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.

See STAR methods in the Journal website with figure legends.

The methods how we evaluate pancreatic insulin contents, beta-cell mass, and beta-cell proliferation will be seen in the STAR methods in the Journal website with this Dryad data deposition. The dataset in each figure is summarized in an excel sheet, occasionally with raw data and its processed data in one folder. Please see the readme file in each folder. Our methods also cover the making of total knockout mice from flox mice, measurement of soluble T-cadherin, production of recombinant soluble T-cadherin, and stable plasmid-based in vivo expression of recombinant soluble T-cadherin from the liver. These methods may be helpful for a wide-range of readers.

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