Summary
Dehydrouramil hydrate hydrochloride (DHU) is an analogue of alloxan which retains the in vivo diabetogenic activity of alloxan but, in contrast to alloxan, is stable in aqueous media at physiological pH. Using rat islets of Langerhans, we have studied the acute effects of DHU on B cell function. Glucose-stimulated insulin release was markedly inhibited by DHU, the concentration of DHU giving 50% inhibition (I50) was 1 mmol/l; this was lowered to 0.5 mmol/1 when the islets were exposed to DHU for 5 min before elevation of glucose concentration. The basis for this change appeared to be a protective effect of glucose, since the inclusion of 3-0-methylglucose during pre-incubation with DHU also attenuated the subsequent inhibition of glucose-stimulated insulin release. The inhibitory effect on glucose-stimulated insulin release of a 5-min exposure to DHU persisted throughout a subsequent 120-min period in the absence of DHU. DHU also inhibited insulin release stimulated by mannose (20 mmol/l) or by 2-ketoisocaproate (20 mmol/l) with I50 of 1 and 0.5 mmol/l respectively. Concentrations of DHU up to 1 mmol/l had no significant effect on islet glucose oxidation or ATP content; 5 mmol/l DHU did not affect the rate of glucose oxidation, but lowered the ATP content by 30% without pre-incubation and by 60% in islets pre-incubated for 5 min with DHU before addition of glucose. Inhibitory effects of DHU were also found on rates of incorporation of [3H]-leucine into insulin plus proinsulin and into total islet protein; however, these parameters were less sensitive to DHU than was insulin release. These effects of DHU were similar to those of alloxan. These data suggest that DHU is an important new tool for studying the mechanism of action of B cell cytotoxic agents; in addition, the fact that DHU is a potential metabolite of uric acid could have relevance to the aetiology of diabetes mellitus.
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References
Dunn JS, Sheehan HL, McLetchie NGB (1943) Necrosis of islets of Langerhans produced experimentally. Lancet 1: 484–487
Cooperstein SJ, Watkins D (1981) Action of toxic drugs on islet cells. In: Cooperstein SJ, Watkins D (eds) The islets of Langerhans. Biochemistry, physiology and pathology. Academic Press, New York, pp 387–425
Poje M, Rocic B (1979) A reinvestigation of alloxan-like compounds derived from uric acid. Tetrahedron Letts 49: 4781–4782
Poje M, Rocic B, Skrabalo Z (1980) β-Cytotoxic action of alloxan and alloxan-like compounds derived from uric acid. Diabet Croat 9: 145–166
Poje M, Rocic B, Sikirica M, Vickovic L, Bruvo M (1983) Oxidation of uric acid. 4. Synthesis, structure and diabetogenic activity of 2,4,6(1H,3H)-pyrimidinetrione-5-iminium salts and their alloxan-like covalent adducts. J Med Chem 26: 861–865
Coll-Garcia E, Gill JR (1969) Insulin release by isolated pancreatic islets of the mouse incubated in vitro. Diabetologia 5: 61–66
Krebs HA, Henseleit K (1932) Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Seylers Z Physiol Chem 210: 33–62
Ashcroft SJH, Crossley JR (1975) The effects of glucose, N-acetylglucosamine, glyceraldehyde and other sugars on insulin release in vivo. Diabetologia 11: 279–284
Ashcroft SJH, Crossley JR, Crossley PC (1975) The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in rat pancreatic islets. Biochem J 154: 701–707
Ashcroft SJH, Weerasinghe LCC, Randle PJ (1973) Interrelationships of islet metabolism, adenosine triphosphate content and insulin release. Biochem J 132: 223–231
Ashcroft SJH, Hedeskov CJ, Randle PJ (1970) Glucose metabolism in mouse pancreatic islets. Biochem J 118: 143–154
Watkins D, Cooperstein SJ, Fiel S (1979) Studies on the selectivity of alloxan for the β-cells of the islets of Langerhans: effect of pH on the in vitro action of alloxan. J Pharm Exp Therap 208: 184–189
Heikkila RE, Winston B, Cohen G, Barden H (1976) Alloxan-induced diabetes: evidence for hydroxyl radical as a cytotoxic intermediate. Biochem Pharmacol 25: 1085–1092
Grankvist K, Marlund S, Sehlin J, Taljedal I-B (1979) Superoxide dismutase, catalase and scavengers of hydroxyl radicals protect against the toxic action of alloxan on pancreatic islet cells in vitro. Biochem J 182: 17–25
Taljedal I-B (1981) On insulin secretion. Diabetologia 21: 1–17
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Tait, S.P.C., Poje, M., Rocic, B. et al. Diabetogenic action of alloxan-like compounds: The effect of dehydrouramil hydrate hydrochloride on isolated islets of langerhans of the rat. Diabetologia 25, 360–364 (1983). https://doi.org/10.1007/BF00253202
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DOI: https://doi.org/10.1007/BF00253202