title: High-fat diet induces early-onset diabetes in heterozygous Pax6 mutant mice.
abstract: BACKGROUND
  Type 2 diabetes is caused by interactions between genetic and environmental factors. Our previous studies reported that paired box 6 mutation heterozygosity (Pax6(m/+)) led to defective proinsulin processing and subsequent abnormal glucose metabolism in mice at 6  months of age. However, high-fat diet exposure could be an important incentive for diabetes development. In this study, we aimed to develop a novel diabetic model imitating human type 2 diabetes by exposing Pax6(m/+) mice to high-fat diet and to explore the underlying mechanism of diabetes in this model.
  
  
  METHODS
  Over 300 Pax6(m/+) and wild-type male weanling mice were randomly divided into two groups and were fed an high-fat diet or chow diet for 6-10  weeks. Blood glucose and glucose tolerance levels were monitored during this period. Body weights, visceral adipose weights, blood lipid profiles and insulin sensitivity (determined with an insulin tolerance test) were used to evaluate obesity and insulin resistance. Proinsulin processing and insulin secretion levels were used to evaluate pancreatic β cell function.
  
  
  RESULTS
  After 6  weeks of high-fat diet exposure, only the Pax6(m/+) mice showed dramatic postloading hyperglycaemia. These mice exhibited significant high-fat diet-induced visceral obesity and insulin resistance and displayed defective prohormone convertase 1/3 production, an increased proinsulin:total insulin ratio and impaired early-phase insulin secretion, because of the Pax6 mutation. Hyperglycaemia worsened progressively over time with the high-fat diet, and most Pax6(m/+) mice on high-fat diet developed diabetes or impaired glucose tolerance after 10  weeks. Furthermore, high-fat diet withdrawal partly improved blood glucose levels in the diabetic mice.
  
  
  CONCLUSIONS
  By combining the Pax6(m/+) genetic background with an high-fat diet environment, we developed a novel diabetic model to mimic human type 2 diabetes. This model is characterized by impaired insulin secretion, caused by the Pax6 mutation, and high-fat diet-induced insulin resistance and therefore provides an ideal tool for research on type 2 diabetes pathogenesis and therapies.
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Peking University Stem Cell Research Centre, Peking University Health Science Center, Beijing, China; Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Ruopeng
authors.initials: R
authors.lastname: Feng
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Wei
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Haining
authors.initials: H
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Tian-pei
authors.initials: TP
authors.lastname: Hong
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wen
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000209:etiology / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D056128:Obesity, Abdominal / Q000150:complications / Q000209:etiology* / Q000503:physiopathology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011236:Prediabetic State / Q000097:blood / Q000150:complications / Q000209:etiology / Q000378:metabolism; D011384:Proinsulin / Q000097:blood / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000378:metabolism; D011897:Random Allocation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014886:Weaning; D015430:Weight Gain
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D052216:Glucagon-Like Peptide 1; D011384:Proinsulin; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1
keywords: Pax6 mutation; high-fat diet; pancreatic β cells; type 2 diabetes