Normal Glucagon Signaling And Glucose Regulation After Near-Total Alpha Cell Loss

Alpha cells, the second most abundant endocrine cell type in the islet, secrete glucagon which acts to counter-regulate insulin’s action by raising blood sugar levels. Recently alpha to beta cell conversion, or transdifferentiation, has been proposed as a therapeutic strategy to restore beta cell mass in individuals with type 1 diabetes. However, a potential concern with this strategy is that the resulting loss of alpha cell mass would result in reduced glucagon secretion and further defects in glucose regulation. To determine the effects of a severe loss of alpha cell mass on glucose regulation in normal and diabetic animals, Dr. Herrera’s team generated a mouse in which alpha cells can be rapidly and efficiently destroyed. Surprisingly, the group found that glucose regulation was normal after ablation of 98% of the alpha cell mass; the remaining 2% of alpha cells were able to compensate for the loss and produce near-normal levels of glucagon. Similarly, ablation of alpha cells in diabetic mice had no effect on diabetes progression or glucose levels compared to diabetic mice with a normal complement of alpha cells. These data suggest that alpha cells are present in great excess, further supporting alpha to beta cell transdifferentiation as a viable therapeutic strategy for type 1 diabetes.

Reference:

Thorel, F., Damond, N., Chera, S. et al. (2011). Normal Glucagon Signaling and Alpha-Cell Function After Near-Total Beta-Cell Ablation in Adult Mice. Diabetes, 60:2872-2882.

Ramifications for Individuals with Type 1 Diabetes:

This early, exploratory research demonstrates that alpha cells are present in great excess and that few alpha cells are capable of producing enough glucagon to ensure normal glucose regulation. With the support of JDRF, alpha to beta cell transdifferentiation is being actively pursued as a potential strategy to restore beta cell mass in individuals with type 1 diabetes; this work helps to alleviate one of the major safety concerns associated with this approach.

JDRF Involvement:

This study was funded in part by JDRF grants to Dr. Herrera.