IMPE Abstracts

Introduction: Diabetes represents a heterogeneous group of metabolic disorders, and monogenic diabetes is thought to affect 1- 5% of the pediatric diabetes population. Monogenic diabetes, typically presenting without autoimmune antibodies, causes neonatal diabetes, maturity-onset diabetes of the young (MODY), and syndromic diabetes. The study aimed to gain insight into the gene regulation pathways altered in MODY diabetes following a meal.

Methods: We performed a standard mixed-meal test and measured glucose and C-peptide levels at different time points in children, young adults with MODY, and antibody-negative diabetes as well as healthy controls. We assessed the RNA-expression profile before the meal and 120 min after the meal. We analyzed the RNA sequencing results using the gencode software.

Results: In the 73 patients with MODY or antibody-negative diabetes (< 18 years old, n=43; young adults ≥ 18 – 25 years old, n=30) and ten healthy controls, we identified eight transcripts (GPR27, PROK2, PER1, S100A8, S100A9, TGFA, ENSG00000260467, and MCEMP1) that were concordant in their differential regulation in all participants. These transcripts can be considered meal-response genes. In the younger group, 200 genes were up- and 11 down-regulated. In the older age group, 311 genes were up- and 24 down-regulated. The following genes were most significantly upregulated in both groups: ALAS1, MTARC1, CDC42EP3, FASTKD5, RHOB, and LMO2. Functional enrichment analysis showed the involvement of the cytokine production, the Toll-like receptor binding, icosanoid binding, long-chain fatty acid binding, and receptor for advanced glycation end products (RAGE) pathways. The analysis of biological processes showed upregulation of immune response, inflammatory response, and defense response pathways.

Conclusion: This study identified the meal-induced transcriptional response in young individuals with monogenic and antibody-negative diabetes. We revealed pathways that regulate insulin secretion, beta-cell mass maintenance, and inflammation.