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

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