Effect of nicotinamide treatment on the residual insulin secretion in Type 1 (insulin-dependent) diabetic patients

Vague, P; Picq, R.; Bernal, M.; Lassmann-Vague, V.; Vialettes, B.

doi:10.1007/bf00265549

Cited by 84 publications

(42 citation statements)

References 31 publications

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“…Administration of nicotinamide prevents rodent diabetes after STZ administration (22) and also blocks the development of diabetes in the nonobese diabetic mouse, a model of spontaneous autoimmune diabetes (42). This nontoxic agent has displayed some limited beneficial effects in human diabetes (43)(44)(45)(46) and is currently being evaluated as a prophylactic agent in first degree relatives of type I diabetic patients possessing islet cell antibodies (47).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Pieper

Brat

Krug

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

277

180

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Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD ؉ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP ؊͞؊), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP ؉͞؊ animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.Type I diabetes (insulin-dependent diabetes mellitus) is a chronic metabolic disorder characterized by a loss of pancreatic islet B cell mass, decreased serum insulin, and hyperglycemia. Although the pathogenic mechanisms of this disease have not been fully characterized, genetic, environmental, and autoimmune factors have been postulated. In particular, development of this disorder is postulated to proceed through generation of oxygen radicals during prediabetic pancreatic islet inflammation (1, 2). One possible mechanism is that autoimmune activation of macrophages damages B cells through release of massive amounts of NO after inducible NO synthase activation, as damage elicited when islets are cocultured with macrophages is prevented by inhibition of NO synthase (3).Focal cerebral ischemic damage is also associated with NO release leading to DNA damage elicited by reactive oxygen species, including peroxynitrite formed from NO. Downstream of this DNA damage, the enzyme poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is stimulated. Nuclear PARP is activated by DNA fragments to transfer branched chains of up to 200 ADP ribose groups from NAD ϩ to acceptor proteins in the nucleus, including histones and PARP itself. PARP activation plays a role in DNA repair, particularly the base excision repair process (4-8), in response to moderate amounts of DNA damage. With excessive DNA damage, however, PARP is so highly activated that its substrate NAD ϩ is critically depleted (9). NAD ϩ is an important enzyme in energy metabolism, and its depletion results in lower ATP production. As ATP is also consumed in efforts to resynthesize NAD ϩ , cells can die from energy loss. Cerebral ischemic damage is greatly diminished in mice with targeted deletion of PARP (PARP Ϫ͞Ϫ) (10, 11) and in animals treated with PARP inhibitors (12, 13). A role of PARP activation in pancreatic damage is also suggested by protection through PARP inhibition of pancreatic islet cells from NO-mediated killing (14, 15). Furthermore, in vitro pancreatic islet cells from PARP Ϫ͞Ϫ mice are resistant to NAD ϩ depletion after exposure to either NO or other reactive oxygen intermediates generated th...

show abstract

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Pieper

Brat

Krug

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

277

180

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show abstract

“…Furthermore, nicotinamide was effective in preventing diabetes mellitus in NOD mice and possibly in human Type I diabetes mellitus [24,25,52]. Nicotinamide has also been shown to reduce the downstream signals of IFNg such as IRF-1 in isolated rat pancreatic islets [22].…”

Section: Discussionmentioning

confidence: 99%

IFNγ/TNFα synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis

Kim

Chang

et al. 2002

Diabetologia

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“…Older clinical studies using nicotinic acid or impure preparations of nicotinamide reported relatively frequent liver enzyme abnormalities [6, 33±35] although more recent studies using a purified form of nicotinamide have not detected any noteworthy adverse effects on liver enzymes [13,15,17,20,36]. This experience is described in more detail below.…”

Section: Liver Toxicitymentioning

confidence: 95%

Safety of high-dose nicotinamide: a review

et al. 2000

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Effect of nicotinamide treatment on the residual insulin secretion in Type 1 (insulin-dependent) diabetic patients

Cited by 84 publications

References 31 publications

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

IFNγ/TNFα synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis

Safety of high-dose nicotinamide: a review

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