Dataset Information

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

ABSTRACT: At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding region near CDKN2A. The disease-associated alleles have been implicated in reduced ?-cell function, but the underlying mechanism remains elusive. In mice, ?-cell-specific loss of Cdkn2a causes hyperplasia, while 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 ?-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched control subjects. Compared with control subjects, 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 ?-cells and liver. To test for direct effects of CDKN2A-loss on ?-cell function, we performed knockdown in a human ?-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrated 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.

SUBMITTER: Pal A

PROVIDER: S-EPMC4724950 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Pal Aparna A Potjer Thomas P TP Thomsen Soren K SK Ng Hui Jin HJ Barrett Amy A Scharfmann Raphael R James Tim J TJ Bishop D Timothy DT Karpe Fredrik F Godsland Ian F IF Vasen Hans F A HF Newton-Bishop Julia J Pijl Hanno H McCarthy Mark I MI Gloyn Anna L AL

Diabetes 20151105 2

At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding 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, while 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 ...[more]

PMID: 26542317

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Dataset Information

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

Publications

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

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