Mechanisms of tolbutamide-stimulation of pancreatic B cells — A reply

Diabetologia, Aug 1980

Dr. J. C. Henquin

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Mechanisms of tolbutamide-stimulation of pancreatic B cells — A reply

Dear Sir Letters to the E d i t o r M e c h a n i s m s o f T o l b u t a m i d e - S t i m u l a t i o n o f P a n c r e a t i c B Cells - A - There is no doubt that the mechanisms of action of sulphonylureas on pancreatic B cells are still incompletely understood. The letter by Dr. Malaisse and his colleagues reinforces one conclusion of my article [ 1 ]: "The basis of the interaction between glucose and tolbutamide, not investigated here, remains to be clarified". The following points in their letter deserve some comments: 1) The proposal that tolbutamide directly interferes with Ca 2+ transport in B cells is interesting, but difficult to evaluate adequately since the reference paper is not available yet [ 2 ]. From abstract reports [ 3, 4 ], it can be appreciated, however, that Malaisse et al. ascribe the insulinotropic activity of sulphonylureas to a Ca2+-ionophoretic capacity, similar to that of the classical Ca2+-ionophore A23187. Such an interpretation does not seem compatible with the evidence that tolbutamide does not penetrate B cells [5]. 2) In the absence of glucose stimulation, tolbutamide decreases Rb § effiux from islet cells [ 6 ]. This original report has been confirmed [ 7 ] and extended [ 1 ]. Furthermore, recent electrophysiological evidence [ 8 ] strongly suggests that the reduction in K § permeability is involved in the depolarization of B cells by tolbutamide. It also shows that increasing the concentration of extracellular Ca 2+ during tolbutamide stimulation tends to repolarize B cells and replaces the continuous electrical activity by regular bursts. These observations [ 8 ] and the measurements of insulin release, Ca 2§ uptake and Rb + effiux [ 1 ] would be difficult to explain, if tolbutamide were acting simply as a Ca2+-ionophore. 3) In the presence of a stimulatory concentration of glucose (8.3mmol/1), tolbutamide surprisingly produces a short-lived increase in Rb § effiux. Such an effect, however, is not specific to sulphonylureas. Potentiation of glucose-stimulated (7 mmol/1) insulin release by 2 mmol/1 theophylline is also attended by an initial and transient rise in the rate of Rb + effiux [ 9 ]. If. one a priori rules out that such a brief event might occur in non-B cells, the most plausible explanation is that it reflects activation of the K + permeability of B cells by a rise in intracellular Ca2+ [ 10 ]. By no means, however, is it sufficient to exclude activation of voltage-dependent Ca channels, the permeability of which depends on the membrane potential and not on the K + permeability per se. Although the electrical effects of tolbutamide on B cells stimulated by glucose have been paid little attention, so far, preliminary data [ 11 ] suggest that the drug increases the duration of the phases of depolarization induced by 11 mmol/1 glucose. No explanation is completely satisfactory for all effects of tolbutamide on B cells; their understanding obviously requires further investigation. I suggest, however, that to avoid unnecessary controversies, more attention be paid to the relevant concentrations of the drug. Thus, it has become clear now [ 1, 8 ], that concentrations of tolbutamide similar to those found in vivo produce, in B cells, ionic, electrical and secretory effects, different from the supposedly "classical" effects described with the high concentrations (>50 ~tg/ml) commonly used in vitro. Yours sincerely, J. C. Henquin Letters to the Editor Diabetologia 9 by Springer-Verlag 1980 Haematocrit, Glycosylated Haemoglobin and Diabetic Microangiopathy Poorly controlled diabetics tend to have higher HbA1 values than well-controlled diabetics and nondiabetics [ 1 ]. It has been suggested that glycosylated haemoglobin, by causing a shift in the oxygen dissociation curve [ 2 ], may lead to local tissue hypoxia and so stimulate erythropoietin production. Ditzel and Standl [ 3 ] have suggested a role for tissue hypoxia in the evolution of microvascular diabetic complications. Not only could local hypoxia be damaging by itself, it could also, by the mechanism outlined induce polycythaemia, increase blood viscosity and so impair flow in the microcirculation. In a recent paper Graham et al. (Diabetologia 18: 205, 1980) claimed that diabetics tend to have a relative polycythaemia which correlates with their HbA1 values when compared with non-diabetics. We would like to raise several points. First, although retinopathy and nephropathy often occur together and are therefore both considered to be examples of microangiopathy, it is not yet proven that they have an identical aetiopathogenesis. Secondly, when severe nephropathy coexists with retinopathy blood analysis may reveal a normocytic normochromic anaemia. When assessing the degree of polycythaemia we agree that red cell mass is the most accurate method currently available but we feel that as a simpler method the packed cell volume (PCV) or haematocrit is a more useful index of (...truncated)


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Dr. J. C. Henquin. Mechanisms of tolbutamide-stimulation of pancreatic B cells — A reply, Diabetologia, 1980, pp. 162-163, Volume 19, Issue 2, DOI: 10.1007/BF00421865