Mutated ATP synthase induces oxidative stress and impaired insulin secretion in β‐cells of female BHE/cdb rats
| Autor: | Zahra Fatehi-Hassanabad, Rodolpho Nino‐Fong, Monique C. Saleh, Rennian Wang, Glenda M. Wright, Catherine B. Chan, Mary-Ellen Harper, Dorota W. Wadowska |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Preproinsulin Endocrinology Diabetes and Metabolism medicine.medical_treatment medicine.disease_cause Islets of Langerhans chemistry.chemical_compound Adenosine Triphosphate Endocrinology Insulin-Secreting Cells Internal medicine Insulin Secretion Internal Medicine medicine Animals Insulin Proinsulin Glucose tolerance test Phosphotransferases (Phosphate Group Acceptor) ATP synthase biology medicine.diagnostic_test Glucose Tolerance Test Rats Nitric oxide synthase Oxidative Stress Proton-Translocating ATPases Phenotype chemistry biology.protein Female Adenosine triphosphate Oxidative stress |
| Zdroj: | Diabetes/Metabolism Research and Reviews. 24:392-403 |
| ISSN: | 1520-7560 1520-7552 |
| DOI: | 10.1002/dmrr.819 |
| Popis: | Background Adenosine triphosphate (ATP) is a critical determinant of β-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 β-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, β-cell apoptosis, and nucleocytoplasmic translocation of pancreas duodenum homeobox-1 (PDX-1) in β-cells indicated increased oxygen radical formation. However, BHE/cdb rats partially compensated for low glucose responsiveness by increasing the number of small islets and β-cell hypertrophy. There was also an increase in the proportion of mature insulin relative to proinsulin (PI) detected within β-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. Copyright © 2008 John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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