology and Metabolism at Konkuk University Hospital. Konkuk University Hospital

PAX4 is a transcription factor involved in the development and maintenance of pancreatic beta cell function. The research team engineered genetically modified mice with the R192H variant, in which the 192nd amino acid of the PAX4 protein is substituted from arginine to histidine, and analyzed their metabolic function and gene expression.

The mice with this variant exhibited normal pancreatic endocrine cell development, but when subjected to metabolic stress through a high-fat diet, they showed decreased glucose handling and impaired insulin secretion. Endoplasmic reticulum stress increased, and gene expression related to maintaining mature beta cell characteristics decreased. In contrast, gene expression associated with beta cell dedifferentiation and alpha cell characteristics increased. This indicates the R192H variant impairs the adaptive and compensatory capabilities of beta cells under increased metabolic stress.

The same tendency was found in long-term follow-up data from Koreans. The researchers analyzed data from 4,242 participants with normal glucose tolerance from the Ansung and Ansan cohorts who were tracked over 14 years. They found that individuals with the PAX4 R192H variant experienced a roughly 1.4-fold faster decline in the index reflecting beta cell function compared to non-carriers. Notably, among those with higher body mass index, the risk of type 2 diabetes was even greater for variant carriers.

The research team explained that these results not only show a statistical association between PAX4 R192H and diabetes, but also present the specific biological mechanism by which the variant impairs beta cell identity and compensatory capacity in situations of obesity and metabolic stress.

Kyungsoo Park, Professor of Endocrinology and Metabolism at Konkuk University Medical Center, said, "Individuals with the PAX4 R192H variant may be particularly vulnerable to weight gain and metabolic stress. These findings could be used to guide early screening based on genetic risk, weight management, lifestyle interventions, and the development of tailored strategies to prevent diabetes in the future." The study was recently published in the international journal Genome Medicine.

This content was produced with the assistance of AI translation services.