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Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms

Catmull, S; Masood, F; Schacht, S; Dolan, R; Stegman, D; Leung, L; Al-Nakkash, L; (2016) Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms. Cellular Physiology and Biochemistry , 40 (1-2) pp. 335-346. 10.1159/000452549. Green open access

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Abstract

BACKGROUND/AIMS: The goal of this study was to determine the effect of dietary genistein (naturally occurring phytoestrogen) on jejunal secretory function in a clinically relevant model of diabetes and obesity, the leptin-defIcient ob/ob mouse. METHODS: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from 12-week old male and female ob/ob and lean C57Bl/6J mice fed a genistein diet (600 mg genistein/kg diet) for 4-weeks. Separate segments of jejunum were frozen for western blot determination of key proteins involved in secretory transport. RESULTS: Basal Isc was signifIcantly decreased (by 33%, P<0.05) in ob/ob females versus leans, and genistein-diet reversed this. Similarly, in males, basal Isc was decreased (by 47%, P<0.05) in ob/ob mice versus leans, and genistein-diet reversed this. Inhibition with either clotrimazole (100 µM, bilateral) or ouabain (100 µM, basolateral) was signifIcantly reduced in ob/ob mice compared to leans (P<0.05), and genistein-diet reversed clotrimazole-sensitive inhibition in ob/ob females, and reversed the ouabain-sensitive inhibition in males (indicating sex-dependent mechanisms). Our data suggested that PDE3 levels were dysregulated in ob/ob females and genistein reversed this. Expression of total CFTR (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in all ob/ob mice compared to leans, and genistein-diet was without effect. Expression of total NKCC1 (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in ob/ob male mice versus leans, and genistein-diet reversed this. CONCLUSIONS: Our data suggests that the reduced basal jejunal Isc in ob/ob female mice is a consequence of reduced CFTR expression, decreased activities of the basolateral KCa channel and Na+/K+-ATPase, and in male mice reduced basal jejunal Isc is a consequence of reduced CFTR and NKCC1 expression, along with decreased activities of the basolateral KCa channel and Na+/K+-ATPase. Genistein-diet has beneficial effects on basal Isc mediated by sex-dependent mechanisms in diabetic mice: in females via increased KCa-sensitive Isc and in males via increased Na+/K+-ATPase activity and increased NKCC1 expression. Improved understanding of intestinal dysfunctions in the ob/ob jejunum, may allow for the development of novel drug targets to treat obesity and diabetes, and may also be of benefit in CF-related diabetes.

Type: Article
Title: Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.1159/000452549
Publisher version: http://doi.org/10.1159/000452549
Language: English
Additional information: © 2016 The Author(s) Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.
Keywords: Animals, Chlorides, Cystic Fibrosis Transmembrane Conductance Regulator, Diabetes Mellitus, Experimental, Diet, Electricity, Female, Genistein, Jejunum, Male, Mice, Inbred C57BL, Mice, Obese, Phosphodiesterase Inhibitors, Sex Characteristics, Sodium-Potassium-Exchanging ATPase, Solute Carrier Family 12, Member 2
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Imaging Neuroscience
URI: https://discovery.ucl.ac.uk/id/eprint/1534931
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