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Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans
Aparna Pal1, Thomas P Potjer2, Soren K Thomsen1
1Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
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 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 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 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 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 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.
Insights
Rare mutations in the CDKN2A gene impact glucose homeostasis. Individuals with these mutations show altered insulin secretion and sensitivity, suggesting CDKN2A
Area of Science:
- Genetics and Molecular Biology
- Endocrinology
- Metabolic Diseases
Background:
- Type 2 diabetes risk signals are near the CDKN2A/B locus, linked to reduced beta-cell function.
- CDKN2A is a candidate effector transcript, with mouse studies showing its role in beta-cell hyperplasia and diabetes.
- Rare CDKN2A loss-of-function mutations cause familial melanoma, providing a human model for studying haploinsufficiency.
Purpose of the Study:
- To investigate the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans.
- To determine if individuals with rare CDKN2A loss-of-function mutations exhibit improved beta-cell function.
- To elucidate the role of CDKN2A in regulating human glucose metabolism.
Main Methods:
- Oral and intravenous glucose tolerance tests were conducted on CDKN2A mutation carriers and matched controls.
- Insulin secretion, insulin sensitivity, and hepatic insulin clearance were assessed.
- Knockdown of CDKN2A in a human beta-cell line (EndoC-bH1) was performed to study direct effects on beta-cell function.
Main Results:
- CDKN2A mutation carriers showed increased insulin secretion, impaired insulin sensitivity, and reduced hepatic insulin clearance compared to controls.
- CDKN2A knockdown in human beta-cells led to increased insulin secretion without affecting proliferation.
- These findings suggest CDKN2A loss impacts multiple tissues, including pancreatic beta-cells and the liver.
Conclusions:
- CDKN2A is a significant regulator of glucose homeostasis in humans.
- The study supports CDKN2A's candidacy as an effector transcript for type 2 diabetes risk alleles.
- Understanding CDKN2A's role offers insights into the mechanisms underlying type 2 diabetes.
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