期刊
PHYSIOLOGICAL REPORTS
卷 10, 期 16, 页码 -出版社
WILEY
DOI: 10.14814/phy2.15425
关键词
eNOS+; - heterozygote mice; Notch-1 pathway; pancreatic exocrine-endocrine transdifferentiation; pancreatic beta cells
类别
资金
- Fondazione Toscana Gabriele Monasterio
- Institute of Clinical Physiology, CNR, Pisa
- Universita di Pisa
eNOS-deficient mice developed insulin resistance and morphological changes in the pancreas, including beta-cell hyperplasia and the appearance of hybrid acinar-beta-cells, under high-fat diet conditions. These changes may be caused by deficient endothelial NO production.
eNOS-deficient mice were previously shown to develop hypertension and metabolic alterations associated with insulin resistance either in standard dietary conditions (eNOS-/- homozygotes) or upon high-fat diet (HFD) (eNOS+/- heterozygotes). In the latter heterozygote model, the present study investigated the pancreatic morphological changes underlying the abnormal glycometabolic phenotype. C57BL6 wild type (WT) and eNOS+/- mice were fed with either chow or HFD for 16 weeks. After being longitudinally monitored for their metabolic state after 8 and 16 weeks of diet, mice were euthanized and fragments of pancreas were processed for histological, immuno-histochemical and ultrastructural analyses. HFD-fed WT and eNOS+/- mice developed progressive glucose intolerance and insulin resistance. Differently from WT animals, eNOS+/- mice showed a blunted insulin response to a glucose load, regardless of the diet regimen. Such dysregulation of insulin secretion was associated with pancreatic beta-cell hyperplasia, as shown by larger islet fractional area and beta-cell mass, and higher number of extra-islet beta-cell clusters than in chow-fed WT animals. In addition, only in the pancreas of HFD-fed eNOS+/- mice, there was ultrastructural evidence of a number of hybrid acinar-beta-cells, simultaneously containing zymogen and insulin granules, suggesting the occurrence of a direct exocrine-endocrine transdifferentiation process, plausibly triggered by metabolic stress associated to deficient endothelial NO production. As suggested by confocal immunofluorescence analysis of pancreatic histological sections, inhibition of Notch-1 signaling, likely due to a reduced NO availability, is proposed as a novel mechanism that could favor both beta-cell hyperplasia and acinar-beta-cell transdifferentiation in eNOS-deficient mice with impaired insulin response to a glucose load.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据