Progressive Erosion of β-Cell Function Precedes the Onset of Hyperglycemia in the NOD Mouse Model of Type 1 Diabetes
- Diego Ize-Ludlow1,
- Yaima L. Lightfoot2,
- Matthew Parker2,
- Song Xue2,
- Clive Wasserfall2,
- Michael J. Haller3,
- Desmond Schatz3,
- Dorothy J. Becker1,
- Mark A. Atkinson2 and
- Clayton E. Mathews2⇓
- 1Department of Pediatrics, Division of Pediatric Endocrinology, Diabetes and Metabolism, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- 2Department of Pathology, University of Florida, Gainesville, Florida
- 3Department of Pediatrics, University of Florida, Gainesville, Florida
- Corresponding author: Clayton E. Mathews, .
OBJECTIVE A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice—the prototypic model for human type 1 diabetes.
RESEARCH DESIGN AND METHODS Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6–14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests.
RESULTS During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity.
CONCLUSIONS There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.
- Received March 18, 2011.
- Accepted May 3, 2011.
- © 2011 by the American Diabetes Association.
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