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.

Dysregulated insulin secretion is associated with pancreatic β-cell hyperplasia and direct acinar-β-cell trans-differentiation in partially eNOS-deficient mice

Novelli, Michela;Masini, Matilde
Co-primo
;
Vecoli, Cecilia;Moscato, Stefania;Funel, Niccola;Mattii, Letizia;Ippolito, Chiara;Campani, Daniela;Neglia, Danilo;Masiello, Pellegrino
2022-01-01

Abstract

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.
2022
Novelli, Michela; Masini, Matilde; Vecoli, Cecilia; Moscato, Stefania; Funel, Niccola; Pippa, Anna; Mattii, Letizia; Ippolito, Chiara; Campani, Daniel...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1154679
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