2477-P: Hepatic Metabolic Alterations and Alpha-Cell Hyperplasia in Mice Overexpressing a Zinc-Binding-Deficient Cry1 Mutant

Introduction and Objective: Mice overexpressing a zinc-binding-deficient CRY1 mutant (CRY1C414A; TG) develop a form of diabetes resembling MODY, characterized by β-cell loss associated with features of a cellular senescence. In TG islets, the α/β-cell ratio is increased, and intra-islet duct cells (IIDCs) increase with age. Notably, α-cell neogenesis and clusters of endocrine cells including α cells are observed within and adjacent to IIDC regions. To explore metabolic mechanisms potentially underlying α-cell hyperplasia in TG, we analyzed hepatic metabolic alterations and hormonal profiles. Methods: Liver tissues were collected from TG and wild-type mice (9-16 months old), and the expression of metabolism-related genes was analyzed by quantitative PCR. Plasma samples were subjected to biochemical analysis using dry chemistry assays. Plasma insulin and glucagon levels were measured by ELISA and sandwich ELISA, respectively. Results: Compared with wild-type controls, TG exhibited increased hepatic expression of G6Pase and Pgc-1α, together with upregulation of urea cycle-related genes (Ass1, Asl) and the methionine metabolism-related gene Ahcy. Biochemical analyses revealed significant increases in blood urea nitrogen (BUN) and non-esterified fatty acids (NEFA), suggesting enhanced hepatic utilization of amino acids and fatty acids. Plasma insulin levels were markedly reduced in TG, while plasma glucagon levels showed a nonsignificant trend toward elevation (Student’s t-test). Conclusion: These findings are consistent with increased hepatic amino acid metabolic flux and activation of the liver-α-cell axis in TG. Hepatic metabolic reprogramming combined with reduced insulin levels and relative glucagon predominance may contribute to α-cell hyperplasia in islets. Furthermore, a glucagon-dominant metabolic environment may facilitate α-cell neogenesis and expansion in IIDC regions, suggesting that altered hepatic metabolism plays a key role in shaping islet cell composition in this CRY1 mutant mouse model. Disclosure S. Okano: None. Y. Sasaki: None. A. Yasui: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Grants-in-Aid for Scientific Research (24K11670); Tohoku University Institute of Development, Aging and Cancer