Apoptosis Is the Mode of β-Cell Death Responsible for the Development of IDDM in the Nonobese Diabetic (NOD) Mouse

Abstract

The NOD/Lt mouse, a widely used model of human autoimmune IDDM, was used to establish the mode of beta-cell death responsible for the development of IDDM. Apoptotic cells were present within the islets of Langerhans in hematoxylin and eosin-stained sections of pancreases harvested from 3- to 18-week-old female NOD/Lt mice (a range of 11-50 apoptotic cells per 100 islets). Immunohistochemical localization of insulin to the dying cells confirmed the beta-cell origin of the apoptosis. Although some islets from age-matched control female NOD/scid mice contained apoptotic cells, virtually all of these cells were insulin negative as determined by immunohistochemistry. The small number of apoptotic insulin-positive cells identified in islets from NOD/scid mice (a range of 0-1 apoptotic cells per 100 islets) was not statistically significant, compared with the numbers recorded in NOD/Lt mice. All dying cells showed the morphological changes characteristic of cell death by apoptosis and stained positively with the TUNEL method for end-labeling DNA strand breaks. The maximum mean amount of beta-cell apoptosis occurring in NOD/Lt mice was at week 15 (50 apoptotic cells per 100 islets), which coincided with the earliest onset of diabetes as determined by blood glucose, urine glucose, and pancreatic immunoreactive insulin measurements. While there was no peak incidence of beta-cell apoptosis throughout the time period studied (weeks 3-18), the incidence of apoptosis decreased at week 18, by which time 50% of the animals had overt diabetes. The low levels of beta-cell apoptosis observed is indicative of a gradual deletion of the beta-cell population throughout the extensive preclinical period seen in this model and would be sufficient to account for the beta-cell loss resulting in IDDM. Apoptosis of beta-cells preceded the appearance of T-cells (CD3-positive by immunohistochemistry) in islets. Lymphocytic infiltration of islets (insulitis) was not detected until week 6. The results show that beta-cell apoptosis is responsible for the development of IDDM in the NOD/Lt mouse and that its onset precedes lymphocytic infiltration of the islets.

Apoptosis and disease progression in the spontaneously diabetic BB/S rat

“…These results are in agreement with studies carried out in the NOD mouse [3] where apoptosis was shown to increase with age and to peak immediately before the onset of diabetes. In another study using NOD mice [4], apoptotic cells were detected as early as 3 weeks of age. In contrast with our studies, this early detection of apoptotic beta-cells preceded the appearance of T cells which, the authors speculated, may have triggered beta-cell destruction and diabetes.…”

“…Recent experimental data indicate that apoptosis plays a part in the destruction of beta-cells during onset of Type I diabetes [4,8]. In vitro, apoptosis has been identified as the main mechanism of cell death in islets and beta-cell lines exposed to cytokines and other cellular insults [3,9].…”

“…The process of apoptosis is so rapid that quantifying apoptosis in vivo is extremely difficult. Despite this, studies in the non-obese diabetic (NOD) mouse model have implicated apoptosis in the mechanism of beta-cell destruction in Type I diabetes mellitus [3,4]. There is, however, still considerable debate about the precise timing and extent of apoptosis.…”

TNF-Related Apoptosis-Inducing Ligand Death Pathway-Mediated Human Beta-Cell Destruction

“…Programmed cell death, or apoptosis is an important pathogenesis in the development of Type I diabetes [1,2,3]. Morphological changes indicative of apoptosis have been observed in normal islets and appear at an increased frequency in islets with Type I diabetes-associated insulitis [3].…”

“…Programmed cell death, or apoptosis is an important pathogenesis in the development of Type I diabetes [1,2,3]. Morphological changes indicative of apoptosis have been observed in normal islets and appear at an increased frequency in islets with Type I diabetes-associated insulitis [3]. Defining the signalling components of apoptosis present in beta cells is important because it could provide insights into potential pathogenic mechanisms and might lead to the development of pharmacological interventions for the treatment of Type I diabetes.…”