Beta-Cell Regeneration

A natural process by which the beta cells of the pancreas, which make and secrete insulin, create new beta cells. Diabetes researchers are keenly interested in exploiting the mechanisms behind this phenomenon to some day prevent, treat, or cure Type 1 diabetes.

It has been known for some time that mammals (including humans) eventually regenerate some types of cells to replace injured cells. There is now growing evidence that we have some ability to regenerate beta cells. In pregnant or obese individuals, for example, the mass and number of beta cells expand considerably to meet the body’s increased insulin requirements.

Beta-cell regeneration raises tantalizing possibilities for the treatment of Type 1 diabetes. The autoimmune destruction of beta cells is gradual, and recent research suggests that many people with long-standing diabetes still appear to have some residual beta-cell function, sometimes even decades after diagnosis. The body’s natural regeneration of beta cells may be hampered by high blood glucose levels, which can damage newly regenerated beta cells, and by the autoimmune process that caused diabetes in the first place.

If researchers could intensify blood glucose control, learn how to turn off the autoimmune response, and give people something that would stimulate beta-cell growth, perhaps regeneration and restoration of functional beta-cell mass might occur, even in people with established Type 1 diabetes. Alternatively, perhaps people in the very earliest stages of Type 1 diabetes could be treated to delay the onset of — or prevent — full-blown clinical diabetes.

Understanding beta-cell regeneration could be a boon to islet transplantation as well. The success of the Edmonton Protocol has shown that islet transplantation can essentially restore insulin independence in individuals with Type 1 diabetes for several years. However, there are not nearly enough donor pancreases available each year to provide islets to everyone who could benefit from an islet transplant. In many cases, it takes multiple donor organs to induce insulin independence in a single transplant recipient. Ideally, this problem could be solved by exploiting the principles of beta-cell regeneration to grow large numbers of functional beta cells from donor organs in tissue culture and then transplanting the expanded beta cells. At the very least, researchers hope that beta-cell regeneration could be used to enhance currently used islet transplantation methods.

Researchers are eager to identify and study substances that can be used to stimulate beta-cell regeneration. One key player is a hormone called glucagon-like peptide-1 (GLP-1). GLP-1 has a number of positive effects in diabetes, including the regeneration of beta cells, protection of those cells against apoptosis (programmed cell death), enhancement of insulin secretion after meals, and suppression of the release of glucose from the liver after meals. A number of pharmaceutical companies are now developing and testing long-acting analogs of GLP-1 in both Type 1 and Type 2 diabetes. In fact, a synthetic, longer-acting GLP-1-like molecule called exenatide, marketed by Amylin Pharmaceuticals and Eli Lilly and Company as Byetta, received approval from the U.S. Food and Drug Administration in April 2005 as an adjunctive treatment for Type 2 diabetes.

The National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring a clinical trial to study the effects of exenatide in people who have had Type 1 diabetes for at least five years but whose pancreases still make some insulin. The trial is designed to determine whether exenatide can improve the pancreas’s ability to make insulin and help control blood glucose. Other researchers also plan to study whether giving GLP-1 or GLP-1 analogs to people receiving islet transplants can improve the success rate of transplantation.

Another potential treatment is the combination of two growth factors called gastrin and epidermal growth factor (EGF), which has been shown to promote beta-cell regeneration in rats. Researchers at Waratah Pharmaceuticals in Woburn, Massachusetts, developed this combination for therapy, calling it Islet Neogenesis Therapy (INT). In 2004, an extended phase I clinical trial of INT in people with Type 1 diabetes, designed to test the safety of the therapy, showed no serious or unexpected side effects.

In a study reported in the Journal of Clinical Endocrinology and Metabolism in 2005, researchers from Waratah and the University of Alberta in Edmonton, Alberta, Canada, cultured human islets for four weeks in medium containing neither agent, gastrin or EGF alone, or a combination of EGF and gastrin. The islets were then cultured for another four weeks in a control medium. At the end of the second four-week period, the group receiving the gastrin-EGF combination had three times as many insulin-producing beta cells as they started with.

Next, the researchers implanted human islets into NOD-SCID mice — mice with a deficient immune system — so as to sidestep transplant rejection and autoimmunity. They then injected some of the mice with the EGF-gastrin combination. In the mice treated with EGF-gastrin, there was an increase in beta cell numbers and insulin levels within the islets. When they injected glucose into the mice, there was a brisk secretion of insulin from the human islet grafts, demonstrating that the beta cells were functional. Research into the promise of beta-cell regeneration continues.

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