Insulin-dependent Diabetes and Gut Dysfunction: The BB Rat Model

Malaisse, Willy; Courtois, Philippe; Scott, Fraser W.

doi:10.1055/s-2004-825920

Cited by 26 publications

(32 citation statements)

References 30 publications

(39 reference statements)

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“…The present study shows that this is also the case in young BBdp rats. Moreover, these animals display several signs of gut damage including a mild coeliac-like enteropathy [10], decreased disaccharidase activity [40] decreased mucin content [14,47], and increased gut permeability to FITC-conjugated dextran 4000 [14,47] and mannitol [11].…”

Section: Discussionmentioning

confidence: 99%

“…5) [46]. The development of enteropathy in the BBdp gut by as early as 30 days [10] could set the stage for the continuing inflammatory damage and increased permeability [11,47] that has been linked to diabetes outcome [48] and is reported to be diet-modifiable [14,47]. A leaky gut could permit the entry of unusually large amounts of soluble dietary wheat antigens through the mucosal barrier.…”

Section: Discussionmentioning

confidence: 99%

“…Our group recently identified a wheat storage globulin-like protein as a candidate diabetes-related antigen in diabetic rats and human patients [4]. There is evidence that the gut is mildly inflamed and abnormally permeable to lumen antigens in BBdp rats [10][11][12][13][14] and in human patients with type 1 diabetes [15][16][17][18]. However, remarkably little is known about the immune state of the gut-associated lymphoid tissue (GALT) in animals or humans that spontaneously develop type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

Chakir¹,

Lefebvre

Wang³

et al. 2005

Diabetologia

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Aims/hypothesis: Type 1 diabetes is the result of an inflammatory T helper 1 (Th1) lymphocyte-mediated beta cell destructive process. The majority of diabetesprone BioBreeding (BBdp) rats fed wheat protein-based diets, such as NTP-2000, develop type 1 diabetes and display a mild coeliac-like enteropathy. Mesenteric lymph nodes (MLNs), which drain the gut, are the major inductive site where dietary antigens are recognised in the gut-associated lymphoid tissue (GALT). We hypothesised that this compartment could be a site of abnormal wheat proteininduced Th1 cell activation. Methods: MLN cells were isolated from BBdp and BB control (BBc) rats that were fed NTP-2000 or a hydrolysed casein (HC)-based diet at ages that pre-date classic insulitis. The inflammatory status, phenotype and proliferation of these cells in response to wheat protein were determined. Results: The expression ratio of T-bet : Gata3, master transcription factors for Th1 and Th2 cytokines, was increased in the MLN from NTP-2000-fed BBdp rats compared with that from BBc rats, mainly due to decreased Gata3 expression. CD3 + CD4 + IFN-γ + T cells were more prevalent in the MLN of wheatfed BBdp rats, but remained at control levels in BBdp rats fed a diabetes-retardant HC diet. BBdp MLN cells proliferated in response to wheat protein antigens in a specific, dose-dependent manner, and >93% of cells were CD3 + CD4 + T cells. This proliferation was associated with a low proportion of CD4 + CD25 + T cells and a high proportion of dendritic cells in the MLN of BBdp rats. Conclusions/ interpretation: Before insulitis is established, the MLNs of wheat-fed BBdp rats contain an unusually high proportion of Th1 cells that proliferate specifically in response to wheat protein antigens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

Chakir¹,

Lefebvre

Wang³

et al. 2005

Diabetologia

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“…Whereas the BBDP rat model spontaneously develops T1D, the BBDR rat model is resistant to T1D onset unless influenced by an environmental change, such as viral infection with Kilham rat virus (32,33). It is currently thought that the increased frequency of T1D in BBDR rats subsequent to Kilham rat virus infection is due to a shift in the balance of Th1 and Th2 lymphocytes (33).…”

Section: T Ype 1 Diabetes (T1d) Is Due To a T Cell (Both Cd4mentioning

confidence: 99%

Inhibition of Type 1 Diabetes Correlated to a Lactobacillus johnsonii N6.2-Mediated Th17 Bias

Lau

Benitez

Ardissone

et al. 2011

The Journal of Immunology

145

115

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Although it is known that resident gut flora contribute to immune system function and homeostasis, their role in the progression of the autoimmune disease type 1 diabetes (T1D) is poorly understood. Comparison of stool samples isolated from Bio-Breeding rats, a classic model of T1D, shows that distinct bacterial populations reside in spontaneous Bio-Breeding diabetes-prone (BBDP) and Bio-Breeding diabetes-resistant animals. We have previously shown that the oral transfer of Lactobacillus johnsonii strain N6.2 (LjN6.2) from Bio-Breeding diabetes-resistant to BBDP rodents conferred T1D resistance to BBDP rodents, whereas Lactobacillus reuteri strain TD1 did not. In this study, we show that diabetes resistance in LjN6.2-fed BBDP rodents was correlated to a Th17 cell bias within the mesenteric lymph nodes. The Th17 bias was not observed in the non-gut–draining axillary lymph nodes, suggesting that the Th17 bias was because of immune system interactions with LjN6.2 within the mesenteric lymph node. LjN6.2 interactions with the immune system were observed in the spleens of diabetes-resistant, LjN6.2-fed BBDP rats, as they also possessed a Th17 bias in comparison with control or Lactobacillus reuteri strain TD1–fed rats. Using C57BL/6 mouse in vitro assays, we show that LjN6.2 directly mediated enhanced Th17 differentiation of lymphocytes in the presence of TCR stimulation, which required APCs. Finally, we show that footpad vaccination of NOD mice with LjN6.2-pulsed dendritic cells was sufficient to mediate a Th17 bias in vivo. Together, these data suggest an interesting paradigm whereby T1D induction can be circumvented by gut flora-mediated Th17 differentiation.

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“…BB rats became diabetic by an autoimmunologic disorder similar to human type 1 diabetes mellitus (34), which is not completely understood but involves mutations of the lyp locus on chromosome 4, lymphopenia, and dysregulation of inflammatory cells, including eosinophils, mast cells, and lymphocytes, which, in turn, lead to insulitis and h-cell destruction (35)(36)(37). The Pfd substrain of BB rats is characterized by the reestablishment of self-tolerance to the h-cells after previous destruction of the h-cells in the pancreas (38,39).…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular Neoplasms Induced by Low-Number Pancreatic Islet Transplants in Autoimmune Diabetic BB/Pfd Rats

2006

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It has been shown that combined high local hyperinsulinism and hyperglycemia after low-number islet transplantation into the livers of streptozotocin-diabetic rats lead to the development of hepatocellular neoplasms but a substantial cocarcinogenic effect of genotoxic streptozotocin could not be ruled out completely. Thus, we herein investigated this model in BB/Pfd rats (n = 805; nine experimental groups), which develop spontaneous autoimmune diabetes similar to human type 1 diabetes. After low-number islet transplantation (n = 450), the liver acini downstream of the islets show insulin-induced alterations: massive glycogen and/or fat accumulation, translocation of the insulin receptor, decrease in glucose-6-phosphatase activity, increase in expression of insulin-like growth factor (IGF)-I, IGF-II/mannose-6-phosphate receptor, insulin receptor substrate-1, Raf-1, and Mek-1, corresponding to clear cell preneoplastic foci of altered hepatocytes known from chemical hepatocarcinogenesis and identical to that in streptozotocin-diabetic Lewis rats. After 6 months, many altered liver acini progressed to other types of preneoplasias often accompanied by an overexpression of the glutathione-S transferase (placental form), IGF-I receptor, and transforming growth factor (TGF)-A. After 12 to 15 and 15 to 18 months, 52% and 100% of the animals showed one or multiple hepatocellular adenomas or hepatocellular carcinomas (HCCs), respectively. Conclusively, this study identifies combined hyperinsulinism and hyperglycemia as a carcinogenic mechanism for the development of HCCs in diabetic rats. Hepatocarcinogenesis is independent from additional genotoxic compounds (i.e., streptozotocin), but is primarily triggered by increased intracellular insulin signaling via pathways associated with cell growth and proliferation, such as the Ras-Raf-mitogen-activated protein kinase pathway and the IGF system, and secondarily involves other growth factors, such as TGF-A. (Cancer Res 2006; 66(3): 1833-43)

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Insulin-dependent Diabetes and Gut Dysfunction: The BB Rat Model

Cited by 26 publications

References 30 publications

Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

Inhibition of Type 1 Diabetes Correlated to a Lactobacillus johnsonii N6.2-Mediated Th17 Bias

Hepatocellular Neoplasms Induced by Low-Number Pancreatic Islet Transplants in Autoimmune Diabetic BB/Pfd Rats

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