Type 1 diabetes (T1D) is characterized by hyperglycemia due to lost or damaged islet insulin-producing β-cells. Rodent models of T1D result in hyperglycemia, but with different forms of islet deterioration. This study focused on 1 toxin-induced and 2 autoimmune rodent models of T1D: BioBreeding Diabetes Resistant rats, nonobese diabetic mice, and Dark Agouti rats treated with streptozotocin. Immunochemistry was used to evaluate the insulin levels in the β-cells, cell composition, and insulitis. T1D caused complete or significant loss of β-cells in all animal models, while increasing numbers of α-cells. Lymphocytic infiltration was noted in and around islets early in the progression of autoimmune diabetes. The loss of lymphocytic infiltration coincided with the absence of β-cells. In all models, the remaining α- and δ-cells regrouped by relocating to the islet center. The resulting islets were smaller in size and irregularly shaped. Insulin injections subsequent to induction of toxin-induced diabetes significantly preserved β-cells and islet morphology. Diabetes in animal models is anatomically heterogeneous and involves important changes in numbers and location of the remaining α- and δ-cells. Comparisons with human pancreatic sections from healthy and diabetic donors showed similar morphological changes to the diabetic BBDR rat model. 1. Introduction Rodent models of diabetes are frequently used in basic science and in industrial environments, such as the pharmaceutical industry. Animal models of diabetes have been used for the past 150 years and were instrumental in the discovery of insulin [1]. In humans with type 1 diabetes (T1D), it is estimated that 70% of the pancreatic β-cell mass has been destroyed by the time clinical signs of the disease are present [2]. Without safe methods of sampling or visualizing the human endocrine pancreas, animals are essential models of the disease. Rodent models have enabled the discovery of key scientific findings, but frequently these findings do not translate to the clinical setting [2]. The common rodent models of T1D include the BioBreeding Diabetes-Resistant (BBDR) rat, the nonobese diabetic (NOD) mice, and the streptozotocin-induced diabetic rodents. Rodents studied for T1D can be broadly classified as having either spontaneous or inducible forms of the disease. In spontaneous diabetes, such as the NOD mouse, the genetic background results in a defined prevalence of the disease [2]. In contrast, with inducible diabetes, the disease is precipitated by exposure to defined antigens or reagents [2]. While the
References
[1]
T. C. Thayer, S. B. Wilson, and C. E. Mathews, “Use of nonobese diabetic mice to understand human type 1 diabetes,” Endocrinology and Metabolism Clinics of North America, vol. 39, no. 3, pp. 541–561, 2010.
[2]
S. Hall and A. Cooke, “Autoimmunity and inflammation: murine models and translational studies,” Mammalian Genome, vol. 22, no. 7-8, pp. 377–389, 2011.
[3]
M. S. Anderson and J. A. Bluestone, “The NOD mouse: a model of immune dysregulation,” Annual Review of Immunology, vol. 23, pp. 447–485, 2005.
[4]
J. P. Driver, D. V. Serreze, and Y. G. Chen, “Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease,” Seminars in Immunopathology, vol. 33, no. 1, pp. 67–87, 2011.
[5]
W. C. Yeung, W. D. Rawlinson, and M. E. Craig, “Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies,” The British Medical Journal, vol. 342, article d35, 2011.
[6]
Z. Laron, “Interplay between heredity and environment in the recent explosion of type 1 childhood diabetes mellitus,” The American Journal of Medical Genetics, vol. 115, no. 1, pp. 4–7, 2002.
[7]
R. Bortell, S. C. Pino, D. L. Greiner, D. Zipris, and A. A. Rossini, “Closing the circle between the bedside and the bench: toll-like receptors in models of virally induced diabetes,” Annals of the New York Academy of Sciences, vol. 1150, pp. 112–122, 2008.
[8]
D. L. Greiner, J. P. Mordes, and E. S. Handler, “Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats,” Journal of Experimental Medicine, vol. 166, no. 2, pp. 461–475, 1987.
[9]
R. Bortell and C. Yang, “The BB rat as a model of human type 1 diabetes,” Methods in Molecular Biology, vol. 933, pp. 31–44, 2012.
[10]
T. Szkudelski, “The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas,” Physiological Research, vol. 50, no. 6, pp. 537–546, 2001.
[11]
J. H. Lee, S. H. Yanga, J. M. Oha, and M. G. Lee, “Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus,” Journal of Pharmacy and Pharmacology, vol. 62, no. 1, pp. 1–23, 2010.
[12]
C. Grant, S. K. Duclos, C. M. Moran-Paul et al., “Development of standardized insulin treatment protocols for spontaneous rodent models of type 1 diabetes,” Comparative Medicine, vol. 62, no. 5, pp. 381–390, 2012.
[13]
R. Loganathan, L. Novikova, I. G. Boulatnikov, and I. V. Smirnova, “Exercise-induced cardiac performance in autoimmune (Type 1) diabetes is associated with a decrease in myocardial diacylglycerol,” Journal of Applied Physiology, vol. 113, no. 5, pp. 817–826, 2012.
[14]
K. Farmer, S. J. Williams, L. Novikova et al., “KU-32, a novel drug for diabetic neuropathy, is safe for human islets and improves in vitro insulin secretion and viability,” Experimental Diabetes Research, vol. 2012, Article ID 671673, 2012.
[15]
H. Huang, K. Farmer, J. Windscheffel et al., “Exercise increases insulin content and basal secretion in pancreatic islets in type 1 diabetic mice,” Experimental Diabetes Research ., vol. 2011, Article ID 481427, 2011.
[16]
M. A. Atkinson and E. H. Leiter, “The NOD mouse model of type 1 diabetes: as good as it gets?” Nature Medicine, vol. 5, no. 6, pp. 601–604, 1999.
[17]
J. Couzin-Frankel, “Clinical studies. Trying to reset the clock on type 1 diabetes,” Science, vol. 333, no. 6044, pp. 819–821, 2011.
[18]
M. Brehm, A. C. Powers, L. D. Shultz, and D. L. Griener, “Advancing animal models of human type 1 diabetes by engraftment of functional human tissues in immunodeficient mice,” Cold Spring Harbor Perspectives in Medicine, vol. 2012, no. 2, Article ID 007757, 2012.
[19]
D. L. Eizirik, D. G. Pipeleers, Z. Ling, N. Welsh, C. Hellerstrom, and A. Andersson, “Major species differences between humans and rodents in the susceptibility to pancreatic β-cell injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 20, pp. 9253–9256, 1994.
[20]
D. Pipeleers, M. van de Winkel, T. Dyrberg, and A. Lernmark, “Spontaneously diabetic BB rats have age-dependent islet β-cell-specific surface antibodies at clinical onset,” Diabetes, vol. 36, no. 10, pp. 1111–1115, 1987.
[21]
P. A. In't Veld and D. G. Pipeleers, “In situ analysis of pancreatic islets in rats developing diabetes. Appearance of nonendocrine cells with surface MHC class II antigens and cytoplasmic insulin immunoreactivity,” Journal of Clinical Investigation, vol. 82, no. 3, pp. 1123–1128, 1988.
[22]
L. Orci, D. Baetens, C. Rufener et al., “Hypertrophy and hyperplasia of somatostatin-containing D-cells in diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 73, no. 4, pp. 1338–1342, 1976.
[23]
L. Wang, N. F. Lovejoy, and D. L. Faustman, “Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay,” Diabetes Care, vol. 35, no. 3, pp. 465–470, 2012.
[24]
J. Trudeau, J. P. Dutz, E. Arany, D. J. Hill, W. E. Fieldus, and D. T. Finegood, “Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?” Diabetes, vol. 49, no. 1, pp. 1–7, 2000.
[25]
G. Bouma, J. M. C. Coppens, S. Mourits et al., “Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice,” The European Journal of Immunology, vol. 35, no. 8, pp. 2386–2396, 2005.
[26]
T. Delovitch and B. Singh, “The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD,” Immunity, vol. 7, no. 6, pp. 291–297, 1997.
