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Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets
Published on: May 11, 2015
Recovery from diabetes in mice by beta cell regeneration
Tomer Nir1, Douglas A Melton, Yuval Dor
1Department of Cellular Biochemistry and Human Genetics, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract:
The mechanisms that regulate pancreatic beta cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing beta cells is often irreversible, adult beta 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 beta cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of beta cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in beta cells, resulting in apoptosis of 70%-80% of beta 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 beta cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving beta cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited beta 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.
Insights
Scientists discovered that surviving pancreatic beta cells can regenerate to restore normal blood glucose levels in diabetic mice. However, certain immunosuppressants hinder this crucial beta cell regeneration process.
Area of Science:
- Endocrinology
- Regenerative Medicine
- Diabetes Research
Background:
- Pancreatic beta cell mass regulation is poorly understood, yet adult beta cell mass fluctuates, suggesting regenerative potential.
- Autoimmune destruction of beta cells, common in type 1 diabetes, is often irreversible.
- This plasticity offers a potential therapeutic target for diabetes treatment.
Purpose of the Study:
- To investigate the dynamics of beta cell regeneration in a mouse model of diabetes.
- To identify factors influencing beta cell regeneration after induced destruction.
Main Methods:
- Developed a transgenic mouse model for inducible beta cell ablation using diphtheria toxin.
- Administered doxycycline to induce beta cell apoptosis, followed by withdrawal to observe regeneration.
- Utilized lineage tracing to determine the source of regenerated beta cells.
- Assessed the impact of immunosuppressants (Sirolimus, Tacrolimus) on beta cell regeneration and glucose homeostasis.
Main Results:
- Inducible ablation of 70%-80% of beta cells led to diabetes and islet architecture destruction.
- Withdrawal of the toxin resulted in spontaneous normalization of blood glucose and islet structure.
- Significant regeneration of beta cell mass was observed, primarily through enhanced proliferation of surviving beta cells.
- Sirolimus and Tacrolimus treatment inhibited beta cell regeneration and prevented glucose homeostasis normalization.
Conclusions:
- Adult beta cells possess a significant capacity for regeneration after substantial loss.
- Enhanced proliferation of surviving beta cells is the primary mechanism for beta cell mass restoration.
- Common immunosuppressants used in islet transplantation can impede beta cell regeneration.
- Regenerative therapies for type 1 diabetes require strategies that halt autoimmunity without inhibiting beta cell repair.
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