Dr. Barbara Ranscht and her lab are working to better understand how T-cadherin—a protein found on the surface of neurons, muscle, and other cells—regulates communication between cells during development and disease. The best way to go about this is to see what happens when the protein is missing. To do this, her lab developed a mouse model that lacks the protein altogether. Using these animals, Dr. Ranscht’s group has revealed that T-cadherin protects the stressed heart and is necessary for new blood vessel growth in injury models.
One day, Dr. Ranscht found herself discussing possible roles for T-cadherin in metabolism with Sanford-Burnham colleagues Dr. Björn Tyrberg and Dr. Fred Levine. The researchers especially wondered about T-cadherin’s role in the pancreas (Drs. Tyrberg’s and Levine’s organ of expertise).
The pancreas regulates sugar (glucose) metabolism through controlled release of the protein hormone insulin. After a meal, beta-cells in the pancreas respond to the suddenly high levels of glucose in the blood by releasing insulin. Insulin then binds to receptors present on many cells in the body. Like a key unlocking a door, insulin binding allows glucose to enter the cell and be used for energy. In type 1 (juvenile) diabetics, the immune system has destroyed a person’s beta-cells. As a result, the pancreas no longer produces insulin, glucose remains high in the blood, and other cells starve. In type 2 diabetics, beta-cells don’t work at full capacity and other cells in the body don’t respond well to insulin, with the same result on blood glucose as in type 1 diabetes.
Since elevated glucose levels are amongst the major signs of a pancreatic dysfunction and since Dr. Ranscht had a few extra T-cadherin-deficient mice, the researchers decided to test their blood glucose levels. To everyone’s surprise, the mice, which otherwise appear normal, turned out to be glucose intolerant, a metabolic condition that often precedes diabetes.
Teaming up, Drs. Ranscht, Tyrberg, Levine and members of their labs took a closer look at T-cadherin in the pancreas. They got another surprise. Remember how T-cadherin is located on the cell surface, anchored in the cell membrane in every organ examined so far? Not so in the pancreas.
“We found T-cadherin in the most unusual location,” Dr. Ranscht explains. “In pancreatic beta-cells, it’s inside the cells, associated with insulin storage granules.”
In line with its unexpected positioning, Drs. Tyrberg and Ranscht found that T-cadherin is required for the second phase of insulin secretion. Here’s what that means… Say you eat a candy bar. The flood of glucose in your blood prompts the immediate release of insulin that’s been poised near the cellular membrane for just such an occasion. T-cadherin-deficient mice still have that immediate insulin burst, but they lack the second phase, which is necessary to sustain insulin secretion and keep cells taking up all that glucose. Without T-cadherin, the mice are left with excess glucose in the bloodstream and cells that are unable to use it to produce energy.
Drs. Ranscht, Tyrberg, and colleagues published these findings November 1 in the journal Islets.
“Unraveling the mechanisms that lead to insulin secretion helps us better understand diabetes—a disease characterized by suboptimal insulin secretion leading to excess glucose in the bloodstream,” explains Dr. Tyrberg. “Here we discovered that T-cadherin is necessary for insulin secretion to proceed normally.”
Dr. Ranscht is equally excited about the possibilities opened up by this study. As she puts it, “We have so many questions about T-cadherin and only answered one in this study. We now know that T-cadherin contributes to the insulin release process and thereby to metabolic balance in these mice. But we don’t know yet exactly how T-cadherin does this.”
Human genome-wide association studies link T-cadherin to cardiometabolic disease, Dr. Ranscht says, and there is some evidence to indicate that people who inherit a defective T-cadherin gene might be more susceptible to developing metabolic syndrome, including diabetes.
The team is now seeking funding to continue these studies to determine exactly how T-cadherin influences insulin release and metabolic disease. According to Dr. Tyrberg, “These findings could ultimately lead to new avenues for improving insulin secretion in diabetes, either directly through drug interactions with T-cadherin or through further discoveries of other proteins that interact with T-cadherin in the insulin secretion process.”
Tyrberg B, Miles P, Azizian KT, Denzel MS, Nieves ML, Monosov EZ, Levine F, & Ranscht B (2011). T-cadherin (Cdh13) in association with pancreatic β-cell granules contributes to second phase insulin secretion. Islets, 3 (6), 327-37 PMID: 21975561