Summary
Increased aggregation of platelets might contribute to the development of vascular complication in diabetes mellitus. In this study release of superoxide anions, intracellular Ca2+ signalling and nitric oxide formation stimulated by the receptor-dependent agonist adenosine 5 ′-diphosphate (ADP) and the receptor-independent stimulus thapsigargin, were compared in platelets isolated from patients with Type II (non-insulin-dependent) diabetes mellitus and healthy control subjects. Diabetes augmented intracellular Ca2+ release and Ca2+ entry to ADP by 40 and 44 % (control subjects: n = 11; diabetic: n = 6), while the median effective concentration (EC50) of ADP to initiate Ca2+ signalling was similar in both groups. The effect of thapsigargin on Ca2+ concentration was increased by 69 % in diabetic patients (control subjects: n = 22; diabetic patients: n = 9). In addition, release of superoxide anions was 70 % greater in diabetic patients (control subjects: n = 9; diabetic patients: n = 6). Treatment of platelets from control subjects with the superoxide anion-generating mixture xanthine oxidase and hypoxanthine or buthioninesulphoximine (BSO) mimicked the effect of diabetes on platelet Ca2+ signalling. The antioxidant glutathione normalized enhanced Ca2+ response in the diabetic group (control subjects: n = 5; diabetic patients: n = 6). Basal and thapsigargin-evoked nitric oxide synthase activity was reduced in the diabetic group by 85 and 64 %, respectively (control subjects: n = 13; diabetic subjects: n = 13). The nitric oxide-donor 2-(N,N-diethylamino)-diazenolate-2-oxide sodium (DEA/NO) normalized enhanced Ca2+ signalling in platelets preincubated with xanthine oxidase and hypoxanthine (n = 12) and in those from diabetics (control subjects: n = 6; diabetic patients: n = 6). Inhibition of nitric oxide synthase by N-nitro-L-arginine (L-NA) augmented thapsigargin-induced Ca2+ signalling by 51 % (n = 8). These data indicate that in diabetes platelet Ca2+ signalling might be enhanced by excessive superoxide production and an attenuated negative direct or indirect feedback control by nitric oxide, due to its reduced production. [Diabetologia (1999) 42: 167–176]
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Received: 29 May 1998 and in final revised form: 2 October 1998
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Schaeffer, G., Wascher, T., Kostner, G. et al. Alterations in platelet Ca2+ signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production. Diabetologia 42, 167–176 (1999). https://doi.org/10.1007/s001250051135
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DOI: https://doi.org/10.1007/s001250051135