Pyridine Nucleotide Depletion in Pancreatic Islets Associated with Streptozotocin-induced Diabetes

Ho, Chen-Kung; Hashim, Sami A.

doi:10.2337/diab.21.7.789

Cited by 57 publications

(23 citation statements)

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“…Recently, Yamamoto and Okamoto [27] demonstrated an increased activity ofpolyadenosine diphosphoribose (poly (ADP-rib)) synthetase, an enzyme participating in DNA-repair, in nuclei from rat pancreatic islets exposed to SZ in vitro. This enzyme uses NAD as a substrate, which is concordant with the documented observation that SZ depletes the NAD content of pancreatic islets [28][29]. It has been demonstrated that enzymically generated oxygen radicals in vitro can cause DNA single strand breaks [30], which presumably activates the enzyme.…”

Section: Discussionsupporting

confidence: 78%

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

Sandler

Andersson

1982

Diabetologia

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Summary. The protective effect on streptozotocin-induced diabetes of dimethyl urea, a hydroxyl radical scavenger, has been evaluated in vivo and in vitro. Pretreatment with dimethyl urea before a single diabetogenic dose of streptozotocin partially protected NMRI mice from hyperglycaemia, whereas the serum glucose of C57BL/KsJ mice increased during week 2 of observation. When the pancreases of these latter mice were examined histologically, insulitis was found in 15 out of 22 animals. The protective effect of dimethyl urea in the NMRI mice was not due to short-term hyperglycaemia induced by the drug, since pretreatment with glucose did not protect from streptozotocin but potentiated its diabetogenic effect. Dimethyl urea reduced the inhibition caused by streptozotocin on proinsulin biosynthesis of NMRI islets in vitro. It is suggested that streptozotocin-induced diabetes in mice may involve generation of hydroxyl radicals which are toxic to islet B cells. If this immediate cytotoxicity is reduced by a scavenger, a more slowly developing hyperglycaemia and an accompanying insulitis may occur in particularly susceptible animals.

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Section: Discussionsupporting

confidence: 78%

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

Sandler

Andersson

1982

Diabetologia

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“…Acute exposure to streptozotocin [2-deoxy-2-(3-methyl-3-nitrosourea)l-D-glucopyranose, STZ] induces massive ␤-cell death and diabetes mellitus in experimental animals (4,5). STZ also causes a rapid depletion of cellular NAD in islets (6)(7)(8)(9), but this depletion is prevented by injection of nicotinamide immediately before or soon after the administration of STZ (10). Okamoto and colleagues (2,11) demonstrated that STZ induces DNA strand breaks and activation of poly(ADP-ribose) polymerase (Parp) with subsequent reduction of NAD levels in the isolated pancreatic islets in vitro.…”

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confidence: 99%

Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes

Masutani¹,

Suzuki²,

Kamada³

et al. 1999

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

272

192

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Streptozotocin (STZ), a glucose analogue known to induce diabetes in experimental animals, causes DNA strand breaks and subsequent activation of poly(ADPribose) polymerase (Parp). Because Parp uses NAD as a substrate, extensive DNA damage will result in reduction of cellular NAD level. In fact, STZ induces NAD depletion and cell death in isolated pancreatic islets in vitro. Activation of Parp therefore is thought to play an important role in STZ-induced diabetes. In the present study, we established Parp-deficient (Parp ؊/؊ ) mice by disrupting Parp exon 1 by using the homologous recombination technique. These mice were used to examine the possible involvement of Parp in STZ-induced ␤-cell damage in vivo. The wild-type (Parp ؉/؉ ) mice showed significant increases in blood glucose concentration from 129 mg͞dl to 218, 370, 477, and 452 mg͞dl on experimental days 1, 7, 21, and 60, respectively, after a single injection of 180 mg STZ͞kg body weight. In contrast, the concentration of blood glucose in Parp ؊/؊ mice remained normal up to day 7, slightly increased on day 21, but returned to normal levels on day 60. STZ injection caused extensive necrosis in the islets of Parp ؉/؉ mice on day 1, with subsequent progressive islet atrophy and loss of functional ␤ cells from day 7. In contrast, the extent of islet ␤-cell death and dysfunction was markedly less in Parp ؊/؊ mice. Our findings clearly implicate Parp activation in islet ␤-cell damage and glucose intolerance induced by STZ in vivo.Various types of DNA damage produced by many environmental chemicals or reactive oxygen species generated by inflammatory reactions contribute to insulin-dependent diabetes mellitus (IDDM) through the induction of ␤-cell death in pancreatic islets (1-3). Acute exposure to streptozotocin [2-deoxy-2-(3-methyl-3-nitrosourea)l-D-glucopyranose, STZ] induces massive ␤-cell death and diabetes mellitus in experimental animals (4, 5). STZ also causes a rapid depletion of cellular NAD in islets (6-9), but this depletion is prevented by injection of nicotinamide immediately before or soon after the administration of STZ (10). Okamoto and colleagues (2, 11) demonstrated that STZ induces DNA strand breaks and activation of poly(ADP-ribose) polymerase (Parp) with subsequent reduction of NAD levels in the isolated pancreatic islets in vitro. These findings suggest the involvement of Parp as a key molecule in STZ-induced ␤-cell death and diabetes through extensive poly(ADP-ribose) formation and NAD depletion, leading to reduction of ATP level and cell death. In agreement with this hypothesis, Parp inhibitors such as 3-aminobenzamide or nicotinamide prevent the depletion of NAD and induction of STZ-induced ␤-cell death (12, 13). However, because Parp inhibitors possess other effects, such as scavenging hydrogen peroxide (14), it is not clear whether and how Parp activity contributes to ␤-cell death and the development of diabetes in vivo. Thus, engineering of a Parp-deficient animal model would be useful for investigating the role of Parp in S...

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“…A single large dose of STZ is sufficient to induce hyperglycemia resulting from loss of pancreatic B cells. This alkylating agent induces high levels of DNA strand breaks in B cells, causing activation of PARP, resultant reduction of cellular NAD ϩ , and cell death (19)(20)(21). Cotreatment of mice with nicotinamide, a PARP inhibitor and precursor of NAD ϩ , attenuates STZ-induced diabetes (22).…”

mentioning

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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Pyridine Nucleotide Depletion in Pancreatic Islets Associated with Streptozotocin-induced Diabetes

Cited by 57 publications

References 0 publications

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes

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

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