期刊
BIOMOLECULES
卷 12, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/biom12101493
关键词
type 1 diabetes; AAV; Manf; gene delivery; NOD mice; beta-cells
资金
- VIB
- Biotechnology and Biological Sciences Research Council (BBSRC) through Institute Strategic Program [BBS/E/B/000C0427, BBS/E/B/000C0428]
- BBSRC Core Capability Grant
- Vetenskapsradet
- Swedish Diabetes Foundation
- Barndiabetesfonden
- FWO
- O.E. och Edla Johanssons
- Sederholm
- Magnus Bergvalls Stiftelse
- Ernfors Fund
- Nils Erik Holmstens
- SEB-Diabetesfonden
This article discusses the causes and mechanisms of insulin-producing beta-cell death in type 1 diabetes. Cellular stress is found to contribute to the loss of beta-cells. By enhancing the expression of the anti-apoptotic protein Manf, the robustness of beta-cells can be improved, leading to a lower incidence of type 1 diabetes.
In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes.
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