Scientists at Sanford-Burnham have published back-to-back papers in the Regenerative Medicine section of the journal Stem Cells, showing how it’s possible to generate new, insulin-producing beta-cells in diabetes. The discovery provides a pharmacologically relevant approach for treating both type 1 and type 2 diabetes.
Fred Levine, M.D., Ph.D., professor and director of the Sanford Children’s Health Research Center, and his team have been on a mission to find new therapies for diabetes. Specifically, they’ve been working on methods to regenerate insulin-producing beta-cells in the pancreas that are damaged or destroyed in diabetes.
Although type 1 and type 2 diabetes are caused by different biological processes, both types of diabetes result in a decrease of functioning beta-cells—the cells in the pancreas that store and release insulin in response to elevated blood-sugar (glucose) levels. Controlling blood-sugar levels needs to be managed by administration of insulin in type 1 diabetes, and weight loss, diet, and/or insulin in type 2 diabetes. There is no cure for type 1 or type 2 diabetes, and treatments for both are aimed at minimizing high blood sugar without causing low blood sugar.
An ideal treatment for diabetes would generate new, functioning beta-cells in the pancreas, potentially eliminating the need for insulin and reversing the chronic, long-lasting effects of the disease. Levine’s most recent studies support the viability of this approach, showing that beta-cells can regenerate, replicate, and function even in cases where significant damage to the pancreas has already occurred.
In their first study, the researchers were able to manipulate alpha-cells in the pancreas—cells that secret glucagon (a molecule that has the opposite effect of insulin)—to create mature, fully functioning, insulin-producing beta-cells. To do this, the scientists used a diabetic mouse model whose beta-cells had been virtually eliminated through a process of chemical manipulation and surgery, called pancreatic duct ligation (PDL). After surgically reversing the PDL, the pancreatic alpha-cells generated functional beta-cells in numbers that restored normal insulin levels. The study is especially important for type 1 diabetes because it provides proof that a normal number of functioning beta-cells can be restored in a pancreas in which essentially all of the beta-cells had been destroyed, a situation analogous to type 1 diabetes.
In the second study, Levine and his team used a molecule he discovered in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics to search for drugs that would stimulate beta-cell replication. After making some minor modifications, they came up with a new compound (BI6015), and tested it in normal mice as well as diabetic mice in which the beta-cells had been destroyed. In both types of mice, BI6015 stimulated a large amount of beta-cell replication. This study is important because it provides a pharmacologically relevant means to stimulate the formation of a large number of new beta-cells, which is necessary for the development of a new treatment for diabetes.
Together, these studies provide “proof of principle” that beta-cells can regenerate, replicate, and function even in cases where significant damage to the pancreas has already occurred. Since increasing the number of fully functional beta-cells is critical to successful, long-term treatment of diabetes, Levine’s studies indicate that this may be a viable route to a definitive treatment for this disease.
Ergeng Hao, Seung-Hee Lee, Fred Levine (2013). Efficient β-cell regeneration by a combination of neogenesis and replication following β-cell ablation and reversal of pancreatic duct ligation Stem Cells DOI: 10.1002/stem.1492