Differential effects on ?-cell mass by disruption of Bardet-Biedl syndrome or Alstrom syndrome genes.

ABSTRACT: Rare genetic syndromes characterized by early-onset type 2 diabetes have revealed the importance of pancreatic ?-cells in genetic susceptibility to diabetes. However, the role of genetic regulation of ?-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 ?-cells. Using zebrafish models of these syndromes, we identified opposing effects on production of ?-cells. Loss of the Alstrom gene, alms1, resulted in a significant decrease in ?-cell production whereas loss of BBS genes, bbs1 or bbs4, resulted in a significant increase. Examination of the regulatory program underlying ?-cell production suggested that these effects were specific to ?-cells. In addition to the initial production of ?-cells, we observed significant differences in their continued maintenance. Under prolonged exposure to high glucose conditions, alms1-deficient ?-cells were unable to continually expand as a result of decreased proliferation and increased cell death. Although bbs1-deficient ?-cells were similarly susceptible to apoptosis, the overall maintenance of ?-cell number in those animals was sustained likely due to increased proliferation. Taken together, these findings implicate discrepant production and maintenance of ?-cells in the differential susceptibility to diabetes found between these two genetic syndromes.

SUBMITTER: Lodh S 

PROVIDER: S-EPMC4690491 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature