High Dose Nicotinamide Fails to Prevent Diabetes in BB Rats

Hermitte, Laurence; Vialettes, B.; Atlef, N.; Payan, Marie-José; Doll, Nicolas; Scheimann, Ann O.; Vague, P

doi:10.3109/08916938909029145

Cited by 22 publications

(9 citation statements)

References 17 publications

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“…These clinical trials are based on numerous studies in animal models of autoimmune diabetes, including the biobreeding rat. Nicotinamide given orally induced tolerance in the biobreeding rat (26), although parenteral administration was ineffective (27). Oral administration of nicotinamide, which has been shown to increase intracellular levels of NAD (61,62), may act indirectly to inhibit autoreactive cells by increasing the NAD levels available at sites of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Both recombinant ART2a and ART2b exhibit NADase activity, metabolizing NAD to nicotinamide and free ADP-ribose (24,25); however, it is unclear what role the NADase activity of ART2 plays in the immunoregulation mediated by ART2 ϩ T cells. Interestingly, the NAD metabolite, nicotinamide, has been shown to lower the incidence of diabetes in the BioBreeding diabetesprone rat if administered orally (26), although parental administration appears to be ineffective (27).…”

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confidence: 99%

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Nicotinamide Adenine Dinucleotide (NAD) and Its Metabolites Inhibit T Lymphocyte Proliferation: Role of Cell Surface NAD Glycohydrolase and Pyrophosphatase Activities

Bortell

Moss

McKenna

et al. 2001

The Journal of Immunology

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The presence of NAD-metabolizing enzymes (e.g., ADP-ribosyltransferase (ART)2) on the surface of immune cells suggests a potential immunomodulatory activity for ecto-NAD or its metabolites at sites of inflammation and cell lysis where extracellular levels of NAD may be high. In vitro, NAD inhibits mitogen-stimulated rat T cell proliferation. To investigate the mechanism of inhibition, the effects of NAD and its metabolites on T cell proliferation were studied using ART2a+ and ART2b+ rat T cells. NAD and ADP-ribose, but not nicotinamide, inhibited proliferation of mitogen-activated T cells independent of ART2 allele-specific expression. Inhibition by P2 purinergic receptor agonists was comparable to that induced by NAD and ADP-ribose; these compounds were more potent than P1 agonists. Analysis of the NAD-metabolizing activity of intact rat T cells demonstrated that ADP-ribose was the predominant metabolite, consistent with the presence of cell surface NAD glycohydrolase (NADase) activities. Treatment of T cells with phosphatidylinositol-specific phospholipase C removed much of the NADase activity, consistent with at least one NADase having a GPI anchor; ART2− T cell subsets contained NADase activity that was not releasable by phosphatidylinositol-specific phospholipase C treatment. Formation of AMP from NAD and ADP-ribose also occurred, a result of cell surface pyrophosphatase activity. Because AMP and its metabolite, adenosine, were less inhibitory to rat T cell proliferation than was NAD or ADP-ribose, pyrophosphatases may serve a regulatory role in modifying the inhibitory effect of ecto-NAD on T cell activation. These data suggest that T cells express multiple NAD and adenine nucleotide-metabolizing activities that together modulate immune function.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nicotinamide Adenine Dinucleotide (NAD) and Its Metabolites Inhibit T Lymphocyte Proliferation: Role of Cell Surface NAD Glycohydrolase and Pyrophosphatase Activities

Bortell

Moss

McKenna

et al. 2001

The Journal of Immunology

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“…This can be called a prediabetes but not a type 2 diabetes model from the point of view of two recent reports [15,16] . In addition, Masiello et al [8] reported that a 350-mg/kg BW NA dose completely prevented alterations induced by 65 mg/kg BW STZ , but in another study [17] it was found that intraperitoneal administration of NA at 500 mg/kg BW/day for 45 consecutive days could not prevent type I diabetes in BB rats. A similar result was also found in another report [18] .…”

Section: Discussionmentioning

confidence: 99%

Nongenetic Model of Type 2 Diabetes: A Comparative Study

Islam¹,

Choi²

2007

Pharmacology

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Seven-week-old male Sprague-Dawley (SD) rats were divided into six groups (LFC, LFD, HFC, HFD30, HFD40, HFD50) to determine whether animals receiving a low-fat (LF) diet plus nicotinamide-streptozotocin (NA-STZ) injection or animals receiving a high-fat (HF) diet plus STZ injection provide a better model of type 2 diabetes. After 2 weeks of feeding, diabetes was induced by intraperitoneal injection of NA (230 mg/kg BW) and STZ (65 mg/kg BW) in LFD, and STZ 30, 40, 50 mg/kg BW to HFD30, HFD40, HFD50 groups, respectively. Fasting blood glucose at 48–72 h and nonfasting blood glucose at 1 week after STZ injection were >200 and >600 mg/dl, respectively, in HFD40 and HFD50 groups while no significant difference was observed among other groups. Serum insulin concentration was significantly (p < 0.05) decreased in LFD, HFC, HFD30, and HFD40 groups compared to LFC and HFD50 groups. One animal died and other animals of the HFD50 group were in a critical condition. Serum lipid and liver glycogen were increased in HFD groups compared to other groups. The results of this study suggest that the HF diet-fed, 40-mg/kg BW STZ-injected SD rat is better than the LF diet-fed NA-STZ-injected rat as an animal model of human type 2 diabetes.

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“…Nicotinamide prevents diabetes in NOD mice (Elliott et al 1993) but not diabetes-prone BB/Mol rats (Hermitte et al 1989) or, to date, in humans (Lampeter et al 1998;Philips and Scheen 2002). GAD and bovine serum albumin (BSA 1 ) are candidate autoantigens in humans and are effective in the prevention of NOD mouse diabetes (Atkinson and Leiter 1999), but ineffective in the BB/Wor//Mol rat (Petersen et al 1997).…”

Section: Translational Modeling Powermentioning

confidence: 95%

Rat Models of Type 1 Diabetes: Genetics, Environment, and Autoimmunity

Mordes

Bortell²,

Blankenhorn³

et al. 2004

ILAR Journal

185

161

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For many years, the vast amount of data gathered from analysis of nonobese diabetic (NOD) and congenic NOD mice has eclipsed interest in the rat for the study of type 1 diabetes. The study of rat models has continued, however, and recently there has been a reanimation of interest for several reasons. First, genetic analysis of the rat has accelerated. Ian4L1, cblb, and Iddm4 are now known to play major roles in rat autoimmunity. Second, rats are amenable to study the interactions of genetics and environment that may be critical for disease expression in humans. Environmental perturbants that predictably enhance the expression of rat autoimmune diabetes include viral infection, toll-like receptor ligation, and depletion of regulatory T cell populations. Finally, data generated in the rat have correctly predicted the outcome of several human diabetes prevention trials, notably the failure of nicotinamide and low dose parenteral and oral insulin therapies.

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High Dose Nicotinamide Fails to Prevent Diabetes in BB Rats

Cited by 22 publications

References 17 publications

Nicotinamide Adenine Dinucleotide (NAD) and Its Metabolites Inhibit T Lymphocyte Proliferation: Role of Cell Surface NAD Glycohydrolase and Pyrophosphatase Activities

Nicotinamide Adenine Dinucleotide (NAD) and Its Metabolites Inhibit T Lymphocyte Proliferation: Role of Cell Surface NAD Glycohydrolase and Pyrophosphatase Activities

Nongenetic Model of Type 2 Diabetes: A Comparative Study

Rat Models of Type 1 Diabetes: Genetics, Environment, and Autoimmunity

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