[HTML][HTML] Recovery from diabetes in mice by β cell regeneration

T Nir, DA Melton, Y Dor - The Journal of clinical …, 2007 - Am Soc Clin Investig
T Nir, DA Melton, Y Dor
The Journal of clinical investigation, 2007Am Soc Clin Investig
The mechanisms that regulate pancreatic β cell mass are poorly understood. While
autoimmune and pharmacological destruction of insulin-producing β cells is often
irreversible, adult β cell mass does fluctuate in response to physiological cues including
pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the
regenerative capacity of the β cell to treat diabetes. We developed a transgenic mouse
model to study the dynamics of β cell regeneration from a diabetic state. Following …
The mechanisms that regulate pancreatic β cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing β cells is often irreversible, adult β cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the β cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of β cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in β cells, resulting in apoptosis of 70%–80% of β cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of β cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving β cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited β cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.
The Journal of Clinical Investigation