期刊
DIABETES
卷 64, 期 1, 页码 193-199出版社
AMER DIABETES ASSOC
DOI: 10.2337/db14-0436
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资金
- University of Pennsylvania Diabetes Research Center [P30-DK-19525]
- University of Pennsylvania Clinical and Translational Research Center [UL1-TR-000003]
- Human Metabolism Resource of the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000003] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020595, P30DK019525] Funding Source: NIH RePORTER
Loss-of-function mutations affecting the cholesterol transporter ATP-binding cassette transporter subfamily A member 1 (ABCA1) impair cellular cholesterol efflux and are associated with reduced HDL-cholesterol (HDL-C) levels. ABCA1 may also be important in regulating beta-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect beta-cell secretory capacity in humans by performing glucose-potentiated arginine tests in three subjects homozygous for ABCA1 mutations (age 25 +/- 11 years), eight heterozygous subjects (28 +/- 7 years), and eight normal control subjects pair-matched to the heterozygous carriers. To account for any effect of low HDL-C on insulin secretion, we studied nine subjects with isolated low HDL-C with no ABCA1 mutations (age 26 +/- 6 years) and nine pair-matched control subjects. Homozygotes for ABCA1 mutations exhibited enhanced oral glucose tolerance and dramatically increased beta-cell secretory capacity that was also greater in ABCA1 heterozygous subjects than in control subjects, with no differences in insulin sensitivity. Isolated low HDL-C subjects also demonstrated an increase in beta-cell secretory capacity but in contrast to those with ABCA1 mutations, exhibited impaired insulin sensitivity, supporting beta-cell compensation for increased insulin demand. These data indicate that loss-of-function mutations in ABCA1 in young adults may be associated with enhanced beta-cell secretory capacity and normal insulin sensitivity and support the importance of cellular cholesterol homeostasis in regulating beta-cell insulin secretion.
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