Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development

Biomolecules. 2022 Oct 16;12(10):1493. doi: 10.3390/biom12101493.

Abstract

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.

Keywords: AAV; Manf; NOD mice; beta-cells; gene delivery; type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Diabetes Mellitus, Type 1* / genetics
  • Diabetes Mellitus, Type 1* / prevention & control
  • Diabetes Mellitus, Type 2*
  • Gene Transfer Techniques
  • Glucose
  • Insulin / genetics
  • Islets of Langerhans* / metabolism
  • Mice
  • Mice, Inbred NOD
  • Nerve Growth Factors

Substances

  • Insulin
  • Glucose
  • Apoptosis Regulatory Proteins
  • MANF protein, mouse
  • Nerve Growth Factors