title: Blood glucose levels regulate pancreatic beta-cell proliferation during experimentally-induced and spontaneous autoimmune diabetes in mice.
abstract: BACKGROUND
  Type 1 diabetes mellitus is caused by immune-mediated destruction of pancreatic beta-cells leading to insulin deficiency, impaired intermediary metabolism, and elevated blood glucose concentrations. While at autoimmune diabetes onset a limited number of beta-cells persist, the cells' regenerative potential and its regulation have remained largely unexplored. Using two mouse autoimmune diabetes models, this study examined the proliferation of pancreatic islet ss-cells and other endocrine and non-endocrine subsets, and the factors regulating that proliferation.
  
  
  RESULTS
  We adapted multi-parameter flow cytometry techniques (including DNA-content measurements and 5'-bromo-2'-deoxyuridine [BrdU] incorporation) to study pancreatic islet single cell suspensions. These studies demonstrate that beta-cell proliferation rapidly increases at diabetes onset, and that this proliferation is closely correlated with the diabetic animals' elevated blood glucose levels. For instance, we show that when normoglycemia is restored by exogenous insulin or islet transplantation, the beta-cell proliferation rate returns towards low levels found in control animals, yet surges when hyperglycemia recurs. In contrast, other-than-ss endocrine islet cells did not exhibit the same glucose-dependent proliferative responses. Rather, disease-associated alterations of BrdU-incorporation rates of delta-cells (minor decrease), and non-endocrine islet cells (slight increase) were not affected by blood glucose levels, or were inversely related to glycemia control after diabetes onset (alpha-cells).
  
  
  CONCLUSIONS
  We conclude that murine beta-cells' ability to proliferate in response to metabolic need (i.e. rising blood glucose concentrations) is remarkably well preserved during severe, chronic beta-cell autoimmunity. These data suggest that timely control of the destructive immune response after disease manifestation could allow spontaneous regeneration of sufficient beta-cell mass to restore normal glucose homeostasis.
authors.affiliation: Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA. klausp@intra.niddk.nih.gov
authors.forename: Klaus
authors.initials: K
authors.lastname: Pechhold
authors.forename: Kerstin
authors.initials: K
authors.lastname: Koczwara
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhu
authors.forename: Victor S
authors.initials: VS
authors.lastname: Harrison
authors.forename: Greg
authors.initials: G
authors.lastname: Walker
authors.forename: Janet
authors.initials: J
authors.lastname: Lee
authors.forename: David M
authors.initials: DM
authors.lastname: Harlan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000473:pathology*; D005434:Flow Cytometry; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD
chemical_list: D001786:Blood Glucose; D007328:Insulin; D004247:DNA; D001973:Bromodeoxyuridine