Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans.

At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a non-coding region near CDKN2A. The disease-associated alleles have been implicated in reduced β-cell function, but the underlying mechanism remains elusive. In mice, β-cell specific loss of Cdkn2a causes hyperplasia whilst overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved β-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched controls. Compared with controls, carriers displayed increased insulin secretion, impaired insulin sensitivity and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A-loss affects a range of different tissues, including pancreatic β-cells and liver. To test for direct effects of CDKN2A-loss on β-cell function, we performed knockdown in a human β-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrate that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes-associated alleles in the region.