Increasing rates of obesity have corresponded with a significant rise in the incidence of type 2 diabetes. A major challenge, however, lies in dissecting the cellular mechanisms associated with obesity-related diabetes. Ciliopathies, disorders caused by dysfunction of primary cilia, are a useful model because the two that are characterized by obesity, Bardet-Biedl Syndrome (BBS) and Alstrom Syndrome, have markedly different rates of type 2 diabetes incidence. Nearly all BBS and Alstrom patients are obese, but a relatively small proportion of BBS patients are afflicted with type 2 diabetes compared with a majority of Alstrom syndrome patients. In light of the fact that most proteins associated with BBS localize to the basal body at the base of primary cilia as does the sole Alstrom protein, ALMS1, this discrepancy suggests the possibility that this structure may act as a molecular switch in glucose regulation. However, the mechanisms by which basal body dysfunction may contribute to type 2 diabetes are unclear. This proposal is aimed at understanding the differential mechanisms by which diabetes arises in BBS and Alstrom Syndrome by focusing on the role of pancreatic cells. We hypothesize that loss of BBS proteins enhances pancreatic ?-cell function whereas loss of ALMS1 depletes it. We will test this hypothesis by examining 1) production of pancreatic ?-cells in zebrafish models of BBS and Alstrom Syndrome, 2) the adaptive capacity of BBS or Alstrom ?-cell mass in response to nutrients and regeneration, and 3) sensitivity to glucose in BBS or Alstrom ?-cells. The overall goal of these studies is to understand the molecular mechanism by which the basal body is associated with ?-cell function, providing significant insight into glucose regulation in obesity ciliopathies.
The mechanisms that determine susceptibility to type 2 diabetes in some obese individuals but not in others are not well understood. The proposed studies seek to address this problem by investigating differences in pancreatic -cell function in two rare obesity disorders that have similar molecular causes but very different rates of diabetes.