title: Advanced glycation end products are direct modulators of β-cell function.
abstract: OBJECTIVE
  Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D).
  
  
  METHODS
  The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE-fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium.
  
  
  RESULTS
  β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors.
  
  
  CONCLUSIONS
  These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.
authors.affiliation: Division of Diabetes Complications, Diabetes and Metabolism Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.forename: Felicia Y T
authors.initials: FY
authors.lastname: Yap
authors.forename: David C K
authors.initials: DC
authors.lastname: Tong
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.forename: Anna
authors.initials: A
authors.lastname: Gasser
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.forename: Diane E
authors.initials: DE
authors.lastname: Webster
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Slattery
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
authors.forename: Spiros
authors.initials: S
authors.lastname: Fourlanos
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000293:Adolescent; D000818:Animals; D002460:Cell Line; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017127:Glycation End Products, Advanced