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 β-cells in genetic susceptibility to diabetes. However, the role of genetic regulation of β-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 β-cells. Using zebrafish models of these syndromes, we identified opposing effects on production of β-cells. Loss of the Alstrom gene, alms1, resulted in a significant decrease in β-cell production whereas loss of BBS genes, bbs1 or bbs4, resulted in a significant increase. Examination of the regulatory program underlying β-cell production suggested that these effects were specific to β-cells. In addition to the initial production of β-cells, we observed significant differences in their continued maintenance. Under prolonged exposure to high glucose conditions, alms1-deficient β-cells were unable to continually expand as a result of decreased proliferation and increased cell death. Although bbs1-deficient β-cells were similarly susceptible to apoptosis, the overall maintenance of β-cell number in those animals was sustained likely due to increased proliferation. Taken together, these findings implicate discrepant production and maintenance of β-cells in the differential susceptibility to diabetes found between these two genetic syndromes.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA.
Sukanya
S
Lodh
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA.
Timothy L
TL
Hostelley
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA.
Carmen C
CC
Leitch
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA.
Elizabeth A
EA
O'Hare
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA zaghloul@umaryland.edu.
Norann A
NA
Zaghloul
D056769:Alstrom Syndrome / Q000235:genetics*; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D016923:Cell Death; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005947:Glucose; D006943:Hyperglycemia / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D060172:Morpholinos / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
C000593600:BBS4 protein, zebrafish; C530188:Bbs1 protein, zebrafish; D008869:Microtubule-Associated Proteins; D060172:Morpholinos; D029961:Zebrafish Proteins; D005947:Glucose