Differential effects on ß-cell mass by disruption of Bardet-Biedl syndrome or Alstrom syndrome genes.
Hum Mol Genet
; 25(1): 57-68, 2016 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-26494903
ABSTRACT
Rare genetic syndromes characterized by early-onset type 2 diabetes have revealed the importance of pancreatic ß-cells in genetic susceptibility to diabetes. However, the role of genetic regulation of ß-cells in disorders that are also characterized by highly penetrant obesity, a major additional risk factor, is unclear. In this study, we investigated the contribution of genes associated with two obesity ciliopathies, Bardet-Biedl Syndrome and Alstrom Syndrome, to the production and maintenance of pancreatic ß-cells. Using zebrafish models of these syndromes, we identified opposing effects on production of ß-cells. Loss of the Alstrom gene, alms1, resulted in a significant decrease in ß-cell production whereas loss of BBS genes, bbs1 or bbs4, resulted in a significant increase. Examination of the regulatory program underlying ß-cell production suggested that these effects were specific to ß-cells. In addition to the initial production of ß-cells, we observed significant differences in their continued maintenance. Under prolonged exposure to high glucose conditions, alms1-deficient ß-cells were unable to continually expand as a result of decreased proliferation and increased cell death. Although bbs1-deficient ß-cells were similarly susceptible to apoptosis, the overall maintenance of ß-cell number in those animals was sustained likely due to increased proliferation. Taken together, these findings implicate discrepant production and maintenance of ß-cells in the differential susceptibility to diabetes found between these two genetic syndromes.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Síndrome de Bardet-Biedl
/
Células Secretoras de Insulina
/
Síndrome de Alstrom
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Hum Mol Genet
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2016
Tipo del documento:
Article