Secretagogin Is Highly Expressed in Enteroendocrine K Cells and Plays a Critical Role in Nutrient-Induced GIP...

Incretin hormones, primarily composed of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted by enteroendocrine cells (EECs) and play crucial roles in maintaining blood glucose homeostasis. Notably, GIP accounts for two-thirds of the entire incretin effect. However, the secretion and function of GIP are impaired in individuals with type 2 diabetes mellitus (T2DM), and the regulatory mechanisms governing GIP secretion remain unclear.

Our study aims to explore the role of an EEC-enriched protein, Secretagogin (SCGN), in the regulation of GIP secretion.

We collected duodenal tissues from both humans and mice to observe the colocalization of SCGN and GIP in EECs. Additionally, we utilized human cohorts and gene-edited mouse models to investigate the effect of SCGN on GIP secretion. Our study included 128 subjects, comprising 64 individuals diagnosed with newly onset diabetes and 64 age- and sex-matched nondiabetic healthy controls. At the animal level, we employed leptin receptor-deficient (db/db) mice and Scgn knockout mice for our investigations.

Our findings indicate that SCGN is abundantly expressed in GIP-producing K cells within the intestinal epithelium of both humans and mice. We observed a positive correlation between SCGN and GIP levels in postprandial states among patients with T2DM, db/db mice, and their healthy controls. Notably, Scgn knockout mice exhibited decreased GIP and insulin secretion. However, SCGN deficiency did not affect K-cell number, GIP mRNA expression, or intestinal morphology.

Collectively, these findings demonstrate that SCGN is a key regulator of nutrient-induced GIP secretion.