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Title: High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction.
Austin Authors: Kooptiwut, Suwattanee;Kebede, Melkam;Zraika, Sakeneh;Visinoni, Sherley;Aston-Mourney, Kathryn;Favaloro, Jenny M;Tikellis, Christos;Thomas, Merlin C;Forbes, Josephine M;Cooper, Mark E;Dunlop, Marjorie E;Proietto, Joseph ;Andrikopoulos, Sofianos
Affiliation: University of Melbourne, Department of Medicine, Heidelberg Repatriation Hospital, 300 Waterdale Road, Heidelberg Heights, Victoria 3081, Australia
Issue Date: 1-Aug-2005
Publication information: Journal of Molecular Endocrinology; 35(1): 39-48
Abstract: Type 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.
Gov't Doc #: 16087720
DOI: 10.1677/jme.1.01720
Type: Journal Article
Subjects: Animals
Base Sequence
Cell Survival
Diabetes Mellitus, Type 2.etiology.genetics.pathology.physiopathology
Glucose.administration & dosage.pharmacology
Glucose Transporter Type 2
Glycosylation End Products, Advanced.metabolism
In Vitro Techniques
Islets of Langerhans.drug effects.pathology.physiopathology
Mice, Inbred C57BL
Mice, Inbred DBA
Monosaccharide Transport Proteins.metabolism
RNA, Messenger.genetics.metabolism
Appears in Collections:Journal articles

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