title: Insulin-producing intestinal K cells protect nonobese diabetic mice from autoimmune diabetes.
abstract: OBJECTIVE
  Type 1 diabetes is caused by an aberrant response against pancreatic β cells. Intestinal K cells are glucose-responsive endocrine cells that might be engineered to secrete insulin. We generated diabetes-prone non-obese diabetic (NOD) mice that express insulin, via a transgene, in K cells. We assessed the effects on immunogenicity and diabetes development.
  
  
  METHODS
  Diabetes incidence and glucose homeostasis were assessed in NOD mice that expressed mouse preproinsulin II from a transgene in K cells and nontransgenic NOD mice (controls); pancreas and duodenum tissues were collected and analyzed by histology. We evaluated T cell responses to insulin, levels of circulating autoantibodies against insulin, and the percentage of circulating antigen-specific T cells. Inflammation of mesenteric and pancreatic lymph node cells was also evaluated.
  
  
  RESULTS
  The transgenic mice tended to have lower blood levels of glucose than control mice, associated with increased plasma levels of immunoreactive insulin and proinsulin. Fewer transgenic mice developed diabetes than controls. In analyses of pancreas and intestine tissues from the transgenic mice, insulin-producing K cells were not affected by the immune response and the mice had reduced destruction of endogenous β cells. Fewer transgenic mice were positive for insulin autoantibodies compared with controls. Cells isolated from mesenteric lymph nodes of the transgenic mice had significantly lower rates of proliferation and T cells from transgenic mice tended to secrete lower levels of inflammatory cytokines than from controls. At 15 weeks, transgenic mice had fewer peripheral CD8(+) T cells specific for NRP-V7 than control mice.
  
  
  CONCLUSIONS
  NOD mice with intestinal K cells engineered to express insulin have reduced blood levels of glucose, are less likely to develop diabetes, and have reduced immunity against pancreatic β cells compared with control NOD mice. This approach might be developed to treat patients with type 1 diabetes.
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Mojibian
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ada W Y
authors.initials: AW
authors.lastname: Lam
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Asadi
authors.affiliation: Institute for Experimental Medicine, Christian Albrechts University Kiel, Kiel, Germany.
authors.forename: Guntram A
authors.initials: GA
authors.lastname: Grassl
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dickie
authors.affiliation: Child and Family Research Institute, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
authors.affiliation: enGene, Inc, Vancouver, British Columbia, Canada.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Cheung
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: tim.kieffer@ubc.ca.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D019858:Enteroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000276:immunology / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D007328:Insulin; D005947:Glucose
keywords: Autoimmunity; GIP; Glucose-Dependent Insulinotropic Polypeptide; Gut K Cells