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Research Models of Diabetes Mellitus
Published in Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla, Heart Dysfunction in Diabetes, 2019
Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla
The use of streptozotocin was originally far removed from diabetes research as well. Streptozotocin was initially discovered in 1960 by Vavra and co-workers53 who isolated the compound from the organism Streptomyces achromogenes (var. 128) which was taken from a soil sample in Kansas. Its original application was as an antibacterial antibiotic53,54 but it also recieved attention as an antitumor and anticarcinogenic agent. Rakienten et al.55 can be credited with the initial discovery of the potent diabetogenic action of streptozotocin. They found that rats and dogs developed hyperglycemia, polydipsia, polyuria, and glycosuria after administration of the drug intravenously at a concentration of 50 mg/kg animal body weight. Its effects were associated with a relatively specific, massive destruction of the pancreatic islets of Langerhans. To date, alloxan and streptozotocin are the only chemical compounds used in research today to produce diabetes in laboratory animals. Because of their general acceptance in the diabetic field, a comprehensive discussion of their use, proposed mechanism of action, and the metabolic and pathological consequences of their use in animals is warranted.
Animal models in diabetes and pregnancy research
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
Catherine Yzydorczyk, Delphine Mitanchez, Umberto Simeoni
In general, human T1D is reproduced by streptozotocin (STZ) administration to rodents during adult life.3 STZ is a nitrosourea derivative isolated from Streptomyces achromogenes.4 It is a powerful alkylating agent that has been shown to interfere with glucose transport5 and glucokinase function6 and able to methylate DNA. Nevertheless, it is generally accepted that the cytotoxicity produced by STZ depends on DNA alkylation.7 STZ, relatively similar to glucose, is transported inside the cell only by the glucose transporter-2 (GLUT-2) (STZ is not recognized by the other GLUTs). Beta cells of the islets of Langerhans express high levels of GLUT-2, therefore making them more vulnerable to STZ toxicity.8
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Streptozotocin (ZanosarTM) [2-deoxy-2-({[methyl(nitroso)amino]carbonyl}amino)-β-D-glucopyranose], a naturally occurring glucosamine-nitrosourea compound, was originally identified as an antibiotic in the late 1950s when isolated from Streptomyces achromogenes by (the then) Upjohn company in Kalamazoo (Michigan) from a soil sample taken from the Blue Rapids in Kansas (USA) (Figure 5.20). Also known as STZ, in the mid-1960s streptozotocin was found to be selectively toxic to the insulin-producing beta cells of the pancreas, causing DNA damage and inducing activation of poly ADP-ribosylation. This observation led to interest in using streptozotocin to develop an animal model of diabetes and as a potential treatment for tumors of the pancreatic beta cells. Therefore, in the 1960s and 1970s the NCI investigated its use in cancer chemotherapy and, as a result, Upjohn Inc filed a patent in 1958 to protect use of the agent in pancreatic cancer. The agent was eventually approved by the FDA in 1982 for the treatment of metastatic cancer of the Islets of Langerhans and rare cancers such as carcinoid tumor (a neuroendocrine tumor), and is marketed as ZanosarTM. In the UK it is recommended by NICE for the treatment of neuroendocrine tumors of pancreatic origin (Figure 5.31). Structure of streptozotocin (ZanosarTM).
Streptozotocin mechanisms and its role in rodent models for Alzheimer’s disease
Published in Toxin Reviews, 2023
Mazzura Wan Chik, Nur Adiilah Ramli, Nurul Aqmar Mohamad Nor Hazalin, Gurmeet Kaur Surindar Singh
STZ is a glucosamine-nitrosourea that originates from the soil bacterium Streptomyces achromogenes. It was first identified as an antibiotic. It is active against Gram-positive and Gram-negative bacteria (Bolzán and Bianchi 2002). Although it is not used as an anti-infective due to its cytotoxicity toward β cells, researchers have found that through structural modification at the C3 position of an STZ analogue, its antimicrobial activity is increased and its toxicity to β cells is reduced (Zhang et al. 2020). It is being used in medicine as an anti-neoplastic agent to treat neoplasms, such as pancreatic neuroendocrine tumors (Okusaka et al. 2015). In research, STZ has been used to induce Type 1 and Type 2 diabetes in mice through its cytotoxicity toward the β cells of the pancreas, which directly influences the balance between glucose metabolism and insulin secretion. STZ, injected intravenously, was able to destroy the pancreatic β cells within 4 days (Akbarzadeh et al. 2007). Prolonged treatment of STZ in male Wistar rats (up to 24 weeks) has shown chronic effects of diabetes, such as cataracts, impaired kidney function, diabetic neuropathy, heart disease, and stroke (Wei et al. 2003). Although initially STZ was used to study diabetes, it was later correlated with brain aging (Wang et al. 2014). The presence of Aβ and accumulation of phospho-τ that are associated with neurite degeneration and neuronal loss were reported to be present in 8-months-diabetic rats (Li et al. 2007).
Platelet-rich plasma improves impaired glucose hemostasis, disrupted insulin secretion, and pancreatic oxidative stress in streptozotocin-induced diabetic rat
Published in Growth Factors, 2019
Marzieh Zarin, Narges Karbalaei, Sara Keshtgar, Marzieh Nemati
In our study, STZ induced-diabetic rats showed impaired GTT and low plasma insulin and high plasma glucose levels during 45 d of experiment compared to control group. STZ is a glucosamine–nitrosourea compound that derived from soil bacterium Streptomyces achromogenes. Use of STZ to induce experimental model of diabetes has been documented as a well-standard method (Furman 2015). STZ is a toxic beta cell glucose analogue that transports into β-cells through the glucose transporter 2 (Glut2) and causes destruction of pancreatic β-cell and DNA damage, in turn, results in hypoinsulinemia and hyperglycemia in diabetic rats (Eleazu et al. 2013).
The protective effect of Satureja bachtiarica hydroalcoholic extract on streptozotocin‐induced diabetes through modulating glucose transporter 2 and 4 expression and inhibiting oxidative stress
Published in Pharmaceutical Biology, 2019
Reyhaneh Joudaki, Mahbubeh Setorki
STZ, an antibiotic produced by Streptomyces achromogenes, is typically used to induce diabetes in experimental models (Abouzed et al. 2018). STZ is taken up by the pancreatic β-cells through the GLUT2 glucose transporter and causes degenerative changes in the cells which leads to the decreased insulin secretion and ultimately hyperglycaemia (Eleazu et al. 2013). The mechanism of STZ action on pancreatic β-cells has not yet been fully understood; however, it is believed that oxidative stress plays an important role in the development of the STZ-induced complications (Sadek et al. 2017). STZ is an unstable molecule that accumulates in the pancreatic β-cells and degrades to carbonium radicals. Carbonium radicals are highly reactive and induce direct toxic effects on pancreatic islet cell; they also show indirect toxic effects by increasing the generation of ROS (Ghanema and Sadek 2012; Sadek et al. 2017). STZ was reported to cause β-cell damage through the induction of DNA fragmentation and methylation (Cardinal et al. 2001). It has also been shown that STZ causes inflammatory response through enhanced infiltration of mononuclear cells and excessive production of inflammatory cytokines in the islets of Langerhans that eventually leads to the β-cells injury and death (Abouzed et al. 2018). Also, studies have shown that increased nitric oxide (NO) production in the pancreas of STZ-treated rats plays an important role in the degeneration of β-cells (Pacher et al. 2005). In STZ-treated rats, serum NO level was reported to be elevated (Coskun et al. 2005), and inhibitors of nitric oxide synthases (NOS) such as LNG-NMDA and aminoguanidine resulted in remarkably reduced hyperglycaemia and β-cells damage (Lukic et al. 1991; Corbett and McDaniel 1996). In our study, hyperglycaemia, lipid peroxidation and decreased serum TAC in STZ-diabetic rats confirmed these mechanisms.