Endocrine Abstracts

A fundamental problem in pancreas biology concerns the dynamics of beta cell mass regulation. While autoimmune or pharmacological destruction of beta cells appears to be irreversible, adult beta cell mass does respond to specific physiological cues such as insulin resistance. This raises the exciting possibility that beta cells have a significant regenerative capacity that could be used to treat diabetes. In support of this notion, recent studies in mouse models of diabetes suggested that mice can regain glycemic control after a diabetogenic injury. However, it is not clear what part of the recovery process is mediated by an increase in beta cell mass.

The long-term objective of our study is to understand the mechanisms determining pancreatic beta cell mass. We wish to quantitatively assess the magnitude of beta cell regeneration after defined beta cell ablation, to determine the cellular origins of regenerating beta cells and to characterize the signals that govern beta cell homeostasis.

As a first step, we have developed a transgenic mouse system that allows for conditional (doxycycline-regulated) expression of diphtheria toxin in pancreatic beta cells. We demonstrate that the addition of doxycycline to the drinking water of transgenic mice leads to beta cell-specific death and the development of severe hyperglycemia. Importantly, doxycycline withdrawal results in normalization of blood glucose levels in most animals, exposing a surprising capacity of the pancreas to recover from a situation similar to type 1 diabetes. Ongoing experiments examine the histological aspects of the recovery process, to determine the magnitude and the mechanisms of beta cell regeneration.