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Mutated ATP synthase induces oxidative stress and impaired insulin secretion in beta-cells of female BHE/cdb rats.

Abstract：

BACKGROUND:Adenosine triphosphate (ATP) is a critical determinant of beta-cell insulin secretion in response to glucose. BHE/cdb rats have a mutation in ATP synthase that limits ATP production, yet develop mild diabetes only with ageing. We investigated the cellular basis for reduced insulin secretion and compensatory mechanisms that mitigate the effects of the ATP synthase mutation. METHODS:In vitro beta-cell function in isolated islets and expression of key regulatory genes was compared with in vivo oral glucose tolerance and insulin sensitivity in BHE/cdb and control rats. RESULTS:BHE/cdb rat islets had reduced responsiveness to glucose stimulation and ATP content was 35% lower than in control islets. Oral glucose tolerance was impaired at both 21 and 43 weeks of age because of a reduction in glucose-stimulated insulin secretion (GSIS). An increase in inducible nitric oxide synthase (INOS, 3-fold) and manganese superoxide dismutase (MnSOD, 1.6-fold), detection of nitrotyrosine, beta-cell apoptosis, and nucleocytoplasmic translocation of pancreas duodenum homeobox-1 (PDX-1) in beta-cells indicated increased oxygen radical formation. However, BHE/cdb rats partially compensated for low glucose responsiveness by increasing the number of small islets and beta-cell hypertrophy. There was also an increase in the proportion of mature insulin relative to proinsulin (PI) detected within beta-cell granules. Increased activation of AMP-dependent kinase (AMPK)-regulated pathways was consistent with increased oxidative stress and with induction of apoptosis and reduction of preproinsulin gene transcription. CONCLUSIONS:The findings are consistent with impaired but partially compensated mechanisms of insulin secretion early in life, but progressive non-compensated impairments due to oxidative stress occurs by age 43 weeks.

journal_name

Diabetes Metab Res Rev

journal_title

Diabetes/metabolism research and reviews

authors

Saleh MC,Fatehi-Hassanabad Z,Wang R,Nino-Fong R,Wadowska DW,Wright GM,Harper ME,Chan CB

doi

10.1002/dmrr.819

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

392-403

issue

eissn

1520-7552

issn

1520-7560

journal_volume

pub_type

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Mutated ATP synthase induces oxidative stress and impaired insulin secretion in beta-cells of female BHE/cdb rats.