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    Acta Histochem, Cytochem, 38 (3): 201-208, 2000, Streptozotocin and Alloxan in Experimental Diabetes: Comparison of the Two Models in Rats erg Islas-Andrade, Ma. Cristina Revilla Monsalve, Jorge Escobedo de la Peit Ana C Polanco, Miguel Angel Palomino and Alfredo Feria Velasco* Unidad de Investigacion Médica en Enfermedades Metabsicas, Centro Médico Nacinal Siglo XXI, ILM.S.S. México Ctyand "Division de Patologia y Bioteenologia Ambiental, CIA TEI, (SEP-CONACYT) Guadalajara, Jalisco, México Received December 24,1999; accepted May 12, 2000 Diabetic animals have contributed to the understanding of the causes, consequences and treatment of diabetes. There are differ ent ways to induce experimental diabetes, chemically induced experimental diabetes has been widely used. Alloxan and strepto- zotocin are the chemicals most used. A comparative study of these two agents was performed in order to determine their effectiveness. Twenty-seven Sprague-Dawley male adult rats were intraperitoneally (.p.) injected with 120 mg/kg BW of alloxan (AL) and 27 with 60 mg/kg BW of streptozotocin (STZ) Key words: 1. Introdu Diabetes mellitus is the name given to a multiple group of disorders with different etiologies. It is charac- terized by derangement in carbohydrate, protein, and fat ‘metabolism caused by the complete or relative insufficiency Of insulin secretion and/or insulin action. Experimental diabetes has the advantage that it allows the analysis of the biochemical, hormonal and morphological events that take place not only during the induction of a diabetic state but also after it has taken place and during its evolution to a severe insulin deficiency or even death. This strategy has reat advantages but it has to be considered that none of the animal models with induced diabetes corresponds ex- actly to the human Type 2 diabetes mellitus, nonetheless they provide models to investigate the pathogenic mechan- isms that lead to hyperglycemia and its consequences [2]. ‘There are several techniques for inducing experimen- tal diabetes which include the chemical destruction, the Correspondence to: Dr. Sergio Islas Andrade, Unidad de Inves: tigacién Médica en Enfermedades Metabélicas, Centio Médico ‘Nacional, IMSS, Apartado Postal 13-800, Colonia Nativitas CP (03500, Mexico City, Mexico, 201 Levels of glucose, insulin, triglycerides and total cholesterol were determined at differ- cent times after the i.p. injection. The effect ‘of the two chemicals on the Langerhans’ islets was histochemically demonstrated, The reversibility of the diabetic state, 20 days after the i.p. injection of AL, was dem- onstrated by the recovery of insulin levels, reduction of the glucose and triglycerides concentration and by positive anti-nsulin antibodies reaction in the pancres STZ proved to induce a more stable and permanent diabetic stat Experimental diabetes, Streptozotocin, Alloxan surgical removal of the 3 cell mass or even the pancrea tectomy, the injury of the ventromedial hypothalamus, feeding with high-fat and high-sugar diets, malnutrition ‘in utero; high dosages of counter-regulatory hormones, particularly glucocorticoids and a prolonged exposure t0 hyperinsulinemia [2, 7, 9, 23]. Hormones like adrenaline, glucagon, glucocorticoids and somatotropin that have an antagonic effect on insulin, when present in excess as a consequence of stress, tumors or other metabolic altera- tions can also provoke hyperglycemia [14]. Different chemical agents are capable of producing the alterations related to the diabetic condition; two of the most widely used are alloxan (AL) and streptozotocin (STZ) (7, 9, 10, 13, 14), AL became the first diabetogenic chemical agent when Dunn and Me Letchie accidentally produced isletcell necrosis in rabbits while researching the nephrotoxicity of uric acid derivates. In vitro, AL. displays exceptionally specific inhibitory and cytotoxic effects on 3 cells, other fslet-cell types being unaffected [7]. However, its mechanism of action is not well known. Some studies point to the fact that alloxan’s initial effect is mediated by a certain interaction at the membrane of 3 cells resulting in selective necrosis (8, 36]. It has been 202 Islas-Andrade et al reported that it inhibits glucose-stimulated insulin release {8] and high doses cause j-cell necrosis and a severe insulin deficiency with ketosis. ‘AL is soluble in water, has a high affinity for the thiol groups and for Zn** and inhibits the hexokinase and other enzymes 8]. In certain species, these chemical characteristics of alloxan are responsible for the non-appearance of its diabetogenic effect. Thus, it is possible thatthe interference with the metabolism of that element may be important in the action ofthe drug [2, 7} Okamoto er al. studying the mechanism of action of AL proposed a model in which the fragmentation of the nuclear DNA of pancreatic j-cells seems to be important for the induction of diabetes and this fragmentation is supposed to be the result of the accumulation of superoxide or hydroxyl radicals (25, 30]. Takasu [34] demonstrated that alloxan and streptozotocin stimulate the generation of H.O- which induces DNA fragmentation, Actually low doses of AL are sill used to induce experimental diabetes, causing a partial reduction of j-cell mass that can produce a mildly insulin-deficient state, without ketosis and also insulin resistance (1, 27, 32). Tt has also been reported that the sensitivity to this agent varies with species, strain, sex, age, and nutritional state [2] On the other hand, the streptozotocin (STZ) is a nitrosourea derivative isolated from the mould Sirep- fomyces griseus. It can induce severe insulin-deficient diabetes in rats and other rodents, ether when given as a single large dose (50-100 mg/kg in rats) or as multiple smaller doses; in the later case, diabetes develops more eradually and appears to have an autoimmune, rather than toxic, basis. Diabetes induced by a single intravenous or intraperitoneal injection of STZ is probably the most widely used experimental model of insulin-dependent diabetes mellitus. With a dosage of 50-60 mg/kg, insulin levels typically fall to 10-30% of normal, leading to hyperglycemia (20-30mmol/1), polyuria, polydipsia and weight loss, however severe ketosis does not develop and the animals can survive for some weeks without insulin replacement. Higher dosages induce moze profound insulin deficiency, resulting in spontaneous ketosis and death if insulin is not given [4] STZ causes j-cell necrosis and diabetes supervenes within 1-2days with damage to the f-cell membrane and induction of DNA strand breaks, leading to activation of poly (ADP-ribose) symthetase and NAD depletion [4] Due to the fact that the experimental animal models do not exactly resemble the conditions of the human diabetes, we most verify that the model we select is the most accurate. So the main objective of this survey was 10 determine the effect of AL and STZ on the Langerhans’ islets of the pancreas of rats and to evaluate the effects of both drugs on the levels of glucose, insulin, triglycerides and total cholesterol at different intervals after an intraperitoneal (.p.) injection Il, Materials and Methods 94 male Sprague-Dawley rats with an average weight of 300g were maintained on a 12/12 hours light-dark cycle with water and food ad libitum. Diabetes was induced by an ip. injection of alloxan 120mg/ke BW in 1.0m of, bidestilled water to 27 rats; and by 60mg/kg BW of streptozotocin in 1.0ml of acetate buffer 0.1M. pH 4.3 to 27 rats. 20 control rats for AL were injected ip. with the same volume of bidestilled water, and 20 control rats for STZ were injected ip. with 1.0ml of acetate buffer 0.1M, pH4.3. Animals were allotted in 9 groups of 3 rats each for AL and also for STZ. Levels of glucose, insulin, total cholesterol and triglycerides were determined 30 min, 1, 2, 5, 7,9, 12, 1S and 20

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