Endocrine Abstracts

JOINT592

[Type 2 diabetes (T2D) is increasingly recognized as a global pandemic. Secretagogin (SCGN), an EF-hand calcium sensor, plays a crucial role in hormone secretion across the pancreas, enteroendocrine cells (EECs), and neural compartments. While pancreatic SCGN expression has been linked to T2D, its role in EECs remains underexplored. In this study, we show that SCGN is significantly downregulated in the intestinal epithelial cells of both T2D patients and diabetic mice. Scgn deficiency in EECs of mice leads to age-associated diabetes by impairing thermogenesis in brown adipose tissue, attributed to reduced circulating levels of 12,13-diHOME, as revealed by metabolomics. Notably, the diabetic phenotypes and impaired heat production are alleviated in germ-free mice receiving stool transplants from Scgn-deficient mice, highlighting the critical role of gut microbiota. Additionally, we find a significant correlation between circulating 12,13-diHOME levels and brown adipose tissue activity in both diabetic patients and mouse models, with 12,13-diHOME levels being substantially lower than in healthy controls. Through extensive data from T2D patient stool transplants, we confirmed the correlation between butyrate in fecal samples and 12,13-diHOME levels in plasma. Our findings suggest that butyrate-producing microbiota can restore 12,13-diHOME levels, offering a promising therapeutic strategy for T2D. In conclusion, our study highlights the role of SCGN in EECs as an important cause of intestinal hormone secretion disorders and provides new insights into the complex interplay between microbiota dysbiosis and T2D.]