title: Progressive erosion of β-cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes.
abstract: OBJECTIVE
  A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice-the prototypic model for human type 1 diabetes.
  
  
  METHODS
  Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests.
  
  
  RESULTS
  During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity.
  
  
  CONCLUSIONS
  There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Diabetes and Metabolism, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ize-Ludlow
authors.forename: Yaima L
authors.initials: YL
authors.lastname: Lightfoot
authors.forename: Matthew
authors.initials: M
authors.lastname: Parker
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haller
authors.forename: Desmond
authors.initials: D
authors.lastname: Schatz
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Becker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
mesh_terms: D000818:Animals; D001120:Arginine; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000209:etiology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D011236:Prediabetic State / Q000503:physiopathology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D001120:Arginine; D005947:Glucose