Species Differences in Susceptibility of Transplanted and Cultured Pancreatic Islets to the β-Cell Toxin Alloxan

Department of Medical Cell Biology, Uppsala University, Uppsala, SE-751 23, Sweden.
General and Comparative Endocrinology (Impact Factor: 2.47). 07/2001; 122(3):238-51. DOI: 10.1006/gcen.2001.7638
Source: PubMed


The beta-cell toxin alloxan, which produces oxygen radicals, is a model substance in studies of type 1 diabetes. Recently, human beta-cells have been found to be relatively resistant to this toxin. To clarify species differences in alloxan diabetogenicity, and oxygen radical toxicity, mouse, rat, rabbit, dog, pig, human and guinea pig islets have been studied after alloxan exposure. Using a standardized in vivo model, where islets were transplanted to nude mice, the different islets were compared. The results demonstrated that mouse and rat islet grafts were morphologically disturbed by alloxan and ROS. Rabbit and dog islet graft morphology was reasonably intact; and human, porcine, and guinea pig islet grafts were all well preserved. Furthermore, ultrastructural signs of apoptosis and necrosis, disturbances in the insulin secretory pattern during and after an alloxan perifusion, and islet lysosomal enzyme activities were studied in vitro in islets from some species. Guinea pig beta-cells were affected by alloxan, but a regeneration process compensated for the observed apoptotic and necrotic cell death. Human islets did not show any signs of alloxan-induced damage in the different models studied. Finally, no correlation between high alloxan sensitivity and high lysosomal enzyme activity was found. Thus, the beta-cell lysosomes are hardly specific targets for alloxan.

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    • "Muller et al. demonstrated clearly that STZ caused lymphocytopenia in mice, which mediates a mild immunosuppressive effect [9]. Although there are several reports on the effects of STZ and ALX on beta cells [5], few investigations have done a side-by-side comparison of their cytotoxic effects in vitro and their effects on the immune system in vivo [13] [14]. The purpose of this study was to compare the immune responses between non-diabetic control mice and mice with STZ-or ALX-induced diabetes. "
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    ABSTRACT: Streptozotocin (STZ) and alloxan (ALX), widely used to induce diabetes in experimental animals, have different structures and mechanisms of action. We investigated those effects of these drugs on the immune system that might influence engraftment efficiency and graft survival in transplantation models, and their cytotoxicity on hematopoietic cell lines. We used the minimum dose to induce diabetes in a mouse, i.e. 180 mg/kg i.v. STZ and 75 mg/kg i.v. ALX. Both groups exhibited significant decrease in body weight during 4 days post-treatment as compared to controls. We found that blood glucose in ALX-injected mice increased faster than in STZ-injected mice. The total number of recovered splenocytes was lower in STZ-injected animals than in ALX-injected animals. The survival periods of rat islet grafts in recipient mice were longer and more diverse in STZ-injected recipients (7-24 days) compared to ALX-injected recipients (6-7 days). The in vitro study showed that ALX was less cytotoxic in cell lines with IC50 values of 2809, 3679 and >4000 mu g/ml for HL60, K562 and C1498 cells respectively. STZ was more toxic, especially in HL60 cells, with IC50 values of 11.7, 904 and 1024 mu g/ml for HL60, K562 and C1498 cells respectively. Furthermore, in response to concanavalin A (Con-A), splenocytes from STZ-injected mice produced higher amounts of interferon-gamma (IFN-gamma) than those from ALX-injected mice. In conclusion, STZ was more cytotoxic than ALX in vitro and in vivo. STZ caused lymphocytopenia, which may result in longer graft survival in STZ-treated animals than in AIX-treated animals.
    Immunology Letters 01/2015; 208(2). DOI:10.1016/j.imlet.2014.12.006 · 2.51 Impact Factor
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    • "Therefore, to further assess the function of encapsulated CyT49-luc derived islets we analyzed their capacity to maintain glucose homoeostasis in the face of murine β-cell destruction. Murine β-cells were eliminated by injection of alloxan at a dose which is selectively toxic to murine but not human β-cells (Lee et al., 2009; Tyrberg et al., 2001). Alloxan rapidly induced diabetes in control animals (without human cell grafts) as blood glucose rose to 700 mg/dL within 96 h (Fig. 2B). "
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    ABSTRACT: There are several challenges to successful implementation of a cell therapy for insulin dependent diabetes derived from human embryonic stem cells (hESC). Among these are development of functional insulin producing cells, a clinical delivery method that eliminates the need for chronic immunosuppression, and assurance that hESC derived tumors do not form in the patient. We and others have shown that encapsulation of cells in a bilaminar device (TheraCyte) provides immunoprotection in rodents and primates. Here we monitored human insulin secretion and employed bioluminescent imaging (BLI) to evaluate the maturation, growth, and containment of encapsulated islet progenitors derived from CyT49 hESC, transplanted into mice. Human insulin was detectable by 7weeks post-transplant and increased 17-fold over the course of 8weeks, yet during this period the biomass of encapsulated cells remained constant. Remarkably, by 20weeks post-transplant encapsulated cells secreted sufficient levels of human insulin to ameliorate alloxan induced diabetes. Further, bioluminescent imaging revealed for the first time that hESCs remained fully contained in encapsulation devices for up to 150days, the longest period tested. Collectively, the data suggest that encapsulated hESC derived islet progenitors hold great promise as an effective and safe cell replacement therapy for insulin dependent diabetes.
    Stem Cell Research 03/2014; 12(3):807-814. DOI:10.1016/j.scr.2014.03.003 · 3.69 Impact Factor
    • "Alloxan, a toxic glucose analogue, selectively destroys β-cells when administered to rodents and many other animal species, resulting in insulin-dependent diabetes mellitus in these animals, with characteristics similar to diabetes in humans.[17] Alloxan, in the presence of intracellular thiols, generates reactive oxygen species in a cyclic reaction with its reduction product, dialuric acid.[18] "
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    ABSTRACT: Strychnos nux-vomica, commonly known as kuchla, contains strychnine and brucine as main constituents. Minor alkaloids present in the seeds are protostrychnine, vomicine, n-oxystrychnine, pseudostrychnine, isostrychnine, chlorogenic acid, and a glycoside. Seeds are used traditionally to treat diabetes, asthma, aphrodisiac and to improve appetite. The present study was aimed to evaluate the various pharmacognostical characters and antidiabetic activity of S. nux-vomica seed. Pharmacognostical characters were performed as per the WHO guideline. Extraction was carried out in petroleum ether, chloroform, alcohol, hydroalcoholic, aqueous, and phytochemical constituents present in extracts were detected by different chemical tests. Among these extracts hydroalcoholic, aqueous extracts were evaluated for antidiabetic activity on the basis of extractive yield and phytoconstituents, in alloxan-induced diabetic rats using gliclazide as standard. Various analytical values of S. nux-vomica extract were established. Phytoconstituents present in S. nux-vomica extracts were detected. S. nux-vomica extracts show antihyperglycemic activity in experimental animals.
    Journal of Ayurveda and integrative medicine 04/2012; 3(2):80-4. DOI:10.4103/0975-9476.96523
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