Soluble T-cadherin promotes pancreatic β-cell proliferation by upregulating Notch signaling.

Endogenous humoral factors that link systemic and/or local insulin demand to pancreatic β-cells have not been identified. Here, we demonstrated that T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin primarily expressed in vascular endothelial cells and cardiac and skeletal muscle cells, but not in pancreatic β-cells, was secreted as soluble forms and was important for β-cell proliferation. Cdh13 (T-cadherin) knockout mice exhibited impaired glucose handling due to attenuated β-cell proliferation under high-fat diet conditions. The gene expression analyses indicated the impairment in cell cycle and Notch signaling in the islets of T-cadherin knockout mice under high-fat diet conditions. In streptozotocin-induced diabetes, the replacement of soluble T-cadherin improved β-cell mass and blood glucose levels in T-cadherin knockout mice. Recombinant soluble T-cadherin upregulated Notch signaling in cultured murine islets. We concluded that soluble T-cadherin could work as an endogenous humoral factor whose signaling pathways including Notch signaling regulate β-cell proliferation under diabetic conditions in mice.
Competing Interests: S.K. belongs to the endowed department by Takeda Pharmaceutical Company, Rohto Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., FUJI OIL HOLDINGS INC., and Kobayashi Pharmaceutical Co., Ltd. N.M. belongs to the endowed department by Kowa Company, Ltd. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the article. All other authors have no conflicts to declare.
(© 2022 The Author(s).)