Is there an autoimmune process in bone? Gene expression studies in diabetic and nondiabetic BB rats as well as BB rat-related and -unrelated rat strains

It is well known that type 1 diabetes is associated with a decrease in bone mass and delayed healing of fractures in human and in animal models of type 1 diabetes. Using well- and poorly compensated diabetic BB/O(ttawa) K(arlsburg) rats spontaneously developing insulin-dependent type 1 diabetes, it was recently shown that, in contrast to all other tissues studied, bone is most influenced by metabolic state and seems to be regulated in a manner different from other organs. Therefore, we studied the expression of additional genes ( Bmp-1, Bmp-4, Vegf, Bglap, Il-1b, Infg, Tnfa, Calca, Sp1, Yy1) in bone of nondiabetic BB rats compared with newly diagnosed and well- and poorly compensated diabetic rats as well as two nondiabetes-prone congenic BB.SHR rats, BB rat-related (WOKW) and -unrelated rat strains (F344). Six males of each group were euthanized, the tibial bone was removed, and total RNA was extracted, transcribed in complementary DNA, and used for real-time PCR. In a comparison of nondiabetic with diabetic groups, the relative gene expression was reduced by >80% in newly diagnosed and in well-compensated diabetic BB/OK rats. The gene expression in poorly compensated rats increased significantly in 7 of 10 genes and was comparable with those of nondiabetic BB/OK rats. In a comparison of gene expression between diabetes-prone BB/OK and nondiabetes-prone BB.1K, BB.4S, WOKW, and F344 rats, there were no significant differences between newly diagnosed and well-compensated BB/OK diabetic rats and nondiabetic BB.1K, BB.4S, WOKW, and F344 rats. On the basis of these findings, we concluded that spontaneous diabetes influences bone gene expression in BB/OK rats, which may be attributed to the genetically determined autoimmune process not only affecting pancreatic β-cells but also bone formation and resorption.

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Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes

Journal of Endocrinology ◽

10.1530/joe-12-0385 ◽

2012 ◽

Vol 216 (2) ◽

pp. 111-123 ◽

Cited By ~ 14

Author(s):

Marika Bogdani ◽

Angela M Henschel ◽

Sanjay Kansra ◽

Jessica M Fuller ◽

Rhonda Geoffrey ◽

...

Keyword(s):

Gene Expression ◽

Type 1 Diabetes ◽

Bb Rat ◽

Antioxidative Defense ◽

Β Cell ◽

Rat Islets ◽

Bb Rats ◽

Acetyl Cysteine ◽

F344 Rats

Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating β cell duress. To identify genes/mechanisms involved with diabetogenesis at the β cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyprats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyprats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2,Gstm4,Gstm7,Gstt1,Gstp1, andGstk1), superoxide dismutases (Sod2andSod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidantN-acetyl cysteine to DRlyp/lyprats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of β cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility.

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Imprinting influences gene expression but not type 1 diabetes development of BB rats

Diabetologie und Stoffwechsel ◽

10.1055/s-2008-1076419 ◽

2008 ◽

Vol 3 (S 1) ◽

Author(s):

I Klöting ◽

P Lutze ◽

R Baguhl ◽

B Wilke

Keyword(s):

Gene Expression ◽

Type 1 Diabetes ◽

Bb Rats ◽

Diabetes Development

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Effect of α-phenyl-N-tert-butylnitrone on diabetes and lipid peroxidation in BB rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-022 ◽

1999 ◽

Vol 77 (3) ◽

pp. 166-174 ◽

Cited By ~ 2

Author(s):

Giugetta Iovino ◽

Stan Kubow ◽

Errol B Marliss

Keyword(s):

Lipid Peroxidation ◽

Type 1 Diabetes ◽

Cell Function ◽

Bb Rat ◽

Bb Rats ◽

Antioxidant Agents ◽

Pancreatic Islet Beta Cell ◽

In Vivo Administration

Oxygen free radicals have been shown to interfere with pancreatic islet beta cell function and integrity, and have been implicated in autoimmune type 1 diabetes. We hypothesized that the spontaneous autoimmune type 1 diabetes of the BB rat would be prevented by in vivo administration of a free-radical spin trap, α-phenyl-N-tert-butylnitrone (PBN). Twenty-eight diabetes-prone (BBdp) and 13 non-diabetes-prone (BBn) rats received PBN (10 mg/kg) subcutaneously twice daily, and 27 BBdp and 12 BBn rats received saline as controls. Rats were treated from age 47 ± 6 days until diabetes onset or age 118 ± 7 days. PBN caused no growth, biochemical, or hematological side effects. Sixteen control BBdp rats became diabetic (BBd, mean age 77 ± 6 days) and six demonstrated impaired glucose tolerance (IGT rats). The incidence of diabetes and IGT was not different in PBN-treated BBdp rats. Saline-treated rats showed no differences in pancreatic malondialdehyde (MDA) contents of BBd, IGT rats, and the BBdp that did not develop diabetes, versus BBn rats (2.38 ± 0.35 nmoL/g). Among rats receiving PBN, BBn had lower pancreatic MDA than BBd and IGT rats (1.38 ± 0.15 vs. 1.88 ± 0.15 and 2.02 ± 0.24 nmoL/g, p < 0.05), but not than BBdp rats (1.78 ± 0.12 nmoL/g, ns). BBn rats receiving PBN also had lower pancreatic MDA than the saline controls (p < 0.05). Thus, PBN is remarkably nontoxic and is able to decrease MDA in the absence of the autoimmune process, but does not prevent diabetes. A combination of PBN with other complementary antioxidant agents may hold better promise for disease prevention.Key words: α-phenyl-N-tert-butylnitrone, type 1 diabetes mellitus, BB rats, lipid peroxidation, malondialdehyde, spin traps.

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Differences in B7 and CD28 family gene expression in the peripheral blood between newly diagnosed young-onset and adult-onset type 1 diabetes patients

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2015.05.012 ◽

2015 ◽

Vol 412 ◽

pp. 265-271 ◽

Cited By ~ 5

Author(s):

K. Pruul ◽

K. Kisand ◽

K. Alnek ◽

K. Metsküla ◽

K. Reimand ◽

...

Keyword(s):

Gene Expression ◽

Type 1 Diabetes ◽

Peripheral Blood ◽

Adult Onset ◽

Newly Diagnosed ◽

Young Onset ◽

Onset Type ◽

Family Gene ◽

Diabetes Patients

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AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. E1076-E1083 ◽

Cited By ~ 26

Author(s):

R. J. McCrimmon ◽

M. L. Evans ◽

R. J. Jacob ◽

X. Fan ◽

Y. Zhu ◽

...

Keyword(s):

Animal Model ◽

Type 1 Diabetes ◽

Glucagon Secretion ◽

Fold Increase ◽

Bb Rat ◽

Exogenous Insulin ◽

Counterregulatory Hormones ◽

Glucose Lowering ◽

Bb Rats

Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagon-secretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that α-cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect.

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