title: Adaptive changes of human islets to an obesogenic environment in the mouse.
abstract: OBJECTIVE
  In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.
  
  
  METHODS
  Non-diabetic Rag2                   (-/-) mice (n = 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA(lc) or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.
  
  
  RESULTS
  Transplanted mice on an HFD gained significantly more weight (p < 0.001) and had higher fasting glycaemia (2-12 weeks; p = 0.0002) and consistently higher fasting human C-peptide levels (2-12 weeks; p = 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (p < 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (p < 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD.
  
  
  CONCLUSIONS
  This longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.
authors.affiliation: Université Lille Nord de France, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Gargani
authors.forename: J
authors.initials: J
authors.lastname: Thévenet
authors.forename: J E
authors.initials: JE
authors.lastname: Yuan
authors.forename: B
authors.initials: B
authors.lastname: Lefebvre
authors.forename: N
authors.initials: N
authors.lastname: Delalleau
authors.forename: V
authors.initials: V
authors.lastname: Gmyr
authors.forename: T
authors.initials: T
authors.lastname: Hubert
authors.forename: A
authors.initials: A
authors.lastname: Duhamel
authors.forename: F
authors.initials: F
authors.lastname: Pattou
authors.forename: J
authors.initials: J
authors.lastname: Kerr-Conte
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse