Insulin-producing β-islet cells in the pancreas can be made aware of a lack of insulin in the blood in a diabetes model, through signals relayed by a soluble signaling molecule called T-cadherin, report scientists at the University of Osaka in Japan. The novel mechanism, reported in the journal iScience on November 7, presents a potential new therapeutic target for treating diabetes.

Insulin is a peptide hormone that controls the absorption of glucose by the liver, fat and skeletal muscle cells. It is key in regulating the use and storage of carbohydrates to meet the body’s demands for energy. Although the cause of type-2 diabetes that affects over 400 million people, is widely understood as an inability of pancreatic β-islet cells to supply adequate insulin, mechanisms that inform insulin producing β-islet cells about insufficient levels of insulin in the systemic circulation, are not clear. Under normal conditions, β-islet cells multiply when the body requires more insulin. However, in diabetes, β-islet cell mass reduces due to lack of cell proliferation.

In studies conducted on mice and cultured islets, the team led by Shunbun Kita, PhD, and Shiro Fukuda, PhD, researchers at the department of metabolic medicine at Osaka University, found a unique member of the cadherin superfamily of proteins called T-cadherin that may provide feedback to the insulin-producing pancreatic cells and controll their proliferation.

Unlike classical cadherins that work as facilitators of cell adhesion, T-cadherins are anchored to GPI (glycosylphosphatidylinositol) and bear no direct attachments to the cytoskeleton. Therefore they are not involved in cell adhesion. Instead, they act as soluble signaling molecules, much like hormones. T-cadherin is usually present on the surface of cells lining blood vessels, and on cardiac and skeletal muscle cells, but not on pancreatic β cells. T-cadherin’s best known binding partner is adiponectin—a factor secreted by fat storing cells.

In the current study, the researchers showed that in addition to functioning at the cell surface, T-cadherin is also secreted in soluble forms that can be transported through the systemic circulation (a humoral factor). Not only do T-cadherins respond to insulin deficiency, they are important for β-cell proliferation.

Pancreatic β-cells do not multiply adequately in mice lacking expression of T-cadherin and fed a high-fat diet. This results in glucose intolerance. Gene expression analyses in these mice showed impaired expression of components of cell cycle regulation and notch signaling, an evolutionarily conserved pathway that regulates cell-fate and tissue homeostasis during development and in adult animals. Notch signaling promotes β-cell proliferation in the pancreas. Therefore, the finding suggests that soluble T-cadherin induces pancreatic β-cells to increase insulin production by stimulating β-cell proliferation through the Notch pathway.

The investigators induced diabetes in T-cadherin knockout mice by injecting the antibiotic streptozotocin. They then administered soluble T-cadherin and found this improved β-cell mass and blood glucose levels in the mice.

“We used artificially synthesized T-cadherin to treat isolated mouse pancreatic islets,” said Iichiro Shimomura, PhD, the senior author of the study. “This promoted Notch signaling in the mouse islets, which could in turn induce β-cell proliferation.”

Overall, these findings in mouse models suggest soluble T-cadherin administration could be an alternative treatment for diabetes, if found safe and effective in human trials.

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