title: Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes.
abstract: Most natural history models for type 1 diabetes (T1D) propose that overt hyperglycemia results after a progressive loss of insulin-secreting β-cell mass and/or function. To experimentally address this concept, we prospectively determined morning blood glucose measurements every other day in multiple cohorts (total n = 660) of female NOD/ShiLtJ mice starting at 8 weeks of age until diabetes onset or 26 weeks of age. Consistent with this notion, a majority of mice that developed diabetes (354 of 489 [72%]) displayed a progressive increase in blood glucose with transient excursions >200 mg/dL, followed by acute and persistent hyperglycemia at diabetes onset. However, 135 of the 489 (28%) diabetic animals demonstrated normal glucose values followed by acute (i.e., sudden) hyperglycemia. Interestingly, diabetes onset occurred earlier in mice with acute versus progressive disease onset (15.37 ± 0.3207 vs. 17.44 ± 0.2073 weeks of age, P < 0.0001). Moreover, the pattern of onset (i.e., progressive vs. acute) dramatically influenced the ability to achieve reversal of T1D by immunotherapeutic intervention, with increased effectiveness observed in situations of a progressive deterioration in euglycemia. These studies highlight a novel natural history aspect in this animal model, one that may provide important guidance for the selection of subjects participating in human trials seeking disease reversal.
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL.
authors.forename: Amanda
authors.initials: A
authors.lastname: Posgai
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL.
authors.forename: Yaima L
authors.initials: YL
authors.lastname: Lightfoot
authors.affiliation: Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and the Diabetes Center, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL.
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haller
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL.
authors.forename: Desmond
authors.initials: D
authors.lastname: Schatz
authors.affiliation: Department of Pathology, University of Florida, Gainesville, FL atkinson@ufl.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy; D018450:Disease Progression; D005260:Female; D006943:Hyperglycemia / Q000097:blood* / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents