Studies on Autoimmunity for Initiation of β-Cell Destruction: VII. Evidence for Antigenic Changes on β-Cells Leading to Autoimmune Destruction of β-Cells in BB Rats

Ihm, Sung-Hee; Lee, Ki-Up; Yoon, Ji‐Won

doi:10.2337/diab.40.2.269

Cited by 22 publications

(6 citation statements)

References 18 publications

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“…Interestingly, we have recently demonstrated enhanced production of 02and H202 in 75-day-old BBdp and 115-day-old BBd rat macrophages [17]. Once attracted into pancreatic islets due to fl-cell-specific antigenic changes [32], or for other as yet unidentified reasons, activated macrophages may release large amounts of NO (Table 1), 02and H202 [171] The increase in NO synthesis in BBdp and BBd macrophages may be sustained by maintaining a sufficient intracellular L-arginine concentration via the recycling of L-citrulline into L-arginine (Table 1), when the cells are present in the inflammatory sites of the pancreatic islets. It is possible that an inhibition of NO synthesis in BBdp rat macrophages may preclude autoimmune destruction of pancreatic f-cells.…”

Section: Discussionmentioning

confidence: 95%

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat

Flynn

1993

Biochemical Journal

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The activity of the arginine-citrulline cycle was investigated in macrophages from the spontaneous immunologically mediated diabetic BB rat. Peritoneal macrophages were prepared from male diabetes-prone (BBdp), diabetic (BBd) and age-matched non-diabetes-prone (BBn) rats. Cells were incubated at 37 degrees C for 2 h in Krebs-Henseleit bicarbonate buffer containing 0.5 mM L-arginine, 0.1 mM L-[ureido-14C]citrulline and 5 mM D-glucose to measure the activity of the arginine-citrulline cycle. The uptakes of citrulline and arginine by macrophages were measured during a 5 min incubation period with L-[ureido-14C]citrulline and L-[2,3-3H] arginine respectively. The production of NO3- (the major stable oxidation product of NO) increased (P < 0.01) by 112% and 151% in 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The conversion of [14C]citrulline into [14C]arginine increased (P < 0.01) by 704%, 892% and 904% in 50- and 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The enhanced NO synthesis in BBdp and BBd macrophages was associated with a 25-35% increase in the uptake of L-arginine. However, there were no differences in the uptake of citrulline between BBdp or BBd macrophages and age-matched BBn cells. Our results demonstrate for the first time the activation of the arginine-citrulline cycle in macrophages in an autoimmune condition. The inherent increase in the recycling of L-citrulline to L-arginine in BBdp and BBd macrophages may reflect an innate metabolic disorder in these cells. This increased L-arginine synthesis from L-citrulline may play a role in sustaining a sufficient intracellular L-arginine concentration for prolonged generation of NO in BBdp and BBd macrophages. A role for NO in the autoimmune destruction of pancreatic beta-cells in insulin-dependent diabetes mellitus warrants further investigation.

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Section: Discussionmentioning

confidence: 95%

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat

Flynn

1993

Biochemical Journal

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“…In all likelihood, this lack of tolerance induction manifests itself by the absence ofcells capable of suppressing islet effectors. Furthermore, the data of Ihm et al (13) suggested that islets from rats of the age at which self tolerance is normally induced, i.e., neonates, lacked certain antigenic determinants, which could explain the lack of islet tolerance in adult DP rats. In support of Ihm's data, Buschard et al (25) reported that diabetes in BB rats can be prevented by the neonatal stimulation of beta cells.…”

Section: Discussionmentioning

confidence: 99%

“…Injection ofislets intrathymically might be one mechanism by which the activity ofthymic APCs, vis-a-vis their role in establishing islet tolerance, could be enhanced. Ihm et al (13) suggested that islets from rats of the age at which self tolerance is normally induced, i.e., neonates, lacked certain antigenic determinants, which could also explain the lack of islet tolerance in adult BB/Wor rats. Intrathymic injection of adult islets containing these antigens could help to reestablish islet tolerance.…”

Section: Introductionmentioning

confidence: 99%

Prevention of diabetes in BB/Wor rats by intrathymic islet injection.

Koevary

Blomberg²

1992

J. Clin. Invest.

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The objective of this study was to determine whether the intrathymic injection of islets can prevent the development of diabetes in BB/Wor rats. Evidence suggests that a failure to induce islet thymic tolerance may be an etiological factor in the development of the disease. It was theorized that the introduction of islets into the thymus might directly induce islet tolerance and thus prevent disease. Islets from diabetes-resistant BB/Wor rats were injected into the thymuses of 23 young diabetes-prone BB/Wor rats; 25 sham-operated animals served as controls. Results showed that 22 of the 25 control rats became diabetic while only 8 of the 23 experimental rats became diabetic (P < 0.0002). The specific lysis of islet cells by spleen cells from nondiabetic experimental and control rats was comparable and less than the lysis induced by spleen cells from diabetic rats. These data demonstrate that the intrathymic injection of islets into diabetes-prone BB/Wor rats is an effective method for preventing the development of autoimmune type I diabetes. (J. Clin. Invest.

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“…Conversely, by administering exogenous insulin in BBdp rats, the incidence of diabetes can be reduced [26]. Transplantation of normal histocompatible islets from Wistar-Furth rats still stimulates the immune attack in BB rats and suggests that an antigen normally expressed in pancreatic islets mediates the autoaggressive T-cell attack [28,29]. The increase in proglucagon mRNA, therefore, resulting in increased GLP-1 and GLP-2 production, may play an important role in increasing the secretory potential of pancreatic islets and ultimate disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Ontogenic changes in proglucagon mRNA in BB diabetes prone and normal rats weaned onto a chow diet

1997

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The bio-breeding (BB) rat is a useful animal model of human insulin-dependent diabetes mellitus (IDDM) [1,2]. The BB rat displays many of the immune irregularities associated with the human disease. As in human IDDM the syndrome is spontaneous and results in the autoimmune destruction of the insulinproducing beta cells of the pancreas [3,4]. It is well established that both forms of diabetes, human and BB are autoimmune.Investigations into the aetiology of IDDM suggest that both genetic and environmental factors are involved [5]. It is now well recognized that diet is an important factor influencing development of diabetes in the BB rat [6,7]. Studies suggest that semi-purified diet may be protective whereas laboratory chow may be more diabetogenic in nature [8,9].Whether the protective effect of a semi-purified diet is due to the presence of a specific protective component or conversely the absence of a diabetogenic component is yet unknown. It is known, however, that the timing of initial exposure and duration of Diabetologia (1997) Summary Weaning onto chow diets causes the highest incidence of diabetes in the BB rat. Changes in gut development and absorption of nutrients in the diabetes prone rat and the subsequent effect on pancreatic function may play a role in the ultimate development of the disease. BB diabetes prone (dp) and BB normal (n) dams were fed chow diets. Pups were killed at various ages ranging from 7 to 30 days. BBdp rats had higher small intestine and colon weights expressed per body weight at all ages (p < 0.0001). RNA content (mg/g) in the jejunum, ileum and colon was higher in the BBdp rats beginning at the critical period at 21 days and maintained at 24 days and 30 days (p < 0.0001). Proglucagon message decreased with age in both BBdp and BBn animals (p < 0.0001). Levels of proglucagon mRNA were higher in BBdp compared to BBn animals only in the ileum at 10 days (p < 0.01). Adjusting for total ileal and colonic RNA content resulted in BBdp animals having higher total colonic proglucagon mRNA at 21, 24 and 30 days (p < 0.0001). Plasma GLP-1(7-36) amide was more than doubled in BBdp compared to BBn animals (p < 0.0005) at 30 days. Expressing sodium-dependent D-glucose co-transporter (SGLT-1), GLUT2 and GLUT5 mRNA per total jejunal RNA shows increased transporter mRNA in BBdp compared to BBn rats at weaning (21 days) (p < 0.05). Radical differences exist between BBdp and BBn animals at 'critical periods' in both proglucagon and glucose transporter gene expression. These differences may help explain altered growth and diseases incidence between these two strains [Diabetologia (1997) 40: 871-878].

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Studies on Autoimmunity for Initiation of β-Cell Destruction: VII. Evidence for Antigenic Changes on β-Cells Leading to Autoimmune Destruction of β-Cells in BB Rats

Cited by 22 publications

References 18 publications

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat

Prevention of diabetes in BB/Wor rats by intrathymic islet injection.

Ontogenic changes in proglucagon mRNA in BB diabetes prone and normal rats weaned onto a chow diet

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