Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotinamide which is an inhibitor of poly (ADPR) synthetase and precursor of NAD has been observed to prevent diabetes in some experimental models possibly by protecting beta cells. To determine whether nicotinamide could cure or prevent type 1 diabetes, we administered large doses (0.5 g/Kg/d) to BB rats. When used in the 45 days following diagnosis nicotinamide failed to bring remission. As a preventive treatment, nicotinamide administered between the 40th and 90th day of age, alone or in association with desferrioxamine did not significantly lower the incidence of diabetes (23% and 30.8% respectively vs. 56.6%). When used earlier, immediately after weaning, nicotinamide did not affect the incidence of diabetes in this model (62.5%). The degree of protection was not comparable with that obtained with cyclosporin A (15% of diabetic animals). Histology study of the pancreas from the animals killed either immediately or 1 year after treatment revealed no endocrine tumor. These findings suggest that in BB rats nicotinamide has little or no effect on the course of autoimmune diabetes mellitus thus dampening the high hopes for this drug in the treatment of human diabetes.
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PMID:High dose nicotinamide fails to prevent diabetes in BB rats. 253 59

A highly sensitive and simplified method for the differential determination of serum ketone bodies has been developed. Serum was deproteinized with perchloric acid, and acetoacetate contained in the supernate was reacted with newly synthesized p-nitrobenzene diazonium fluoroborate at 37 degrees C for 10 min. The formed hydrazo compound was converted by alkali to the more stable azo compound which has a peak absorbance at 645 nm. For the determination of 3-hydroxybutyrate, this was enzymatically converted to acetoacetate using 3-hydroxybutyrate dehydrogenase, LDH, NAD and pyruvate. Using 0.2 ml serum, acetoacetate and 3-hydroxybutyrate could be quantitated in 30 min. The described method is five times more sensitive than the enzymatic photometric method and can detect individual ketone bodies at concentrations as low as 20 mumol/l. Differential determination of serum levels of ketone bodies is clinically useful for the diagnosis of type 1 diabetes and in monitoring diabetic control.
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PMID:Sensitive and simplified method for the differential determination of serum levels of ketone bodies. 664 Sep 49

IDDM is caused by an immune-mediated destruction of the insulin-producing beta cells. Beta cells are destroyed by induction of oxygen-derived free radicals (FR) and nitric oxide (NO), which results in perturbation of the mitochondrial respiratory system and DNA strand breaks. As a result of beta cell destruction, islet cell antibodies (ICA) can be demonstrated in the circulation. These antibodies can be detected up to eight years prior to overt IDDM. Nicotinamide, a vitamin B3 derivative, interferes with the immune mediated beta-cell destruction by reducing the content of FR and NO and thereby reducing their deleterious effects. At the same time, nicotinamide increases the intracellular NAD pool, thus increasing the energy supply of the cell. Nicotinamide protects against chemically induced as well as spontaneous diabetes in animal models of the disease. Recently, open clinical studies have suggested that nicotinamide when administered to humans can prevent or delay clinical onset of IDDM. To test the possible preventive effect of nicotinamide in IDDM, a prospective, randomized, placebo-controlled study is needed. A multicentre study including 18 European countries, Israel and Canada is planned to start during 1993.
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PMID:[Nicotinamide and prevention of insulin-dependent diabetes mellitus. Rationale, effects, toxicology and clinical experiences. ENDIT Group]. 814 Jun 61

Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N'-p-nitrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDM. We report here that Vacor specifically inhibits the NADH:ubiquinone reductase activity of complex I in mammalian mitochondria. The activity of other respiratory enzymes of mitochondria is unaffected by Vacor at concentrations that completely inhibit the redox and energetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in insulinoma cells and pancreatic islets and is also consistent with the doses reported in cases of human poisoning. These results indicate that the toxic and diabetogenic action of Vacor primarily derives from the inhibition of mitochondrial respiration of NAD-linked substrates in the high-energy demanding cells of the pancreatic islets. This newly identified mechanism of the pathological effects resulting from Vacor intoxication could constitute a paradigm in which to understand environmental or metabolic causes of IDDM.
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PMID:Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with the rodenticide Vacor. 886 57

Autoimmune processes are involved in pancreatic beta cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against protein tyrosine phosphatase/IA2 (IA2-Ab) appear in the circulation years before clinical onset and permit increasingly precise disease prediction. Increasing knowledge of the pathogenesis of type 1 diabetes in animal models and humans suggests that progression to disease is not inevitable in those with indications of autoimmune processes directed against islet beta cells, and that these processes may prove vulnerable to intervention. The conditions therefore exist for screening and attempted intervention in pre-type 1 diabetes. This review will discuss the theoretical and practical background to a major controlled trial using one of a number of interventions currently under consideration. Nicotinamide, a soluble B group vitamin, has for many years been known to protect beta cells against a variety of noxious stimuli. It is at high doses a free radical scavenger, a potent inhibitor of the enzyme poly (ADP-ribose) polymerase (PARP), and prevents depletion of intracellular NAD. Although its benefits have been marginal or absent in recently diagnosed patients, promising pilot studies have been performed in ICA positive first degree relatives and schoolchildren. 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, which, in view of the numbers involved, has necessarily been launched on an international collaborative basis.
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PMID:Theory and practice of nicotinamide trials in pre-type 1 diabetes. 888 46

In order to reveal sequel of events responsible for increase in red cell cytosolic glucose-6 phosphate (G-6P) content of diabetic patients the enzyme producing and transforming G-6P were assayed. Increase in the activity of hexokinase and decrease in phosphoglucoisomerase activity was observed in mild insulin dependent diabetes mellitus (mIDDM) rat erythrocytes. Increase and decrease in activity of hexokinase and phosphoglucoisomerase respectively will increase the cytosolic glucose-6 phosphate content. Thus any substance which autoregulate the activity of hexokinase and maintains critical level of G-6P necessary for generation of ATP and coenzymes (NADPH & NAD+) in the prevailing hyperglycemic state can be a potential therapeutic agent for diabetic patients.
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PMID:Activation of hexokinase by mild insulin dependent diabetes mellitus in rat erythrocytes. 937 21

Human type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta cells during islet inflammation. Cytokines and reactive radicals released during this process contribute to beta-cell death. Here we show that mice with a disrupted gene coding for poly (ADP-ribose) polymerase (PARP-/- mice) are completely resistant to the development of diabetes induced by the beta-cell toxin streptozocin. The mice remained normoglycemic and maintained normal levels of total pancreatic insulin content and normal islet ultrastructure. Cultivated PARP-/- islet cells resisted streptozocin-induced lysis and maintained intracellular NAD+ levels. Our results identify NAD+ depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of the disease in individuals at risk of developing type 1 diabetes.
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PMID:Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin. 1008 88

Treatment with high doses of nicotinamide (niacinamide, vitamin B3) prevents or delays insulin-deficient diabetes in several animal models of type 1 diabetes and protects islet cells against cytotoxic actions in vitro. In recent-onset type 1 diabetes, nicotinamide administration improves beta-cell function, without significantly decreased insulin requirements. This review discusses the possible mechanism of action of nicotinamide in vivo. It is proposed that the key target of nicotinamide is the poly(ADP-ribose)polymerase (PARP), and to a lesser extent (mono)ADP-ribosyl transferases (ADPRTs). Suppression of PARP activity by nicotinamide not only decreases consumption of NAD+, the substrate of PARP, but also has major regulatory effects on gene expression, as shown for the major histocompatibility complex class II gene. In addition, PARP activity controls early steps of apoptosis. The possible suppression of ADPRTs by nicotinamide would also affect CD38, a membrane-bound external ADP-ribosyl transferase with potent immunoregulatory properties. Taken together, it is proposed that high doses of nicotinamide primarily affect ADP-ribosylation reactions in beta-cells as well as in immune cells and the endothelium. As a consequence, cell death pathways and gene expression patterns are modified, leading to improved beta-cell survival and an altered immunoregulatory balance.
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PMID:Nicotinamide in type 1 diabetes. Mechanism of action revisited. 1009 94

Recent genome screening studies have identified novel regions of possible interest for susceptibility to type 1 diabetes. One of these is a 30-35 cM region mapping to 16q22-q24 (D16S515-D16S520), where also the gene encoding NAD(P)H: quinone oxidoreductase (NQO1) maps. Data has suggested association of a polymorphism (P187S) in the NQO1 gene and type 1 diabetes. NQO1 is involved in protection against oxidative stress, which is likely to be involved in beta-cell destruction. By use of the transmission disequilibrium test (TDT), we analyzed the P187S polymorphism for association to type 1 diabetes in a population-based sample of 247 Danish nuclear type 1 diabetic families. Random transmission patterns were observed to all affected offspring (p(tdt) = 0.82), to index cases (P(tdt) = 0.77), as well as to unaffected offspring (P(tdt) = 0.93). Hence, the NQO1 polymorphism is not likely to be an etiological mutation underlying the reported linkage of the 16q22-q24 region.
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PMID:No linkage of P187S polymorphism in NAD(P)H: quinone oxidoreductase (NQO1/DIA4) and type 1 diabetes in the Danish population. DIEGG and DSGD. Danish IDDM Epidemiology and Genetics Group and The Danish Study Group of Diabetes in Childhood. 1044 60

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic beta-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced beta-cell death.
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PMID:Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-Ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes. 1197 44


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