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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK102001-01A1
Application #
8818418
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2014-09-25
Project End
2019-08-31
Budget Start
2014-09-25
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$345,375
Indirect Cost
$120,375
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201