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Diabetes. 2018 Oct 23. pii: db180285. doi: 10.2337/db18-0285. [Epub ahead of print]

Transient PAX8 Expression in Islets During Pregnancy Correlates With Beta Cell Survival Revealing a Novel Candidate Gene in Gestational Diabetes Mellitus.

Author information

1
Pancreatic Islet Development and Regeneration Unit/Laboratory of Aging Biology, Centro Andaluz de Biologı́a Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain.
2
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
3
Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland.
4
Amarna Therapeutics, Seville, Spain.
5
Department of Endocrinology and Nutrition, Hospital Divino Espírito Santo, Ponta Delgada 9500-370, Portugal.
6
Pancreatic Islet Development and Regeneration Unit/Laboratory of Aging Biology, Centro Andaluz de Biologı́a Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain. benoit.gauthier@cabimer.es.

Abstract

Transient Pax8 expression was reported in mouse islets during gestation while a genome-wide linkage and admixture mapping study highlighted PAX8 as candidate gene for diabetes mellitus (DM). Herein we sought the significance of PAX8 expression in mouse and human islet biology. Pax8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8 A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her type 2 diabetic father while absent in control subjects. The p.T356M variant did not alter protein stability or cellular localization whereas its trans-activation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 impacts islet viability and PAX8 could be considered as a candidate gene for the study of GDM.

PMID:
30352879
DOI:
10.2337/db18-0285

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