aston-highglucose-2005.pdf (162.5 kB)
High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction
journal contribution
posted on 2005-08-01, 00:00 authored by S Kooptiwut, M Kebede, S Zraika, S Visinoni, Kathryn Aston-MourneyKathryn Aston-Mourney, J Favaloro, C Tikellis, M Thomas, J Forbes, M Cooper, M Dunlop, J Proietto, S AndrikopoulosType 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.
History
Journal
Journal of molecular endocrinologyVolume
35Issue
1Pagination
39 - 48Publisher
BioScientificaLocation
Bristol, EnglandPublisher DOI
ISSN
0952-5041eISSN
1479-6813Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2005, BioScientificaUsage metrics
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advanced glycation end productaminoguanidineglucokinaseglucoseglucose transporter 2hexokinaseinsulinScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismHUMAN PANCREATIC-ISLETSGLYCATION END-PRODUCTSB-CELL FUNCTIONBETA-CELLCHRONIC EXPOSUREDIABETIC-NEPHROPATHYGENE-EXPRESSIONMESSENGER-RNAHIT CELLSIN-VITRO
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