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

The effect of syngeneic transplantation of islet tumors induced by streptozotocin-nicotinamide treatment into Fisher inbred diabetic rats was studied. Transplantation of 10 mg of tumor tissue under the kidney capsule of severely diabetic animals resulted in complete amelioration in 9 of 14 animals. Partial improvement was noted in three animals, whereas only one animal showed no change in diabetic condition within 4 months. Improvement in diabetes was accompanied by gain in body weight, decrease in blood sugar level and urinary glucose excretion, and normalization of glucose tolerance. After removal of the kidney containing the tumor grafts, the animals reverted to a severe diabetic condition, suggesting that the tumor graft supplied the insulin needs of the diabetic animals. The graft tissue exhibited in vitro insulin synthesis and secretion in response to 16.7 mM glucose.
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PMID:Reversal of diabetes by the isotransplantation of nicotinamide-streptozotocin-induced islet adenoma in rats. 627 54

Nicotinamide (10 mmol/kg) and 3-aminobenzamide (1.25 mmol/kg), poly(ADP-ribose) synthetase inhibitors, were injected intravenously to rats either 30 min before the intravenous administration of 12 mg/kg alloxan or 50 mg/kg streptozotocin ("pretreatment") or 5 min after the administration ("posttreatment"). Fifteen minutes after the injection of the diabetogenic agents, pancreatic islets were isolated from the rats and proinsulin synthesis was determined. Proinsulin synthesis was decreased in islets from rats treated with alloxan or streptozotocin. Pretreatment with poly(ADP-ribose) synthetase inhibitors was found to protect against alloxan- or streptozotocin-induced decrease in proinsulin synthesis. By posttreatment with poly(ADP-ribose) synthetase inhibitors, streptozotocin-induced decrease in proinsulin synthesis was also significantly reversed, whereas the decrease induced by alloxan was not.
Diabetes 1983 Apr
PMID:Effect of poly(ADP-ribose) synthetase inhibitor administration to rats before and after injection of alloxan and streptozotocin on islet proinsulin synthesis. 629 67

Alloxan and streptozotocin, which produce diabetes mellitus in experimental animals, have been known to inhibit various functions of pancreatic islets including proinsulin synthesis. However, little is known about the mechanisms underlying the action of these agents in pancreatic islets. Our recent in vivo and in vitro study using rats and isolated islets showed that one of the primary targets of the diabetogenic agents is the DNA of pancreatic islets. The first step is the generation of hydroxyl radical by alloxan which attacks DNA to produce strand breaks. In the case of streptozotocin, the alkylating activity of this compound may be causally related to its ability to induce DNA strand breaks. Subsequently, the fragmented DNA activates poly(ADP-ribose) synthetase which depletes cellular NAD. Since NAD is the most abundant of cellular coenzymes and participates in many biological reactions in mammalian cells, the reduction in intracellular NAD to such a nonphysiological level may severely affect islet cell functions including proinsulin synthesis. These results, in turn, raise the possibility that insulin-dependent diabetes may be preventable by inhibiting the occurrence of DNA strand breaks or the poly(ADP-ribose) synthetase. In fact, by poly(ADP-ribose) synthetase inhibitors such as nicotinamide and picolinamide, alloxan- and streptozotocin-induced NAD depletion was completely prevented, and B-cell functions including proinsulin synthesis proceeded normally. However, poly(ADP-ribose) synthetase inhibitors did not prevent the DNA strand breaks at all. Therefore, B-cells may survive with the residual DNA damage within their genome. About one year after the combined administration to rats of alloxan or streptozotocin with poly(ADP-ribose) synthetase inhibitors, diabetes did not develop but islet B-cell tumors were found frequently. This suggests that insulin-dependent diabetes and B-cell tumors are closely related with respect to their developmental processes. In other words, DNA breaks initiate two kinds of pathological state in B-cells, one is degeneratively and the other is oncogenically expressed.
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PMID:DNA strand breaks and poly(ADP-ribose) synthetase activation in pancreatic islets--a new aspect to development of insulin-dependent diabetes and pancreatic B-cell tumors. 631 40

Ninety percent depancreatized rats received daily intraperitoneal injection of 0.5 g/kg nicotinamide and 0.05 g/kg 3-aminobenzamide, potent inhibitors of islet poly(ADP-ribose) synthetase. One to three months after the partial pancreatectomy, urinary and plasma glucose levels in nicotinamide- and 3-aminobenzamide-treated rats were markedly lower than those in saline-treated control rats. Morphologic examination of the remaining pancreata revealed that islets in the poly(ADP-ribose) synthetase inhibitor-treated rats were markedly enlarged and consisted largely of B-cells. These results suggest that poly(ADP-ribose) synthetase inhibitors induce islet B-cell regeneration, thereby preventing or improving diabetes mellitus in partially depancreatized rats.
Diabetes 1984 Apr
PMID:Amelioration of diabetes mellitus in partially depancreatized rats by poly(ADP-ribose) synthetase inhibitors. Evidence of islet B-cell regeneration. 632 38

Human ingestion of the rodenticide Vacor has been implicated in the onset of diabetes mellitus. We report here studies of the effects of Vacor on cultured rat pancreatic beta cells and fibroblasts to determine if this agent preferentially intoxicates insulin-producing beta cells. Cytotoxicity in beta cells was monitored both by phase contrast microscopy and the release of insulin into the culture medium. Changes in cellular protein were correlated with morphologic observations to determine fibroblast viability. Beta cells were 10-fold more sensitive to the toxic effects of Vacor than were fibroblasts. Vacor toxicity was reduced by treatment with nicotinamide but was unchanged by 3-O-methyl glucose. Both of these agents reduced the toxic effects of the known beta cell poison streptozotocin. The present studies indicate that Vacor possesses a toxic affinity for pancreatic beta cells and that its mechanism of toxicity may be similar but not identical to that of streptozotocin.
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PMID:Effects of the rodenticide Vacor on cultured rat pancreatic beta cells. 634 29

Rats with chronic streptozotocin (SZ) diabetes develop dilatation of the alimentary tract, loss of fecal consistency, and autonomic neuropathy involving unmyelinated axons of the extrinsic innervation of the small bowel. Diabetic autonomic neuropathy involving the ileal mesenteric nerves is characterized by modest to marked dilatation of axons by distinctive subcellular organelles identical to those described in experimental and clinical axonal dystrophies. Axonopathy is confined to the alimentary tract; examination of myelinated and unmyelinated axons of the sciatic (midthigh level) and distal somatic nerves of the tail of diabetic animals with prominent ileal axonopathy failed to demonstrate significant numbers of dystrophic axons. The prevention or reversal of diabetic autonomic neuropathy by a variety of experimental manipulations clearly indicates that the lesions we have demonstrated in chronically SZ-induced diabetic animals were produced by diabetes and were not the result of a direct neurotoxic effect of the diabetogenic agent streptozotocin. Animals did not develop axonopathy after simultaneous administration of SZ and nicotinamide, a procedure which prevents pancreatic beta-cell necrosis and induction of diabetes while exposing the nervous system to a possible neurotoxic agent. Selected animals that were given SZ, became diabetic, and subsequently received daily insulin therapy or pancreatic islet transplantation also did not develop axonopathy. Transplantation of pancreatic islets 6 mo after induction of diabetes, a time at which mesenteric axonopathy was well developed, quickly reestablished normoglycemia, and within 3 mo resulted in nearly complete resolution of the neuropathy. Mild chronic diabetes maintained for 5-6 mo failed to produce significant levels of axonopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1983 Jun
PMID:The effect of pancreatic islet transplantation and insulin therapy on experimental diabetic autonomic neuropathy. 641 60

Streptozotocin, an antibiotic widely used for induction of diabetes in experimental animals and for the treatment of pancreatic neoplasms, was shown to be a potent methylating agent reacting with DNA in vitro to form methylated purines. The reaction was similar in extent and relative proportions of methylation products to that produced by N-methyl-N-nitrosourea, the aglycone of streptozotocin. When streptozotocin was administered to rats by i.v. injection, DNA was methylated with the formation of 7-methylguanine, O6-methylguanine, 3-methyladenine, and 7-methyladenine in liver, kidney, intestine, and pancreas. In contrast to N-methyl-N-nitrosourea which produced approximately equal amounts of methylation in DNA of liver, brain, and kidney, streptozotocin caused virtually no methylation in brain DNA; but, both liver and kidney DNA were alkylated to a greater extent than with N-methyl-N-nitrosourea. This methylation of renal DNA may account for the ability of streptozotocin to induce renal tumors. Streptozotocin produced significant methylation of pancreatic DNA which, if concentrated in the beta-cells, may account for their destruction. Pretreatment with nicotinamide reduced the extent of methylation of pancreatic DNA but did not affect the methylation in the liver or kidney. Methylation of beta-cell DNA in the pancreas may lead to the initiation of tumors if the extent of alkylation is not so great that cell death occurs.
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PMID:Alkylation of DNA in rat tissues following administration of streptozotocin. 645 79

A clinical syndrome, characterized by acute diabetic ketoacidosis associated with a toxic neuropathy, developed in five men who intentionally ingested a recently introduced rodenticide (Vacor) containing N-3-pyridylmethyl-N'-p-nitrophenyl urea (RH-787). A 7-yr-old boy, who accidentally ingested this poison, died within 14 h. Marked insulinopenia, without a reduction in glucagon levels, suggested a specific beta-cytotoxic effect, which was supported after autopsy in three cases by histopathologic evidence of extensive beta cell destruction. Lethal effects in rats prevented investigation of RH-787's diabetogenicity in vivo; however, studies in isolated rat islets confirmed a direct inhibitory effect, which was prevented by concomitant incubation with nicotinamide, suggesting a mechanism of action similar to that of streptozotocin. We detected islet cell-surface antibodies in two of four patients studied. These findings indicate that this nongenetic, acquired form of insulinopenic diabetes, which has persisted in the surviving patients for up to 3 yr, presents a unique opportunity to test in man the concept that hyperglycemia and the accompanying metabolic consequences of insulinopenia can induced diabetic microangiopathy in the absence of genetic predisposition.
Diabetes 1980 Dec
PMID:Insulinopenic diabetes after rodenticide (Vacor) ingestion: a unique model of acquired diabetes in man. 677 23

For the prediction of type I diabetes in first degree relatives of type I diabetics, a variety of laboratory methods are now available. Thus, screening for serum antibodies against the body's own insulin, islet cells and the enzyme glutamate decarboxylase, represents a simple and well-established routine examination used for early diagnosis. The combination of various parameters such as e.g. the age of the person at risk, antibody status (nature, number, combination or titer of the antibodies) and capacity for early insulin secretion following i.v. glucose loading, permits us to predict, with quite good accuracy, the risk years before there are any clinical manifestations. These successes of early diagnosis have led to new concepts of immunoprophylaxis for the prevention of type I diabetes. Thus, at the present time two highly promising studies involving the prophylactic administration of insulin or nicotinamide in persons at risk are underway in Germany, the results of which to date suggest that a new epoch of immunotherapeutic treatment of this disease may be in the offering.
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PMID:[Prediction of type I diabetes by antibody screening]. 749 55

Complete loss of pancreatic insulin function in insulin-dependent diabetes is thought to be due to an autoimmune cytokine-mediated destruction of the beta-cell. The effects of several classes of agents on interleukin-1 beta (IL-1 beta)-induced suppression of insulin secretion, beta-cell NAD levels, and beta-cell viability were examined. After overnight incubation of isolated rat islets with 15 U/ml IL-1 beta and 11 mM glucose, sequential hourly insulin secretory responses to the same glucose concentration, 22 mM glucose, and 22 mM glucose plus forskolin were severely inhibited to 10-37% of the control value. Islet NAD levels were also sharply reduced to 43% of the control value after 24-h exposure to IL-1 beta, but not after 1 or 3 h, demonstrating the same time course as that for inhibition of insulin secretion. Exposure to IL-1 beta also decreased islet cell viability measured as trypan blue exclusion. Only 1 mM N-methyl arginine, an inhibitor of nitric oxide synthase, completely protected all three parameters of beta-cell function from damage by IL-1 beta. Nicotinamide and thymidine prevented the IL-1 beta-induced loss of cell viability and suppression of NAD, but had no effect on sustaining insulin secretion. Antioxidants, steroids, and several neuropeptides also did not prevent inhibition or restore the secretory response. Thus, the loss of the secretory response appears to be more narrowly restricted to nitric oxide radical damage induced by exposure to IL-1B.
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PMID:Interrelationship of changes in islet nicotine adeninedinucleotide, insulin secretion, and cell viability induced by interleukin-1 beta. 750 26


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