Glucose stimulation of insulin release involves closure of ATPsensitive K+ channels, depolarization, and Ca2+ influx in B cells. Mouse islets were used to investigate whether glucose can still regulate insulin release when it cannot control ATP-sensitive K+ channels. Opening ofthese channels by diazoxide (100-250 Mmol/liter) blocked the effects of glucose on B cell membrane potential (intracellular microelectrodes), free cytosolic Ca2+ (fura-2 method), and insulin release, but it did not prevent those of high K (30 mmol/liter). K-induced insulin release in the presence of diazoxide was, however, dose dependently increased by glucose, which was already effective at concentrations (2-6 mmol/liter) that are subthreshold under normal conditions (low K and no diazoxide). This effect was not accompanied by detectable changes in B cell membrane potential.Measurements of 'Ca fluxes and cytosolic Ca2" indicated that glucose slightly increased Ca2+ influx during the first minutes of depolarization by K, but not in the steady state when its effect on insulin release was the largest. In conclusion, there exists a mechanism by which glucose can control insulin release independently from changes in K+-ATP channel activity, in membrane potential, and in cytosolic Ca2+. This mechanism may serve to amplify the secretory response to the triggering signal (closure of K+-ATP channels -depolarization -Ca2" influx) induced by glucose. (J. Clin. Invest. 1992. 89:1288-1295

Glucose stimulation of insulin release involves closure of ATPsensitive K+ channels (K+-ATP channels), depolarization, and Ca" influx in B cells. However, by using diazoxide to open K+-ATP channels, and 30 mM K to depolarize the membrane, we could demonstrate that another mechanism exists, by which glucose can control insulin release independently from changes in K+-ATP channel activity and in membrane potential (Gembal et al. 1992. J. Clin. Invest. 89:1288-1295). A similar approach was followed here to investigate, with mouse islets, the nature of this newly identified mechanism. The membrane potential-independent increase in insulin release produced by glucose required metabolism of the sugar and was mimicked by other metabolized secretagogues. It also required elevated levels of cytoplasmic CO', but was not due to further changes in CO'. It could not be ascribed to acceleration of phosphoinositide metabolism, or to activation of protein kinases A or C. Thus, glucose did not increase inositol phosphate levels and hardly affected cAMP levels. Moreover, increasing inositol phosphates by vasopressin or cAMP by forskolin, and activating protein kinase C by phorbol esters did not mimic the action of glucose on release, and down-regulation of protein kinase C did not prevent these effects. On the other hand, it correlated with an increase in the ATP/ADP ratio in islet cells. We suggest that the membrane potential-independent control of insulin release exerted by glucose involves changes in the energy state of B cells. (J. Clin. Invest. 1993.91:871-880.)

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Dear Sir, Protein glycation is assumed to be one of the main reasons for a generation of diabetic complications [1]. This process has been reported to be affected by ascorbic acid [2]. Examinations on healthy volunteers have shown the inhibiting effect of oral ascorbic on protein glycation [3]. We decided to investigate the effect of oral ascorbic acid supplementation on fructosamine and HbAlc levels in Wistar rats with streptozotocin diabetes. Diabetic and non-diabetic rats were divided into control and untreated groups, and groups treated with ascorbic acid added to drinking water (1 g/litre) for 3 months. Blood was sampled from the tail vein of non-fasted animals at the start of the study and 1, 2, and 3 months after the initial administration of ascorbic acid. Blood was assayed for glucose, fructosamine and HbAlc. Supplementation with ascorbic acid did not cause any significant changes in blood glucose levels throughout the study in the diabetic or the non-diabetic rats. Figure I shows that there were no significant changes in either fructosamine or HbAlc levels in non-diabetic rats treated with ascorbic acid. The initial values were 129.5 _+ 13.7 gmol/1 and 1.91 + 0.12 %, respectively, and remained at this level during supplementation. They did not differ from those observed in untreated non-diabetic rats. In contrast, ascorbic acid supplementation affected the HbAlc concentration in diabetic rats. The initial HbAlc concentrations of diabetic rats were 2.06 + 0.09% and 2.21 +0.07% in the treated and untreated group, respectively. HbAI~ levels in diabetic rats rose significantly in both groups but they remained higher in the untreated group [2.74 + 0.06 vs 2.36 + 0.08 % (p < 0.01), 2.96 + 0.07 vs 2.40+0.08% (p <0.001) and 3.51+0.06 vs 2.66+0.06% (p < 0.001) at 1, 2, and 3 months, respectively]. Ascorbic acid administration had a small effect on plasma fructosamine concentration. The statistically significant difference between groups was found at 3 months; 227.4 + 19.5 gmol/1 (treated diabetic) vs 316.3 + 20.5 gmol/1 (untreated diabetic) (p < 0.01). It has been suggested that the fructosamine assay is a measurement of many serum glycated proteins which may be susceptible in different ways to ascorbic acid influence [3]. Similarly, Sinclair et al. [4] did not find significant differences in plasma fructosamine levels in diabetic patients treated with ascorbate for 6 weeks. Our results indicate that ascorbic acid administration decreases the rate of protein glycation, which may be important in prevention of secondary diabetic complications.