Alloxan-induced diabetes is a model of type 1 DM, but type 2 DM is a more common risk factor for CVD. Extract treatment also significantly reduced serum concentrations of triglyceride, total cholesterol, and low-density lipoprotein (LDL)-cholesterol and enhanced serum level of high-density lipoprotein (HDL). Blood glucose levels were estimated with glucometer before treatment, 2h and 1- 4 weeks after administration of extracts. The responses are accompanied by corresponding inverse changes in plasma insulin and sequential ultrastructural changes resulting in necrotic beta cell death. The pooled mean difference in fasting blood glucose among subjects receiving Zn supplementation is 18.13 mg/dL lower than that in placebo groups, as illustrated in Figure 3. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Lipid peroxidation in chemical diabetes appears to be due to hyperglycemia and not the agent, because the pattern of changes is not agent specific. The diabetogenicity of alloxan is... 2.2. P.J. PHILLIP A. Studies of glycemic control and neuropathy have also supported the glucose hypothesis.24, Vyacheslav Buko, ... Ilya Zavodnik, in Nano- and Microscale Drug Delivery Systems, 2017. Alloxan produce diabetes mellitus with a single dose of administration through selective necrosis of pancreatic β- cells of islets of langerhans that initiate insulin deficiency. Production and hosting by Elsevier Sp. The molecular organization of the node, paranode, and juxtaparanode is highly complex and has been reviewed elsewhere.240 The integrity of the junction between the myelin loops and the axolemma depends on the expression and docking of both Schwann cell proteins (neurofascin, periaxin, and ezrin) and axonal proteins (contactin, caspr). Noté /5. Zn might play an important role in appetite regulation and its administration by stimulating leptin production. Table 3. Peter A.J. Evidence for the Preventive Effect of Zn Supplementation on Diabetes. Figure was created based on a published study. Alloxan induces a multiphasic... 2.3. Yassa and Tohamy also demonstrated that leaf extract ameliorates streptozotocin-induced diabetes mellitus in adult rats (Gupta et al., 2012; Yassa and Tohamy, 2014). After 12 h, a 10% glucose solution was offered to the animals to prevent hypoglycemia (27,28). In diabetic rats, alloxan diabetes was induced by intraperitoneally injecting 1 ml of 5% alloxan at the beginning of the study Group Glycaemic Treatment status A Nondiabetic 1 ml distilled water (intraperitoneally) per day for 10 days B Diabetic 1 ml of a 5% solution of alloxan monohydrate at a dose of 125 mg/kg C Diabetic Alloxan monohydrate+glibenclamide (10 mg/kg). Alloxan induced diabetes of 4 days duration produced metabolite changes in brain compatible with severe reduction in cerebral metabolism (phosphocreatine increased 70%), and reduced phosphofructokinase activity (fructose diphosphate levels fell 38%). Alloxan has two distinct pathological effects: it selectively inhibits glucose-induced insulin secretion through specific inhibition of glucokinase, the glucose sensor of the beta cell, and it causes a state of insulin-dependent diabetes through its ability to induce ROS formation, resulting in the selective necrosis of beta cells. They demonstrated that Zn supplementation appeared to affect the early insulin response to glucose differentially among those with the rs13266634 genotype and that Zn supplementation could be beneficial for diabetes prevention and/or treatment for individuals based on the presence of the SLC30A8 variation. Zn supplementation increased serum Zn by 15% and urinary Zn by 56%. It is normally and largely compromised in diabetes. It also normalized the reduced mRNA expression of fatty acid synthase in the liver of diabetic rats. We use cookies to help provide and enhance our service and tailor content and ads. tathione (GSH) during the alloxan-induced diabetes melli- There were no significant differences between the control tus. In 1967 Chase and Tubbs reported that carnitine acyl transferase and hence fatty acid oxidation are inhibited by 2-bromostearate (see Ref. This observation necessitated the review of alloxan as a diabetogenic agent in animal studies. In vitrostudies proved that alloxan mediate cytotoxic action by production of ROS that cause destruction of β- cells.24,25 Alloxan-induced diabetes is one of the widely used model to induce Type I diabetes mellitus in the the experimental animals. Glucose-lowering effects of M. oleifera extracts have been reported. We enhanced water-solubility of sertraline by complexation with 2-hydroxypropyl-β-cyclodextrin (HPβCD) and evaluated the pharmacological properties of the HPβCD:sertraline complex in rats with alloxan-induced diabetes. This causes an insulin-dependent diabetes mellitus (called "alloxan diabetes") in these animals, with characteristics similar to type 1 diabetes in humans. Each point represents the mean value 6 SEM; n was group and the silymarin group in liver GSH (Fig. VII, Oxidative Stress and Excitatory Neurotoxins in Neuropathy, Diabetes Control, Long-Term Complications, and Large Vessel Disease, The Supramolecular Complex of Sertraline With Cyclodextrins: Physicochemical and Pharmacological Properties, Nano- and Microscale Drug Delivery Systems. In conclusion, our results suggest that glycolytic metabolism and glucose uptake are altered in diabetic atherosclerosis. In 5 of 23 animals, brain glycogen levels … Alloxan diabetes and streptozotocin diabetes Figure 1 shows a schematic diagram of the tetraphasic and triphasic blood glucose responses induced by alloxan and streptozotocin, respectively, when injected [22]. The only cogent neurophysiologic argument to explain the deficit has come from the suggestion of increased refractoriness of nodes of Ranvier in diabetes leading to deferred activation and propagation.37,38,155 This change may derive from impairment of voltage-gated Na+ channels, but it has also been attributed to reduced driving gradient for Na+, and this has been attributed in turn to impaired activation of Na+, K+-ATPase.126 The hypothesis then suggests that the depletion of myo-inositol, derived from exaggerated polyol pathway flux, limits the synthesis of inositol-containing phospholipids and that DAG, which is derived from these lipids, regulates activation of subunits of the membrane Na+, K+-ATPase.125 This hypothesis still lacks substantive proof, and the role of impaired Na+, K+-ATPase activity in the development of conduction deficits remains contentious. The ability of therapeutic compounds including medicinal plants to restore glycemic balance or homeostasis in hyperglycemic condition is an index of their antidiabetic function and relevance. IN ALLOXAN INDUCED DIABETIC RATS HTML Full Text. For the most part these have followed the first demonstration of a conduction deficit in diabetic rats,90 by concentrating on MNCV. Modulation of NADPH oxidase subunit expression is another way of preventing ROS formation and restoring erectile function by SAC in diabetic rats; it was suggested that the poor efficacy of conventional insulin treatment for diabetic erectile dysfunction may be associated with an elevated level of ROS in penile tissue (Yang et al., 2013). Leptin did not change either in the placebo group or Zn group.73 In contrast to this study, another triple-masked, randomized, placebo-controlled, crossover trial was conducted among 60 obese Iranian children who were randomly assigned to two groups of equal number; one group received 20 mg Zn and the other group received placebo for 8 weeks. Other such stresses include overfeeding and obesity, aging, and a number of intercurrent diseases. Alloxan, in t… Supplementation of Zn by subcutaneous or intraperitoneal injection, drinking water, and dietary food were all effective in preventing diabetes. Zn supplementation significantly improved these deleterious changes in these obese children with a decrease in plasma leptin level along with other changes.63. Diabetes was induced by intraperitoneal injection of 120 mg/kg b.w. The mechanism of DNA damage induced by alloxan was investigated using 32P-labeled human DNA fragments. However, pregnancy is only one of a variety of environmental stresses that may aggravate the manifest disease or transform the latent form into the clinical state. Abd El Latif et al. In addition, high-sensitivity C-reactive protein (hs-CRP) and markers of insulin resistance were decreased significantly in the Zn group but increased in the placebo group. Although glomerular lesions in several animal models of diabetes are similar to those seen in diabetic nephropathy in humans, the time course of the development of the lesions is difficult to compare with that seen in human diabetes. On this ground, one will logically expect a preference for use of alloxan in experimental diabetes studies. Figure 3. Olayaki and coauthors have investigated the effect of oral administration of methanol extracts of this plant on glucose tolerance, glycogen synthesis, and lipid metabolism in rats with alloxan-induced diabetes (Olayaki et al., 2015). By continuing you agree to the use of cookies. However, it is certain that the male is as capable of transmitting induced glucose intolerance as is the female, thus, precluding the maternal milieu as being etiologic. CAD severity was assessed with … These results are suggested that the complexation of SER with the cyclodextrin derivative improves the pharmacological effect of sertraline, probably due to enhanced drug bioavailability. A later study demonstrated that if dogs with alloxan-induced diabetes were treated with the poor-control regimen for 2.5 years, followed by the good-control regimen for 2.5 years, they developed an intermediate number of microaneurysms.11 This prescient study suggested that secondary intervention was not as effective as primary prevention, and it forecast the results of human studies that would follow almost 10 years later. The deficit is preventable in the short term (generally about 1 month) by maintenance of tight glycemic control with insulin.124,200 A similar deficit in MNCV is present in the BB rat when control of glycemia is allowed to lapse to a minimal life-preserving level.125,203 Improvement of the quality of glycemic control attenuates the MNCV deficit.126 More detailed examination of nerve conduction in different nerve trunks of STZ-diabetic rats revealed velocity deficits in all branches of the innervation of the lower limb, including some that carry predominantly sensory fibers.52. One of the most common alterations is a reduction in cuprozinc SOD. However, other studies have found mixed results.67 Forty Korean obese women aged 19–28 years were recruited for a study of Zn's effects on glucose metabolism. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. The pooled mean for total cholesterol in the Zn-supplemented group was 32.37 mg/dL lower than that in placebo groups. We use cookies to help provide and enhance our service and tailor content and ads. This chapter discusses the transmission of alloxan diabetes and other diabetogenic influences. Thus treatment of STZ-diabetic rats from the onset of diabetes for short periods (around 1 month) with an ARI results in an MNCV that is not significantly lower than that seen in control rats and is significantly higher than that measured in untreated diabetic littermates. z o.o. Intraperitoneal glucose tolerance was assessed and serum glucose, insulin, and lipids were measured at the end of the experiment. Effects of sulforaphane are attributed to activation of the Nrf2-dependent antioxidant response-signaling pathway, induction of phase 2 enzymes and peroxisome proliferator-activated receptors, attenuation of oxidative stress, and inactivation of NF-κB (a key modulator of inflammatory pathways). Effect of alloxan-induced diabetes on substrate kinetics of serum BChEIn view of the dramatic changes in serum BChE activity, we extended our studies and looked at the substrate kinetic Table 2 Effect of alloxan-induced diabetes on serum BChE activity (nmol/min per ml serum) in male and female rats. However, dietary supplementation with PB (6 g/kg extract for 4 weeks administered orally using an intragastric tube) ameliorated the alloxan‐induced diabetes in a manner comparable with that of the reference antidiabetic drug glibenclamide. Complex patterns of changes in antioxidant enzymes have been described in different tissues in streptozocin diabetes.188,189 Liver and kidney have reduced catalase and SOD. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. This has been demonstrated for ICI 105552,329 sorbinil,376 zenarestat,169 tolrestat,224 ponalrestat,294 and fidarestat.161 Furthermore, a group of rats left untreated over the first 3 weeks of their STZ-induced diabetes, and displaying a significant MNCV deficit at that time, showed a return of MNCV to normal levels over 3 weeks of treatment with sorbinil.331 Thus in the short term the deficit is reversible. Others have suggested that the NCV deficit derives from molecular dislocation of the myelin loops from the axolemma in the paranodal region.293 This would result in a loss of the electrical insulation between the Na+ channels in the nodal membrane and the insulated K+ channels of the juxtaparanode.354 The result of this would be inappropriate rectification of the nodal action potential and inevitable slowing of conduction. The way in which the polyol pathway might act to cause the development of the conduction velocity deficit has received much attention in the past. Nevertheless, they uniformly support the role of therapies that normalize blood glucose levels to prevent and/or delay the progression of retinopathy, nephropathy, and neuropathy. Group 1 participants received 20 mg Zn, and group 2 received placebo on a regular daily basis for 8 weeks. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent 'alloxan diabetes'. Glycemic homeostasis refers to glucose balance or control within circulation in living organisms. Sulforaphane could prevent nephropathy, diabetes-induced fibrosis, and vascular complications. ), India. There was a 56% reduction in brain lactate concentration, but pyruvate levels were unchanged. V. Kuete, in Medicinal Spices and Vegetables from Africa, 2017. Diabetes was induced in fasted mice by using intraperitoneal (IP) injection of alloxan (180 mg/kg). As the paramutational process continues, the regulator genes involved in carbohydrate metabolism become altered in some individuals, permitting expression of diabetes in these people, despite normal parents or even a monozygotic twin. Administration of either (-)epicatechin or (+)catechin (250 mg/kg, i.p. Glucose-lowering effects of M. oleifera extracts have been reported. Studies in animal models appear to demonstrate that nephropathy can be prevented or even reversed when diabetic animals are treated with pancreatic transplantation or with intensive insulin therapy. Zn supplementation potentially preventing alloxan-induced diabetes was reported initially by Tadros et al., but they experimented with multiple minerals including Zn, Mn, Cr, and Co.102 Consequently Yang and Cherian,113 followed by others, investigated the prevention of diabetes by Zn supplementation alone. Alloxan and streptozotocin are the most popular diabetogenic agents used for assessing the antidiabetic or hypoglycemic capacity of test compounds. Allo- 8 for each point. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL:, URL:, URL:, URL:, URL:, URL:, URL:, URL:, URL:, URL: In addition, animal models of renal disease have several limitations. In general, this protective effect of Zn was examined utilizing several fold increases in the concentration of Zn in plasma and pancreas, and controlling for factors related to food intake, body weight gain or tissue copper content. In the STZ-diabetic rat, a slowing of MNCV develops about 2 weeks after the onset of diabetes124,156,200,329 and persists for several months.211,358 Diabetic rats show conduction velocities of about 80% of their nondiabetic counterparts (see earlier citations). Forest plots showing effects of Zn supplementation on FBG (fasting blood glucose), HbA1c (glycated hemoglobin), TC (total cholesterol), LDL (low-density lipoprotein), and HDL (high-density lipoprotein) cholesterol. BCTI (4 mM) was used as substrate in the assay. L'alloxane exerçant une toxicité sélective sur les cellules pancréatiques productrices d'insuline, il est utilisé en laboratoire pour induire un diabète insulinoprive sur des modèles animaux. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive … Alloxan is selectively toxic to insulin-producing pancreatic beta cells because it preferentially accumulates in beta cells through uptake via the GLUT2glucose transporter. After 4 weeks, BMI, fasting glucose, and Zn concentration in plasma and erythrocyte did not change in either group, although Zn concentration in the urine increased in the group with Zn supplementation. Administration of alloxan (150 mg/kg body weight, i.p.) However in diabetes research, among the diverse models, chemically-induced are highly preferable by investigators covering alloxan- and streptozotocin-induced rodent models. to male Wistar rats induced a reproducible and persistent diabetes mellitus as evidenced by elevated serum glucose and low serum insulin concentrations. Supplementation of type 2 diabetics with broccoli sprouts, which have a high sulforaphane content, resulted in increased total antioxidant capacity of plasma and decreased oxidative stress index, lipid peroxidation, serum triglycerides, oxidized low-density lipoprotein (LDL)/LDL cholesterol ratio, serum insulin, insulin resistance, and serum high-sensitivity C-reactive protein (CRP) (Bahadoran et al., 2013). The Mechanisms Of Alloxan- And Streptozotocin-induced Diabetes, Volume 51, Issue2 , pp 216226 | Cite as The mechanisms of alloxan- and streptozotocin-induced diabetes Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. Alloxan-induced diabetes is one of he widely used model to induce Type I diabetes mellitus in the the experimental animals. The assertion that pathogenetic factors other than polyol pathway flux and metabolites contribute to the development of a shortfall in MNCV in chronic diabetes receives support from work with gangliosides. Zn supplementation prevents diabetes induced by single dose of STZ or alloxan, as well as preventing diabetes induced by multiple low doses of STZ. Garlic and onion sulfoxide amino acids were effective in reduction of blood glucose in streptozotocin-induced as well as, Medicinal Spices and Vegetables from Africa, Gupta et al., 2012; Yassa and Tohamy, 2014, Control of Glucose Metabolism in the Human Fetus and Newborn Infant, Selected Topics in the History of Biochemistry Personal Recollections. In one model, animals with chemically induced (alloxan or streptozotocin) diabetes are treated with insulin with the goal of achieving tight or loose control of blood glucose levels.10,11 In another model, pancreatectomized animals are treated with pancreatic or isolated islet cell replacement.12,13 Finally, animals with genetic diabetes (with models of autoimmune diabetes such as the NOD mouse or BB rat, or with models of type 2 diabetes) and various degrees of glycemia have been studied.14,15 Most studies have demonstrated primary prevention of complications with intensive therapy aimed at maintaining glucose levels close to the physiologic range. Martin G. Goldner, Gabriel Spergel, in Advances in Metabolic Disorders, 1972. I was able to show in perfused rat heart that inhibition of fatty acid oxidation with 2-bromostearate reversed the insulin resistance in cardiac muscle in alloxan diabetes [24]. Their study revealed that the aqueous extract of M. oleifera leaves possesses potent hypoglycemic effects through the normalization of elevated hepatic pyruvate carboxylase enzyme and regeneration of damaged hepatocytes and pancreatic β-cells via its antioxidant properties. Effects of Zn supplementation on insulin resistance and plasma glucose level in obese children. 2. Their contribution may be prevented by ganglioside treatment. Methods . However, in these animals, revert back to the blood glucose values reverted back to normal in a week. At present the conditions required for development of human fetal or neonatal glucokinase have not been identified; but the same failure to accelerate glucose up take in the immediate postnatal period has been recorded (Section V, A). Testis and … Properties of Alloxan. Chemical features of alloxan and their contribution to its diabetogenicity. Third, rats in which transplants of pancreatic islet cells do not succeed in correcting glucose levels also show improvement in renal results.12 As with retinopathy, studies of nephropathy in animal models can lend support to, but cannot prove, the glucose hypothesis. A significant reduction was observed in height of bone crest in diabetic animals at 3, 6, 9 and 12 months, which was associated with … Alloxan diabetes induced by treatment with alloxan on the seventeenth day also will prevent development of glucokinase activity; but replacement therapy with insulin between the 21st and 24th day will permit the normal development of glucokinase activity, and restore normoglycemia. LDL cholesterol in the Zn-treated group also was also significantly lower (11.19 mg/dL, p < 0.05) than that in placebo group (Figure 3). LLEWELYN, ... P.K. Alloxan-Induced Diabetes Mellitus Organosulfur Compounds as Nutraceuticals. These results are summarized in Table 3. The compromise when exacerbated, leads to several complications including retinopathy, nephropathy and neuropathy which are collectively known as diabetic complications and are the principal actors in co-morbidity and eventual mortality often associated with diabetes. It has been found that in many research studies, the dose of alloxan used to induce diabetes was suboptimal. Abstract Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. alloxan. After receiving Zn, in either group 1 or group 2, the mean fasting plasma glucose (FPG), insulin, and homeostasis model assessment for insulin resistance (HOMA-IR) decreased significantly, while BMI, waist circumference, and triglycerides (TG) did not significantly change. England, who graduated from the Bristol biochemistry department in 1965, provided sound quantitative evidence that increased glucose 6-phosphate concentration mediates inhibitory effects of fatty acid oxidation on hexokinase and hence of intracellular glucose utilization [25].