Evidence of the Regenerative Capacity of Pancreatic ß Cells In Diabetic Mice

Regulation of pancreatic ß cell mass is poorly understood, though there is evidence that the tissue mass fluctuates in both normal and hyperglycemic states. The present study used a doxycycline-triggered expression of diphtheria toxin A to create diabetic mice by selectively depleting pancreatic ß cells. These animals exhibited traits characteristic of diabetes, including ß cell depletion (down 70%-80%), low pancreatic insulin levels, and hyperglycemia. Withdrawal of doxycycline resulted in spontaneous disease reversal in young and adult animals over a prolonged period. The new ß cells arose via increased proliferation, rather than reduced apoptosis. Moreover, the proliferation, which increased within 48 hours of initiating the diphtheria toxin A induced cell death (and before the onset of hyperglycemia) was attributed to increased ß cell replication by a lineage tracing experiment. No evidence was found of the involvement of progenitor cell differentiation in the recovery process. Finally, the effect of two immune suppressant drugs (Sirolimus and Tacrolimus) on ß cell regeneration was tested, with surprising results. These therapeutic agents, which are recommended in the Edmonton protocol for use with islet cell transplants, prevent ß cell proliferation and may, therefore, contribute to the gradual failure of the transplanted tissue.

The results of this study demonstrate the inherent regenerative capacity of the pancreatic islets and thereby support early clinical intervention that protects ß cells from autoimmune destruction. However, only immune suppressants that do not inhibit ß cell proliferation should be used for this therapy. The model employed in this study probably would facilitate the identification of appropriate medicines.

The results also suggest directions for future investigation of the mechanism(s) controlling tissue mass. Replication of ß cells commenced rapidly after diphtheria toxin A production, even before hyperglycemia was recorded. This suggests that apoptosis directly (e.g., via chemokine release during cell death) or indirectly (e.g., via macrophage infiltration) may play a triggering role in the initiation of regeneration.

Message posted by: Keith Markey