Endocrine Abstracts

JOINT1391

Background & aim: It is unclear which genes causing congenital hyperinsulinism (HI) can also cause diabetes later in life due to possible beta-cell exhaustion from excess insulin secretion. To test this, we screened for pathogenic variants in the three most common dominant HI genes in a large cohort of individuals with diabetes referred for MODY testing and in a large population cohort.

Methods: We examined dominantly acting pathogenic HI-causing variants in ABCC8, GCK, GLUD1 in 2,413 individuals with early-onset diabetes (<40 y) referred for MODY genetic testing. We repeated the analyses in 24,203 individuals with late-onset diabetes from the UK Biobank (UKB). We examined enrichment of pathogenic variants in these cohorts compared to total of 395,625 controls.

Results : We did not find pathogenic HI-causing GCK or GLUD1 variants in individuals with early- or late-onset diabetes, suggesting these etiologies do not increase diabetes risk. In contrast we found a significant enrichment of dominant ABCC8 HI variants in the MODY cohort compared to control population (odds ratio 43, 95%CI 4–375, P=0.0023). The phenotype of the 9 individuals with diabetes and a dominant ABCC8 HI variant in MODY cohort was not suggestive of type 1 or 2 diabetes and they lacked pathogenic variants in all known monogenic diabetes genes. They were diagnosed at median age of 16 years [IQR, 12.5;16.0]. All were negative for islet auto-antibodies and had low Type 1 diabetes Genetic Risk Score (<15thcentile). Their median BMI was 26.7 kg/m², seven (78%) had family history of diabetes, and only 2 (22%) neonatal-HI. A dominant ABCC8 HI variant was detected in only 1 of 24,203 individuals with diabetes in the UKB.

Conclusion: Our results suggest that dominant loss-of-function HI variants can cause diabetes later in life but this is limited only to the ABCC8 gene. Although further understanding is needed about treatment, these variants should be screened to determine the aetiology of early-onset diabetes.