Studies of the diabetogenic action of streptozotocin.
TL;DR: While the B-cytotoxic effects of streptozotocin resemble those of alloxan, their specificity is very much greater, as demonstrated by the wide margin between diabetogenic dose and general toxicity.
Abstract: SummaryStreptozotocin is a highly effective cytotoxic agent for pancreatic B-cells. After intravenous administration of 65 mg streptozotocin per kg, damage to B-cells is apparent as early as one hour after intravenous administration of the drug. Frank necrosis associated with phagocytosis is best seen after 7 hours, when pancreatic insulin release and hypoglycemia are also noted. By 24 hours, pancreatic insulin content is reduced to 5% of normal or less. While the B-cytotoxic effects of streptozotocin resemble those of alloxan, their specificity is very much greater, as demonstrated by the wide margin between diabetogenic dose and general toxicity.
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TL;DR: The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model.
Abstract: The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.
996 citations
Cites background or result from "Studies of the diabetogenic action ..."
...Previous reports from this laboratory have dealt with a preliminary characterization (1) of the diabetogenic action of streptozotocin discovered by Rakieten, Rakieten, and Nadkarni (2), as well as with a detailed morphologic evaluation1 of the ultrastructural alterations of pancreatic A-cells brought about by the administration of this agent....
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...Since there was no significant decrease in the pancreatic IRI content at that time, and since ,8-granules still seemed rather well preserved, both when examined histochemically (aldehyde-thionine) and when examined with the electron microscope (1), it is possible that soluble, "nongranular" insulin was released first....
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...Absence of recovery of pancreatic IRI content associated with persistently low yet significant serum IRI levels indicates continued synthesis with immediate release of insulin in the presence of hyperglycemia, an interpretation entirely consistent with the morphological finding of small numbers of surviving P-cells (1)....
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...Contrary to the suggestions of others (3, 4), it was shown that the diabetogenic action of streptozotocin results primarily from its highly specific cytotoxic action on the p-cells of the islets of Langerhans with rapid and irreversible necrosis (1)....
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TL;DR: Ulastructural evidence of abundant type C viruses within beta cells of treated mice suggests that streptozotocin may activate murine leukemia virus in vivo in susceptible hosts.
Abstract: Multiple small injections of streptozotocin in mice produce pancreatic insulitis, with progression to nearly complete beta cell destruction and diabetes mellitus. The timing and appearance of the inflammatory islet lesions suggest but do not prove that streptozotocin acts by initiating a cell-mediated immune reaction. Ultrastructural evidence of abundant type C viruses within beta cells of treated mice suggests that streptozotocin may activate murine leukemia virus in vivo in susceptible hosts.
982 citations
TL;DR: Protocols for producing STZ‐induced insulin deficiency and hyperglycemia in mice and rats and creating animal models for type 2 diabetes using STZ are described.
Abstract: Streptozotocin (STZ) is an antibiotic that produces pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this unit are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition.
820 citations
Cites background from "Studies of the diabetogenic action ..."
...This action was characterized by Junod et al. (1969) based on earlier work (Junod et al., 1967) showing that the diabetogenic effects are due to selective destruction of pancreatic islet βcells....
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...(1969) based on earlier work (Junod et al., 1967) showing that the diabetogenic effects are due to selective destruction of pancreatic islet βcells....
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TL;DR: The literature is reviewed and data from pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice are provided with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.
Abstract: Streptozotocin (STZ)-induced diabetes mellitus (DM) offers a very cost-effective and expeditious technique that can be used in most strains of rodents, opening the field of DM research to an array of genotypic and phenotypic options that would otherwise be inaccessible. Despite widespread use of STZ in small animal models, the data available concerning drug preparation, dosing and administration, time to onset and severity of DM, and any resulting moribundity and mortality are often limited and inconsistent. Because of this, investigators inexperienced with STZ-induced diabetes may find it difficult to precisely design new studies with this potentially toxic chemical and account for the severity of DM it is capable of inducing. Until a better option becomes available, attempts need to be made to address shortcomings with current STZ-induced DM models. In this paper we review the literature and provide data from our pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.
449 citations
TL;DR: Current knowledge regarding the genotoxicity of STZ is presented, indicating that free radicals are involved in the production of DNA and chromosome damage by this compound.
Abstract: Streptozotocin (Streptozocin, STZ, CAS No. 18883-66-4) is a monofunctional nitrosourea derivative isolated from Streptomyces achromogenes. It has broad spectrum antibiotic activity and antineoplastic properties and is often used to induce diabetes mellitus in experimental animals through its toxic effects on pancreatic β cells. STZ is a potent alkylating agent known to directly methylate DNA and is highly genotoxic, producing DNA strand breaks, alkali-labile sites, unscheduled DNA synthesis, DNA adducts, chromosomal aberrations, micronuclei, sister chromatid exchanges, and cell death. This antibiotic was found to be mutagenic in bacterial assays and eukaryotic cells. STZ is also carcinogenic; a single administration induces tumors in rat kidney, liver, and pancreas. Several lines of evidence indicate that free radicals are involved in the production of DNA and chromosome damage by this compound. Because of the use of STZ as an antineoplastic agent, the study of its genotoxicity has considerable practical significance. The purpose of this review is to present our current knowledge regarding the genotoxicity of STZ.
376 citations
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TL;DR: The accumulated evidence suggests that in rabbits the antipyretic effect of salicylate is not central on the hypothalamus but is peripheral on the leucocyte to inhibit formation or release of its pyrogen.
Abstract: SummarySodium salicylate is antipyretic in experimental endotoxin fevers in rabbits but is not significantly antipyretic in fevers induced by leucocytic pyrogen. The in vitro production of pyrogen by leucocytes is significantly decreased by salicylate. The accumulated evidence suggests that in rabbits the antipyretic effect of salicylate is not central on the hypothalamus but is peripheral on the leucocyte to inhibit formation or release of its pyrogen.
21 citations