title: Changes in beta cell function occur in prediabetes and early disease in the Lepr (db) mouse model of diabetes.
abstract: Type 2 diabetes is a progressive disease that increases morbidity and the risk of premature death. Glucose dysregulation, such as elevated fasting blood glucose, is observed prior to diabetes onset. A decline in beta cell insulin secretion contributes to the later stages of diabetes, but it is not known what, if any, functional beta cell changes occur in prediabetes and early disease.
  
  
  
  The Lepr (db) mouse (age 13-18 weeks) was used as a model of type 2 diabetes and a two-photon granule fusion assay was used to characterise the secretory response of pancreatic beta cells.
  
  
  
  We identified a prediabetic state in db/db mice where the animals responded normally to a glucose challenge but have elevated fasting blood glucose. Isolated islets from prediabetic animals secreted more and were bigger. Insulin secretion, normalised to insulin content, was similar to wild type but basal insulin secretion was elevated. There was increased glucose-induced granule fusion with a high prevalence of granule-granule fusion. The glucose-induced calcium response was not changed but there was altered expression of the exocytic machinery. db/db animals at the next stage of disease had overt glucose intolerance. Isolated islets from these animals had reduced insulin secretion, reduced glucose-induced granule fusion events and decreased calcium responses to glucose.
  
  
  
  Beta cell function is altered in prediabetes and there are further changes in the progression to early disease.
authors.affiliation: School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.|Charles Perkins Centre, University of Sydney, John Hopkins Drive, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: Oanh H
authors.initials: OH
authors.lastname: Do
authors.affiliation: Westmead Hospital, Sydney, NSW, 2145, Australia.|Westmead Institute for Medical Research, PO Box 412, Westmead, Sydney, NSW, 2145, Australia.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gunton
authors.affiliation: School of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.affiliation: School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia. p.thorn@uq.edu.au.|Charles Perkins Centre, University of Sydney, John Hopkins Drive, Camperdown, Sydney, NSW, 2050, Australia. p.thorn@uq.edu.au.
authors.forename: Peter
authors.initials: P
authors.lastname: Thorn
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005089:Exocytosis / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D011236:Prediabetic State / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D007328:Insulin
keywords: Beta cell; Compound exocytosis; Exocytosis; Insulin granules; Islets; Prediabetes; Progression