Primary Cilium, An Unsung Hero in Maintaining Functional β-cell Population

A primary challenge in type 2 diabetes (T2D) is the preservation of a functional population of β-cells, which play a central role in regulating blood glucose levels. Two congenital disorders, Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS), can serve as useful models to understand how β-cells are normally produced and regenerated. Both are characterized by obesity, loss of β-cells, and defects in primary cilia - the sensory center of cells. Primary cilia are cellular protrusions present in almost every vertebrate cell. This antenna-like organelle plays a crucial role in regulating several signaling pathways that direct proper development, proliferation, and homeostasis. Mutations in genes expressing ciliary proteins or proteins present at or near the base of the cilium lead to disorders, collectively called ciliopathies. BBS and Alström syndrome are such disorders. Though both BBS and Alström patients are obese, their childhood diabetes rates are vastly different, suggesting distinct pathogenesis underlying these two ciliopathies. Clinical studies suggest that BBS patients are protected against early onset diabetes by sustained or enhanced β-cell function. In contrast, Alström patients are more prone to develop diabetes. They have hyperinsulinemia, yet their β-cells fail to sense glucose and to regulate insulin secretion accordingly. These data suggest a potential role for primary cilia in maintaining a functional β-cell population and that defects in cilia or in ciliary proteins impair development and function of β-cells. Identifying the respective roles of primary cilia and ciliary proteins, such as BBS and ALMS1 may shed light on β-cell biology and uncover potentially novel targets for diabetes therapy.