Regenerating Beta Cells in the Pancreas: Implications for Diabetes Therapy

Insulin produced by the pancreas is essential for maintaining normal blood glucose homeostasis. Such homeostasis is essential for normal growth and to give cells throughout the body the energy they need to function normally. Type 1 diabetes, or juvenile diabetes, is marked by a loss of the pancreatic beta cells that produce insulin through an autoimmune reaction. Once this occurs, type 1 diabetics require an exogenous source of insulin through daily injections. A new study published in Nature observed that other types of cells that compose the pancreas, alpha cells, can convert into beta cells in mice. Understanding how this process occurs has implications for restoring normal pancreas function in treating diabetes.

The authors specifically ablated pancreatic beta cells in mice by placing the diphtheria toxin receptor downstream of the insulin promoter. Using this design, only cells that produce insulin will produce diphtheria toxin receptor. Diphtheria toxin can then be administered to the mice to specifically destroy beta cells in the pancreas. Following toxin administration, the authors observed a near complete loss of beta cells followed by a regeneration period where insulin producing cells reappeared.

Beta cells were labeled before diphtheria toxin treatment with yellow fluorescent protein (YFP) to determine if it was non-ablated beta cells regenerating. Interestingly, the beta cells did not regenerate from cells spared by diphtheria toxin treatment, as YFP cells did not expand significantly and unlabeled cells were secreting insulin. The beta cells that expanded secreted glucagon in addition to insulin, suggesting alpha cells may convert into beta cells. To address this, the authors labeled alpha cells with YFP before beta cell ablation. As hypothesized, the YFP cells began to secrete insulin after diphtheria treatment. Genes expressed exclusively in beta cells before toxin treatment, such as Nkx6.1, began to be expressed in alpha cells after expansion as well.

Understanding this process has implications for the treatment of type 1 diabetes, as beta cells are lost over time. The authors point out that it is unclear if regenerated cells would be lost by autoimmunity, and suggest such an approach may have to be introduced after immune mediated beta cell destruction is under control. This work may also have a role in type II diabetes, as chronic hyperglycemia is thought to lead to beta cell loss. Regenerating beta cells for these patients may be beneficial to prevent chronic medication usage and improve health.

References:

Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010 Apr 22;464(7292):1149-54.

Maedler K, Donath MY. Beta-cells in type 2 diabetes: a loss of function and mass. Horm Res. 2004;62 Suppl 3:67-73.