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

Gale, E.A.M.

doi:10.1159/000184828

Cited by 34 publications

(18 citation statements)

References 16 publications

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“…Other examples of diseases that stem from cell depletion include Alzheimer's disease (46), Parkinson's disease (47), Huntington's disease (48), blindness caused by loss of retinal photoreceptor cells (49), deafness caused by cochlear hair cell loss (50), and diabetes resulting from ␤ cell depletion (51). In each case, the depletion of highly specialized "terminally differentiated" cells caused by a range of mechanisms and often superimposed on genetic susceptibilities seems to be a common pathway driving progressive organ failure.…”

Section: Discussionmentioning

confidence: 99%

Podocyte Depletion Causes Glomerulosclerosis

Wharram

Goyal

Wiggins³

et al. 2005

Journal of the American Society of Nephrology

675

583

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Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.

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Section: Discussionmentioning

confidence: 99%

Podocyte Depletion Causes Glomerulosclerosis

Wharram

Goyal

Wiggins³

et al. 2005

Journal of the American Society of Nephrology

675

583

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“…Our finding that the onset of hyperglycemia is delayed in PARP ϩ͞Ϫ mice suggests that even partial inhibition of PARP is therapeutic. In most patients, when type I diabetes is first diagnosed, the autoimmune process is ongoing, with the pancreas having sustained only a portion of its ultimate damage (41). Thus, treatment with PARP inhibitors at the time of diagnosis may slow disease progression.…”

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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“…In diabetic patients, niacinamide protects beta cells mainly by blocking PARS activity in response to oxygen free radicals [4]. Gale [11] also showed that nicotinamide protected beta cells against these toxic stimuli of oxygen radicals. The PARS inhibitor, nicotinamide (3 mM), attenuates cell injury and death as well as the increase in PARS activity caused by hydrogen peroxide in human cardiac myoblasts [3].…”

Section: Introductionmentioning

confidence: 99%

The Protective Effect of Niacinamide on Ischemia-Reperfusion-Induced Liver Injury

et al. 2001

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Reperfusion of ischemic liver results in the generation of oxygen radicals, nitric oxide (NO) and their reaction product peroxynitrite, all of which may cause strand breaks in DNA, which activate the nuclear enzyme poly(ADP ribose)synthase (PARS). This results in rapid depletion of intracellular nicotinamide adenine dinucleotide and adenosine 5′-triphosphate (ATP) and eventually induces irreversible cytotoxicity. In this study, we demonstrated that niacinamide, a PARS inhibitor, attenuated ischemia/reperfusion (I/R)-induced liver injury. Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 min. Thereafter, flow was restored and the liver was reperfused for 90 min. Blood samples collected prior to I and after R were analyzed for methyl guanidine (MG), NO, tumor necrosis factor (TNF-α) and ATP. Blood levels of aspartate transferase (AST), alanine transferase (ALT) and lactate dehydrogenase (LDH) which served as indexes of liver injury were measured. This protocol resulted in elevation of the blood NO level (p < 0.01). Inflammation was apparent, as TNF-α and MG levels were significantly increased (p < 0.05 and p < 0.001). AST, ALT and LDH were elevated 4- to 5-fold (p < 0.001), while ATP was significantly diminished (p < 0.01). After administration of niacinamide (10 mM), liver injury was significantly attenuated, while blood ATP content was reversed. In addition, MG, TNF-α and NO release was attenuated. These results indicate that niacinamide, presumably by acting with multiple functions, exerts potent anti-inflammatory effects in I/R-induced liver injury.

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

Cited by 34 publications

References 16 publications

Podocyte Depletion Causes Glomerulosclerosis

Podocyte Depletion Causes Glomerulosclerosis

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

The Protective Effect of Niacinamide on Ischemia-Reperfusion-Induced Liver Injury

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