Nicotinamide treatment in the prevention of insulin‐dependent diabetes mellitus

Mandrup‐Poulsen, Thomas; Reimers, Jørgen; Andersen, Henrik Ullits; Pociot, Flemming; Karlsen, Allan E.; Bjerre, Ulla; Nerup, Jørn

doi:10.1002/dmr.5610090410

Cited by 43 publications

(17 citation statements)

References 76 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...

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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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“…In order to try to elucidate the mechanisms by which NA exerts its protective effects, we looked at its role in preventing damage induced by oxidative stress, a mechanism that may indeed be operational during in vitro processing in the isolation procedure (32)(33)(34). To mimic oxidative stress, hydrogen peroxide (H 2 O 2 ) was used at 50 or 200 lM for 18 h. We evaluated necrotic cell (%) by 7-AAD and beta-cell fractional apoptosis by TMRE staining, with a novel islet cell assessment method that we have recently described (30).…”

Section: Islet Transplantation Into Patients With Type I Diabetesmentioning

confidence: 99%

“…NA has a demonstrated cyto-protective ability, which could potentially be beneficial for clinical islet transplantation (10)(11)(12)(13)(14). Furthermore, it has been recently reported that islets express and synthesize tissue factor (TF), which triggers a detrimental thrombotic reaction after hepatic portal islet infusion (15,16).…”

Section: Introductionmentioning

confidence: 99%

Improved Human Islet Isolation Using Nicotinamide

Ichii

Wang²,

Messinger

et al. 2006

American Journal of Transplantation

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We investigated the effects of nicotinamide (NA) supplementation of the processing medium during islet isolation. One hundred and two human pancreata were processed for clinical transplantation after preservation either in the University of Wisconsin (UW) or using the two-layer method (TLM). Pancreata were then divided into four groups and retrospectively analyzed. Group I: UW preservation followed by processing without NA, Group II: UW preservation and processing with NA, Group III: TLM preservation without NA, Group IV: TLM preservation with NA. We observed a significant increase in islet yield in Group II (4343 ± 348 IEQ/g) [mean ± SEM], compared to Group I (2789 ± 348 IEQ/g) (p = 0.005). Similarly, a significant increase in islet yield was observed when NA was used in the processing of organs preserved with TLM (Group IV: 5538 ± 413 vs. Group III: 3500 ± 629; p = 0.02). Furthermore islet yield was higher in Group IV than in Group II (p < 0.05). The percentages of preparations that qualified for transplantation were 25, 47, 45, 69% in Groups I, II, III, IV, respectively. Addition of NA to the processing medium significantly improved islet yields in both the UW and TLM preservation protocols, allowing for a higher percentage of islet preparations to qualify for clinical transplantation.

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“…The promising outcome of these human pilot studies supports the rationale for the use of nicotinamide out lined above, and provides a compelling case for a con trolled clinical trial of its effects [22]; such a trial is now under way.…”

Section: Nicotinam Ide As a Therapeutic Agentmentioning

confidence: 88%

Molecular Mechanisms of Beta-Cell Destruction in IDDM The Role of Nicotinamide

Gale¹

1996

Horm Res

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Autoimmune processes are involved in pancreatic β-cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against the 37/ 40 K antigen appear in the circulation years before clinical onset and permit increasingly precise disease prediction. A cellular immune response causes pancreatic infiltration, while macrophages and Th-cells appear to be implicated – via local release of cytokines – in β-cell destruction. Generation of free radicals, DNA strand breaks, activation of the enzyme poly (ADP-ribose) polymerase (PARP), and depletion of intracellular nicotinamide adenine di-nucleotide (NAD) appear to be common factors in β-cell death, whether mediated by oxygen radicals, nitric oxide, or streptozotocin. Nicotinamide, a soluble B group vitamin which offers protection against these toxic stimuli, is at high doses a free radical scavenger, a potent inhibitor of PARP, and protects against depletion of intracellular NAD. A sound scientific rationale therefore exists for its use in human prediabetes, and promising pilot studies have been performed in ICA-positive first-degree relatives and school children. No serious side effects have been reported from its use at the doses proposed in man or other species. There is therefore a sound case for submitting this agent to a controlled clinical trial.

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Nicotinamide treatment in the prevention of insulin‐dependent diabetes mellitus

Cited by 43 publications

References 76 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

Improved Human Islet Isolation Using Nicotinamide

Molecular Mechanisms of Beta-Cell Destruction in IDDM The Role of Nicotinamide

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