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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To increase knowledge about the defense mechanisms of pancreatic beta-cells exposed to acute injury, the patterns of protection exerted by 3-aminobenzamide and nicotinamide against the effects of streptozotocin have been studied in vivo and in vitro. It was found that 3-aminobenzamide, a strong inhibitor of the NAD-consuming nuclear enzyme poly(ADP-ribose) synthetase, is maximally effective against streptozotocin-induced diabetes in the rat when administered 45-60 min after the beta-cytotoxic agent, unlike nicotinamide, which exerts best protection when given very close to streptozotocin. A partial protection is still afforded by 3-aminobenzamide administered as long as 120 minutes after streptozotocin. In isolated islets, each protective agent, if added to the incubation medium 20 or even 40 minutes after the exposure of the islets to streptozotocin, is able to partially prevent the effects of the damaging drug on glucose-stimulated insulin release. However, best protection in vitro is obtained when either 3-aminobenzamide or nicotinamide is added simultaneously with the toxic agent. Our results support the concept that the reversibility of streptozotocin-induced acute damage in beta-cells depends on the preservation of intracellular NAD pools during critical time intervals. This can be achieved by two different partially overwhelming mechanisms: a) early stimulation of NAD biosynthesis (prevailing effect of nicotinamide) and b) strong inhibition of poly ADP-ribosylation activity (main effect of 3-aminobenzamide).
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PMID:Protection by 3-aminobenzamide and nicotinamide against streptozotocin-induced beta-cell toxicity in vivo and in vitro. 214 20

Human fetal pancreas (HFP) is a potential source of beta-cells for transplantation to insulin-dependent diabetic patients. We have previously described a method for tissue culture of HFP that results in the in vitro development of isletlike cell clusters (ICCs) containing a minority of insulin-positive cells. Recently we found that nicotinamide, an inhibitor of poly(ADP-ribose) synthetase, induces an increased islet cell DNA replication both in vivo and in vitro. In this study, this culture technique was used to evaluate the effects of addition of 10 mM nicotinamide on HFP explants cultured in RPMI-1640 medium plus 10% human serum. ICCs developed in 11 of 19 consecutive cultures with nicotinamide increased the yield of ICCs by 40%. Also, the insulin content of ICCs increased approximately 50% with nicotinamide supplementation, although measurements of DNA indicated an unchanged number of cells in each ICC. Neither the rates of insulin release in response to 16.7 mM glucose plus 5 mM theophylline nor the (pro)insulin or total protein biosynthesis rates were affected by nicotinamide addition. The combined results of this study suggest that nicotinamide is useful for stimulating the formation of ICCs from HFP.
Diabetes 1989 Jan
PMID:Tissue culture of human fetal pancreas. Effects of nicotinamide on insulin production and formation of isletlike cell clusters. 252 29

We examined the effects of desferrioxamine (DFX), a potent inhibitor of the formation of oxygen-derived hydroxyl radicals, and nicotinamide (NIC), a poly(ADP-ribose) synthetase inhibitor and a weak free-radical scavenger, on two models of immune destruction of murine islets [i.e., allograft rejection and multiple low-dose streptozocin (STZ)-induced insulitis]. Freshly isolated or low-temperature-cultured BALB/cJ islets were transplanted beneath the kidney capsules of C57BL/6J recipients. The recipients were treated with NIC alone (500 mg.kg-1.day-1), DFX alone (4.2 mg/day x 14 days), or NIC + DFX. Only recipients treated with NIC + DFX, receiving cultured islets, showed a mean graft survival time significantly longer than control mice receiving freshly isolated or cultured islets. Control CD-1 mice treated with multiple low doses of STZ developed insulitis and diabetes. Treatment with NIC alone, DFX alone, or NIC + DFX decreased the severity of hyperglycemia relative to the controls. Treatment with DFX alone was more effective than NIC alone or NIC + DFX. Only the group treated with DFX alone had a lower incidence of diabetes (mean plasma glucose level greater than 200 mg/dl) than the controls after 4 wk. Histologically, islets from control mice showed severe insulitis, islet destruction, and absence of stainable insulin, whereas islets from DFX-treated mice showed only mild peri-insulitis and a relative preservation of beta-cell granulation. Our study showed that NIC and DFX partially protect islets from immune destruction in allograft rejection and in low-dose STZ-induced insulitis. Apparently, hydroxyl radicals play important roles in both of these models.
Diabetes 1989 Mar
PMID:Oxygen free-radical scavengers and immune destruction of murine islets in allograft rejection and multiple low-dose streptozocin-induced insulitis. 252 36

The initial step in streptozocin (STZ)-induced beta-cell toxicity has been hypothesized to be the alkylation of specific sites on DNA bases. The enzymatic removal of these lesions results in single-strand breaks that over-activate the nuclear enzyme poly(ADP-ribose) synthetase and critically deplete the cell of NAD. Our studies were performed to quantitatively evaluate the extent of DNA damage in beta-cells and correlate this damage with toxicity. Monolayer cultures of neonatal rat beta-cells were used to determine cytotoxicity and DNA damage after exposure to STZ or the aglycone N-methyl-N-nitrosourea (MNU). Toxicity in beta-cells was determined by correlating morphological alterations observed by phase-contrast microscopy with decrements in immunoreactive insulin release. The extent of DNA damage was determined by alterations in nucleoid density and quantitation of N7-methylguanine formation. Toxicity tests revealed that STZ and MNU were not toxic at equimolar concentrations. Streptozocin was toxic at 10(-3) M, whereas only mild toxicity was observed with MNU at 10(-2) M. Surprisingly, however, at equimolar concentrations the two drugs caused comparable DNA-strand breaks as evidenced by their ability to shift the nucleoid migration ratio in neutral sucrose gradients. Additionally, quantitation of N7-methylguanine formation after exposure to equimolar concentrations of the drugs demonstrated that the two alkylated DNA to the same extent. These findings suggest that factors in addition to the activation of poly(ADP-ribose) synthetase must be responsible for the toxicity seen with STZ, because MNU at a nonlethal concentration is capable of causing comparable DNA damage.
Diabetes 1986 Aug
PMID:Mechanisms of nitrosourea-induced beta-cell damage. Alterations in DNA. 294 32

This study was conducted in order to clarify whether the poly(ADP-ribose) synthetase inhibitors, nicotinamide and 3-aminobenzamide, have any influence upon the content and physicochemical properties of insulin and glucagon in streptozotocin (STZ)-treated rat pancreas. STZ-treated rats received intraperitoneal injection of 350 mg/kg nicotinamide or 50 mg/kg 3-aminobenzamide 15 min before and 180 min after the administration of STZ and once a day thereafter for 23 weeks. The blood glucose levels and body weight of nicotinamide- and 3-aminobenzamide-treated rats did not differ from those of the control rats at the end of the experiment. The insulin content in poly(ADP-ribose) synthetase inhibitor-treated rat pancreas was restored partially and reached approximately 60% of the control level, while the glucagon content did not differ from that in the normal rats. Treatment with poly(ADP-ribose) synthetase inhibitor resulted in no alteration in the physicochemical properties of extracted insulin and glucagon. Immunohistological examination of the pancreas revealed that insulin- and glucagon-containing cells in the islets in the poly(ADP-ribose) synthetase inhibitor-treated rat appeared to be normalized. These results suggest that poly(ADP-ribose) synthetase inhibitor normalizes the function but not the insulin content of B cells and that it does not act on A cells in STZ-treated rat pancreas. Restoration of the insulin content would be large enough to keep the function of B cells normal.
Diabetes Res Clin Pract
PMID:Effect of poly(ADP-ribose) synthetase inhibitor administration to streptozotocin-induced diabetic rats on insulin and glucagon contents in their pancreas. 295 3

Administration of poly(ADP-ribose) synthetase inhibitors such as nicotinamide to 90% depancreatized rats induces regeneration of pancreatic islets, thereby ameliorating the surgical diabetes (Yonemura, Y., Takashima, T., Miwa, K., Miyazaki, I., Yamamoto, H., and Okamoto, H. (1984) Diabetes 33, 401-404). In screening the regenerating islet-derived cDNA library, we came across a novel gene encoding a 165-amino acid protein. The gene was expressed in regenerating islets but not in normal pancreatic islets, insulinomas, or regenerating liver. In 90% depancreatized and nicotinamide-injected rats, the expression of the gene was increased 1 month after the partial pancreatectomy and reached a peak 3 months after the operation. The increase in expression of the gene was temporally correlated with the increase in size of regenerating islets and the decrease in urinary glucose level. The gene was also found to be activated in hyperplastic islets of aurothioglucose-treated mice. Thus, the expression of the gene in both regenerating and hyperplastic islets suggests possible roles for this gene in replication, growth, and maturation of islet beta-cells. We also found that a human pancreas-derived cDNA library contained a homologue to the gene.
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PMID:A novel gene activated in regenerating islets. 296

It has been hypothesized that the critical step in streptozocin (STZ)-induced beta-cell toxicity is the overactivation of the nuclear enzyme poly(ADP-ribose) synthetase resulting from DNA strand breaks. Overactivation of this enzyme leads to a lethal depletion of its substrate, NAD, in the beta-cell. However, recently it has been shown that a lethal concentration of STZ and a nontoxic concentration of its nitrosoamide moiety methylnitrosourea (MNU) damage beta-cell DNA to the same extent and cause comparable amounts of DNA strand breaks. This study was performed to determine whether STZ and MNU activate poly(ADP-ribose) synthetase to the same extent. Monolayer cultures of islet cells from neonatal rats were exposed to concentrations of MNU and STZ of 10(-3) to 10(-2) M. The results show that both chemicals caused comparable activation of the enzyme at all concentrations tested. These data demonstrate that activation of poly(ADP-ribose) synthetase alone is not the critical step in STZ-induced beta-cell toxicity. Based on this finding, it appeared possible that STZ may be selectively sequestered into some critical site in the beta-cell other than the nucleus. Therefore, studies were initiated with 14C-labeled STZ and MNU to determine whether STZ might be distributed in the beta-cell differently than MNU. Total cellular DNA and protein from both RINr (clone 38) and islet cell monolayers were separated on hydroxylapatite columns after exposure to 14C-labeled chemicals. The amount of label incorporated into each fraction was determined by liquid scintillation spectrometry, and the ratio of label incorporated in protein to that in DNA was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1988 Feb
PMID:Mechanisms of nitrosourea-induced beta-cell damage. Activation of poly (ADP-ribose) synthetase and cellular distribution. 296 35

A common mechanism has been proposed for the beta-cell toxins alloxan (ALX) and streptozocin (STZ) involving the formation of single-strand breaks in DNA that lead to the overactivation of the enzyme poly(ADP-ribose) synthetase and the critical depletion of its substrate NAD. If the toxins act via this common mechanism, the poly(ADP-ribose) synthetase inhibitors nicotinamide and thymidine would be expected to affect the formation of DNA single-strand breaks in a similar fashion. To test the effects of these inhibitors, the formation of single-strand breaks in the DNA of insulin-secreting RINr cells was monitored by assessing changes in the supercoiling of nucleoids after exposure to STZ, ALX, or methylnitrosourea (MNU). With the inclusion of nicotinamide or thymidine and STZ or MNU, more single-strand breaks in RINr cell DNA were detected. These results would be expected if nicotinamide and thymidine acted through inhibition of poly(ADP-ribose) synthetase. However, when the inhibitors were used in combination with ALX, fewer single-strand breaks were present. This suggests a reduction in ALX-induced hydroxyl radicals available to interact with DNA. Because nicotinamide has been demonstrated to be a hydroxyl-radical scavenger, the ability of thymidine to scavenge hydroxyl radicals was investigated. Thymidine, like nicotinamide, was found to be a potent scavenger of hydroxyl radicals. Thus, the mechanisms by which nicotinamide and thymidine protect against the toxic effects of STZ or ALX appear different. These findings suggest that the actions of beta-cell toxins are more complex than simply the overactivation of a single enzyme.
Diabetes 1988 Aug
PMID:Mechanisms of nicotinamide and thymidine protection from alloxan and streptozocin toxicity. 296 36

A major obstacle for islet transplantation in insulin-dependent diabetes mellitus is to obtain a sufficient amount of islet tissue. This may partly be overcome if the cell replication in the grafted islet preparation could be stimulated in the recipient. In the present study adult mice were treated for 14 days with daily injections of nicotinamide (500 mg/kg body weight) or saline. Subsequently, the autoradiographic labeling index in the cells of the pancreatic islets were calculated in normal mice and in syngeneic islets transplanted into alloxan-diabetic mice. Treatment with nicotinamide caused a more than three-fold increase in the islet cell labeling index in the endogenous pancreatic islets, and also a 50% increase in the cell replication rates of the transplanted islets. It thus appears that nicotinamide enhances islet cell replication, possibly through an inhibition of poly(ADP-ribose) synthetase activities.
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PMID:Stimulation of cell replication in transplanted pancreatic islets by nicotinamide treatment. 296 53

We have shown previously that alloxan and streptozotocin, two major diabetogenic agents, cause DNA strand breaks in rat pancreatic islets and stimulate nuclear poly(ADP-ribose) synthetase, thereby depleting intracellular NAD level and inhibiting proinsulin synthesis (Okamoto, H. (1981) Mol. Cell. Biochem. 37, 43-61; Yamamoto, H., Uchigata, Y., and Okamoto, H. (1981) Nature 294, 284-286). In the present study, superoxide dismutase and catalase, scavengers of radical oxygens, were found to protect against islet DNA strand breaks and inhibition of proinsulin synthesis induced by alloxan. The radical scavengers did not affect islet DNA strand breaks or inhibition of proinsulin synthesis induced by streptozotocin. On the other hand, compounds that inhibit islet nuclear poly(ADP-ribose) synthetase were found to protect against alloxan- as well as streptozotocin-induced inhibition of proinsulin synthesis. The poly(ADP-ribose) synthetase inhibitors were ineffective in protection against DNA strand breaks induced by the agents. These results may provide an important clue for elucidating the prevention of insulin-dependent diabetes as well as for understanding the cause of diabetes.
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PMID:Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocin-induced islet DNA strand breaks and against the inhibition of proinsulin synthesis. 628 Dec 56


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