PAX4 gene delivery improves β-cell function in human islets of Type II diabetes

Abstract

Aim: Type II diabetes (T2D) stems from insulin resistance, with β-cell dysfunction as a hallmark in its progression. Studies reveal that β cells undergo apoptosis or dedifferentiation during T2D development. The transcription factor PAX4 is vital for β differentiation and survival, thus may be a potential enhancer of β-cell function in T2D islets. Materials & methods: Human PAX4 cDNA was delivered into T2D human islets with an adenoviral vector, and its effects on β cells were examined. Results: PAX4 gene delivery significantly improved β-cell survival, and increased β-cell composition in the T2D human islets. Basal insulin and glucose-stimulated insulin secretion in PAX4-expressing islets were substantially higher than untreated or control-treated T2D human islets. Conclusion: Introduced PAX4 expression in T2D human islets improves β-cell function, thus could provide therapeutic benefits for T2D treatment.

Plain language summary

Type II diabetes (T2D) results from insulin resistance, with β-cell dysfunction playing a pivotal role in its progression. Deficits in β-cell mass and function have been attributed primarily to β-cell death through apoptosis; however, recent studies suggest β-cell failure can also arise from β-cell dedifferentiation – that is, β cells undergo a loss of mature identity, adopting either progenitor-like or glucagon-producing α cell states during T2D development. Therefore, a strategy preventing β-cell dedifferentiation while promoting its survival is beneficial for T2D treatment. In this study, we explored whether PAX4, a critical transcription factor for β differentiation and survival, could alleviate β-cell dysfunction in human islets derived from T2D patients. To accomplish that, human PAX4 cDNA was delivered into human islets isolated from T2D donors by an adenoviral vector-based vector, Ad5.Pax4 and its effects on β-cell function were evaluated. The results showed PAX4 expression significantly improved β-cell survival and increased β-cell composition in the T2D islets. Notably, PAX4-treated T2D islets exhibited significantly higher basal insulin secretion and glucose-stimulated insulin secretion than control-treated islets. The data demonstrate that PAX4 gene delivery into T2D human islets enhances β-cell mass and function, and thus may offer therapeutic benefits in the treatment of T2D.

Article highlights

• Type II diabetes (T2D) arises from insulin resistance, with β-cell dysfunction as a hallmark in its progression, underscoring the need for therapies that enhance β-cell function.

• The transcription factor PAX4 plays critical roles in β differentiation and survival, making it a potential enhancer of β-cell function in T2D human islets.

• PAX4 gene delivery mediated by an adenoviral vector, Ad5.Pax4, increases the composition of β cells, enhances their survival, and improves their function in T2D human islets.

• PAX4 gene delivery may offer therapeutic benefits for T2D treatment by restoring β-cell function through Pax4's effects on β differentiation and survival, thereby improving glucose homeostasis and overall disease management.

Keywords: :

• α cells
• β-cell dysfunction
• β cells
• gene delivery
• human islets
• Pax4
• transdifferentiation
• Type II diabetes

Author contributions

Y Zhanga and KR Parajulia designed and performed experiments; VA Fonsecaa edited the manuscript; H Wu analyzed data and wrote the manuscript.

Financial disclosure

The study was supported by NIDDK grant DK107412 and Susan Harling Robinson Fellowship in Diabetes Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors have confirmed that they obtained approval from Tulane Institutional Review Board (IRB reference number: 17-1008117) for the use of human islets, which has been designated as non-human subject research.

Acknowledgments

Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) (RRID: SCR_014387) at City of Hope, NIH Grant #2UC4DK098085.

Additional information

Funding

The study was supported by NIDDK grant DK107412 and Susan Harling Robinson Fellowship in Diabetes Research.