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Endocrinology Vol. 139, No. 3 993-998
Copyright © 1998 by The Endocrine Society

ARTICLES

A Minimum of Fuel Is Necessary for Tolbutamide to Mimic the Effects of Glucose on Electrical Activity in Pancreatic ß-Cells1

Jean-Claude Henquin

Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, UCL 55.30, B 1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. J. C. Henquin, Unité d’Endocrinologie et Métabolisme, UCL 55.30, avenue Hippocrate 55, B-1200 Brussels, Belgium.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Glucose stimulation of pancreatic ß-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K+ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (>7 mM) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K+ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse ß-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 µM) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mM glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the ß-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mM glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mM was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the ß-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K+ channels is not the only mechanism by which glucose controls electrical activity in ß-cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE SECRETION of most hormones is regulated by the binding of extracellular messengers to receptors. Insulin secretion is no exception when pancreatic ß-cells are stimulated by hormones or neurotransmitters. However, the increase in insulin secretion that is brought about by glucose and other nutrients results from an acceleration of ß-cell metabolism (1, 2, 3, 4, 5). This acceleration generates several signals, among which adenine nucleotides are currently thought to play a key role. A rise in the ATP/ADP ratio in the cytoplasm causes closure of ATP-sensitive K+ channels (K+-ATP channels), which leads to membrane depolarization. Because of the rhythmic activation of voltage-dependent Ca2+ channels, the membrane potential then starts to oscillate in slow waves, with bursts of Ca2+ spikes on the plateau. When the concentration of glucose is raised from threshold (6–7 mM) to maximum values (25–30 mM), the duration of the active periods increases, whereas that of the silent intervals decreases, so that the membrane eventually remains persistently depolarized at the plateau potential with continuous spike activity (6, 7, 8, 9, 10, 11).

Although not all mechanisms of the control of this electrical activity by metabolism have been elucidated, there is no doubt that K+-ATP channels are key participants. These channels are tetramers of a complex of two proteins: SUR 1, the high affinity sulfonylurea receptor (SUR), and Kir 6.2, an inward rectifier K+ channel (12, 13, 14). SUR endows the pore-forming Kir 6.2 with sensitivity to sulfonylureas and diazoxide. Because it possesses two nucleotide-binding domains, SUR was also thought to mediate the effects of adenine nucleotides on the channel. Although this remains true for the stimulatory action of Mg2+-ADP (15), the inhibitory site of ATP could be located on SUR or Kir 6.2 itself (16). The regulation of the channel is further complicated by the influence of nucleotides on the binding of sulfonylureas and diazoxide to SUR and on their action on the channel activity (review in Ref.17).

Addition of a low concentration of tolbutamide (5 µM) to a medium containing 10–11 mM glucose reproduced the increase in electrical activity induced by raising the glucose concentration (18, 19). This ability of the sulfonylurea to mimic the most subtle effect of glucose prompted the suggestion that blockade of K+-ATP channels, whether achieved by a drug or by changes in metabolism, might be the sole regulator of the electrical activity. However, other experiments have shown that the opening of K+-ATP channels by low concentrations of diazoxide did not completely mimic the decrease in electrical activity brought about by a lowering of the glucose concentration (20). It should be borne in mind that these effects of tolbutamide or diazoxide were characterized while ß-cells were under the influence of a constant, stimulatory concentration of glucose (18, 19, 20). If the interaction with SUR is sufficient to control K+-ATP channel activity, and if the latter is really the sole regulator of the electrical activity, tolbutamide should also mimic the effects of glucose when the sugar is present in a low concentration or is absent. This question was addressed in the present study.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The experiments were performed with islets of fed female NMRI mice killed by decapitation. A piece of pancreas was fixed in a perifusion chamber, and a few islets were partially microdissected by hand. The membrane potential of a single cell within the islet was continuously measured with a high resistance microelectrode (21). ß-cells were identified by the typical electrical activity that they display in the presence of 15 mM glucose. The perifusion medium was a bicarbonate-buffered solution containing 122 mM NaCl, 4.8 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, and 20 mM NaHCO3. It was continuously gassed with a mixture of 95% O2-5% CO2, and its pH was 7.4 at 37 C. Tolbutamide was obtained from Hoechst (Frankfurt, Germany), and sodium azide (NaN3) was purchased from Merck (Darmstadt, Germany).

The results are illustrated by recordings that are representative of four to seven experiments performed with different mice. The effects shown correspond to the first addition of tolbutamide and, therefore, cannot be influenced by any residual effect of the drug or desensitization of the preparation. When changes in the membrane potential were quantified, the results are given as the mean ± SEM. Differences between means were considered significant at P < 0.05, by unpaired t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The impalement of ß-cells always occurred during stimulation with 15 mM glucose, which induces typical electrical activity (11, 21). After about 20 min of regular activity, the preparation was perifused with a medium containing 0 or 3 mM glucose. The electrical activity stopped, and the membrane potential of ß-cells increased to stable values between -60 and -70 mV (Figs. 1Go-3).



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  		Figure 1. Effects of tolbutamide on the membrane potential of mouse ß-cells perifused with a low glucose medium for various periods of time. ß-cells were impaled with the microelectrode during perifusion with a medium containing 15 mM glucose, and the perifusion with the same medium continued for about 20 min after the electrical activity had become stable. Then, the preparation was perifused with a medium containing 3 or 0 mM glucose (G) for 6 or 20 min before the addition of 15 or 25 µM tolbutamide, as indicated on the top of each panel. The four records were obtained in ß-cells from different mice.

 
Addition of tolbutamide after 6 min of perifusion with 3 mM glucose induced concentration-dependent responses. At 15 µM, tolbutamide caused a progressive depolarization, with an initial burst of spikes followed by slow waves of the membrane potential with spikes on the plateau (Fig. 1AGo). These slow waves typically decreased in frequency and usually stopped after several minutes. At 25 µM, tolbutamide caused a faster (P < 0.05) depolarization and continuous electrical activity (Fig. 1BGo and Table 1Go). However, the frequency and the amplitude of the spikes progressively decreased with time, and slow waves of the membrane potential appeared in some cells. The ß-cell response was not significantly accelerated when tolbutamide was used at the concentration of 100 µM (Table 1Go), but slow waves did not appear.


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  		Table 1. Influence of a low glucose medium on tolbutamide-induced depolarization and electrical activity in ß-cells

 
The effect of a given concentration of tolbutamide also depended on the duration of the initial perifusion with low glucose medium. After 20 instead of 6 min in the presence of 3 mM glucose, the onset of the depolarization by 25 µM tolbutamide was not significantly delayed, but the rate of depolarization was lower (P < 0.05), so that the time before the appearance of the first spike was doubled (Table 1Go). Moreover, ß-cells consistently displayed slow waves of electrical activity under these conditions (Fig. 1CGo).

That the low (3 mM) glucose concentration in the medium exerted an influence on the above responses is demonstrated by similar experiments carried out in the absence of glucose. After 6 min of perifusion with a glucose-free medium, 25 µM tolbutamide caused a rapid depolarization and electrical activity (Table 1Go), usually characterized by a period of continuous spikes followed by a few slow waves. Then the electrical activity stopped while the membrane remained partially depolarized (Fig. 1DGo). When tolbutamide was used at 100 µM, the electrical activity did not stop within the experimental time. When the period of glucose deprivation was extended to 20 min, 25 µM tolbutamide consistently caused a small depolarization, but did not induce electrical activity (Fig. 2AGo). The maximum depolarization averaged 10 ± 1 mV, which was insufficient to reach the threshold potential at which the slow waves start. For instance, in the series of experiments illustrated in Fig. 1CGo, the difference between the resting and threshold potentials was 15 ± 1 mV. Addition of 3 mM glucose to the medium containing 25 µM tolbutamide was followed by a small further depolarization and the appearance of slow waves of membrane potential with bursts of spikes (Fig. 2BGo).



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  		Figure 2. Effects of tolbutamide on the membrane potential of mouse ß-cells perifused with a glucose-free medium (G0) for 20 min. The changes in the composition of the medium are indicated on the top of each panel. Record B is the direct continuation of A. Record C was obtained in a ß-cell from another mouse; the interruption corresponds to an interval of 6 min.

 
In contrast to 3 mM glucose, increasing the tolbutamide concentration to 100 µM did not evoke slow waves, but quickly depolarized the ß-cell membrane to the plateau potential and triggered continuous spike activity (Fig. 2CGo). Intermediate concentrations of the sulfonylurea were thus tested after 20 min in the absence of glucose. It proved very difficult to induce slow waves under these conditions. In the experiment shown in Fig. 3Go, raising the tolbutamide concentration from 50 to 75 µM was followed by the appearance of two slow waves, whereas 100 µM evoked a few more. In other cells, no slow waves were induced by 50–75 µM tolbutamide, and 100 µM caused a persistent depolarization as shown in Fig. 2CGo.



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  		Figure 3. Effects of increasing concentrations of tolbutamide on the membrane potential of a mouse ß-cell perifused with a glucose-free medium (G0) for 20 min. Record B is the direct continuation of A.

 
Modulation of the electrical activity by tolbutamide was possible, but still difficult, in the presence of 3 mM glucose. In the experiments illustrated in Fig. 4Go, stimulation with 15 µM tolbutamide after 6 min of perifusion with 3 mM glucose induced a rapid depolarization with continuous spikes followed by slow waves that eventually stopped. Raising the concentration of tolbutamide to 25 µM depolarized the membrane again and restored slow waves after about 2 min of continuous activity. These slow waves progressively decreased in duration, but were augmented, at least transiently, when the concentration of tolbutamide was increased to 35 µM (Fig. 4BGo). In most cells, however, 35 µM tolbutamide did not increase the duration of the slow waves, but caused a continuous depolarization to the plateau.



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  		Figure 4. Effects of increasing concentrations of tolbutamide on the membrane potential of a mouse ß-cell perifused with a medium containing 3 mM glucose (G3) for 6 min. Record B is the direct continuation of A.

 
It was much easier to modulate slow waves by changing the glucose concentration. After 20 min of perifusion with 3 mM glucose, 20 µM tolbutamide progressively depolarized ß-cells and triggered slow waves of the membrane potential (Fig. 5AGo). These clearly increased in duration, whereas the intervals became shorter when the concentration of glucose was raised to 5 and then 7 mM (Fig. 5Go, B and C). Alone, 7 mM glucose is the threshold concentration in the presence of which weak electrical activity is present in one third of ß-cells (22).



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  		Figure 5. Effects of increasing concentrations of glucose on the membrane potential of a mouse ß-cell perifused with a medium containing 20 µM tolbutamide. The changes in the composition of the medium are indicated on the top of each panel. The three records show a whole experiment without interruption.

 
In the absence of glucose, ß-cell metabolism is fueled by endogenous substrates (23). To evaluate their possible influence on the response to sulfonylurea, the preparation was perifused with a glucose-free medium, and sodium azide, an inhibitor of cytochrome oxidase, was used to inhibit mitochondrial ATP production and lower the ATP/ADP ratio in the cytoplasm (7, 24). The mitochondrial poison reversibly stopped the spike activity induced by 100 µM tolbutamide, but only slightly repolarized the membrane (Fig. 6AGo). When 50 µM tolbutamide was added to a glucose-free medium containing 2 mM azide, the ß-cell membrane depolarized, but only abortive slow waves and spikes appeared. Upon removal of azide, typical slow waves started, faded out, and reappeared (Fig. 6Go, B and C). After a final addition of azide, slow waves were abolished, and the membrane remained depolarized at a level similar to that reached when tolbutamide was added after 20 min in the absence of glucose (compare Fig. 6CGo with Fig. 2Go).



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  		Figure 6. Influence of sodium azide (NaN3) on the effects of tolbutamide (Tolb) on the membrane potential of mouse ß-cells perifused with a glucose-free medium. The changes in the composition of the medium are indicated on the top of each panel. Record C is the direct continuation of B, in which azide was added 4 min before tolbutamide. Record A was obtained in a ß-cell from another mouse.

 
The ability of high concentrations of glucose and tolbutamide to overcome the inhibitory effects of azide on the electrical activity were then compared. When ß-cells were depolarized with 50 µM tolbutamide in the absence of glucose, 2 mM azide stopped the spikes and caused partial repolarization (by 17 ± 2 mV) to a potential that was 23 ± 2 mV above the resting potential, i.e. well above the threshold potential. Yet, no electrical activity was present (Fig. 7Go). Raising the concentration of tolbutamide to 250 µM depolarized the membrane to the plateau again, but spikes did not reappear until azide was washed out (Fig. 7AGo). In contrast, 20 mM glucose reversibly caused depolarization and spike activity despite the continuous presence of azide (Fig. 7BGo). Therefore, the abrogation of electrical activity by azide cannot be ascribed simply to opening of K+-ATP channels or to a direct inhibition of Ca2+ channels.



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  		Figure 7. Interactions among tolbutamide, azide (NaN3), and glucose (G) on the membrane potential of mouse ß-cells. The changes in the composition of the medium are shown on the top of each panel. The two records were obtained in ß-cells from different mice.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results presented in this study are consistent with the idea that an inhibition of K+-ATP channels mediated by SUR is not the only mechanism by which the signals issued from glucose metabolism control electrical activity in pancreatic ß-cells.

It has previously been shown that the combination of low concentrations of glucose (3 mM) and tolbutamide (25–35 µM) induces slow waves of the membrane potential resembling those triggered by stimulatory concentrations of the sugar (19, 25). Whether sulfonylureas have the same property in the absence of glucose had not been carefully investigated, and the few available results were controversial (11, 19).

This study shows that the effects of tolbutamide on ß-cell membrane potential are not only influenced by the presence of a low glucose concentration, but that they also depend on the duration of ß-cell exposure to the low glucose medium. As a rule, the magnitude of the electrical activity triggered by tolbutamide was inversely related to the duration and extent of fuel deprivation. It was possible to induce slow waves of the membrane potential with tolbutamide in the absence of exogenous fuel. However, selected experimental conditions were required to disclose this property, which disappeared with time. This characteristic may be attributed either to the progressive loss of an important signal (e.g. phosphorylation) produced during the initial exposure to glucose or to the progressive exhaustion of continuously metabolized endogenous fuels. The second possibility is supported by the rapid and reversible inhibition by azide of the effects of tolbutamide on electrical activity in the glucose-free medium.

High concentrations of tolbutamide (250 µM) or glibenclamide (4 µM) have previously been used to prevent or reverse poisoning-induced hyperpolarization of ß-cells (24, 26). In the present study using low concentrations of tolbutamide, the suppression of electrical activity by ß-cell poisoning was accompanied by a partial repolarization of the membrane, which is ascribed to opening of K+-ATP channels because it could be reversed by increasing the concentration of the drug. The opening of K+-ATP channels in the presence of tolbutamide may indicate either that the efficacy of the sulfonylurea to block the channels is decreased by the poison, or that a substantial proportion of the channels is still under metabolic control in the presence of 50 µM tolbutamide. Patch-clamp techniques have revealed complex interactions between metabolic factors and sulfonylureas (27). Although the phosphorylation state of K+-ATP channel does not seem to influence the action of the drugs, their potency is increased by channel-blocking nucleotides. Moreover, sulfonylureas shift the competition between inhibitory and stimulatory nucleotides toward the inhibitory ones (17, 27). This may explain the recent reports of functional uncoupling between SUR and Kir 6.2 during metabolic inhibition of ß-cells (28, 29).

A similar mechanism may contribute to, but cannot entirely explain the present findings. Thus, the partial repolarization caused by azide in the presence of 50 µM tolbutamide could also be reversed by glucose. This is attributed to the ability of the sugar to increase the ATP/ADP ratio slightly despite the presence of 2 mM azide, a concentration that is not maximally inhibitory (24). However, although both glucose and tolbutamide reversed the repolarization by azide, only glucose restored Ca2+ spikes, which indicates that metabolism does not simply close K+-ATP channels. Because the Na+ pump is electrogenic, its reactivation would cause hyperpolarization and decrease spike activity (30), just the opposite of the observed effect. Metabolic stimulation of Ca2+-ATPases, which pump Ca2+ into the endoplasmic reticulum or the extracellular space (31), would lower the intracellular Ca2+ concentration and relieve Ca2+ channels from a possible inactivation by excessive cytoplasmic Ca2+ (32). This interpretation is difficult to reconcile with the evidence that the intracellular Ca2+ concentration in tolbutamide-stimulated ß-cells is lower after than before poisoning with cyanide or dinitrophenol (33). A positive regulation of voltage-dependent Ca2+ channels by metabolism (34) is more plausible.

Comparison of the effects of glucose and tolbutamide on the slow waves of membrane potential also reveals differences in the actions of the two agents. Small stepwise increases in the glucose concentration within a range that did not extend beyond the threshold concentration (7 mM) exerted consistent, clear effects on the appearance and duration of the slow waves of membrane potential in the presence of 20–25 µM tolbutamide. In contrast, it proved very difficult to increase the slow wave duration by stepwise increases in the tolbutamide concentration. This was sometimes possible in the presence of 3 mM glucose and was exceptional in its absence. In the majority of cells, higher tolbutamide concentrations caused a jump of the membrane potential from the threshold to the plateau level, where continuous spike activity started.

Importantly, the present results do not detract from the possible role of K+-ATP channels in the smooth regulation of ß-cell membrane potential (lengthening of slow waves and shortening of intervals) by increasing glucose concentrations. They simply imply that an additional effect produced by metabolism and not by tolbutamide is also necessary, which may explain how the sulfonylurea mimics the effects of glucose in the presence of a stimulatory concentration of the sugar (18, 19). Whether this additional action of glucose is regulatory or simply permissive cannot be answered by the present study. Two nonexclusive possibilities can be envisaged. First, the regulation of K+-ATP channels by nucleotides involves a negative feedback action of the influx of Ca2+ (35), which causes a decrease in the ATP/ADP ratio (Detimary, P., P. Gilon, and J. C. Henquin, manuscript in preparation). Second, the activity of Ca2+ channels (34), of Cl- channels (36), and perhaps of other channels potentially involved in the electrical activity (10, 37) is under metabolic control.

The stimulation of insulin release by tolbutamide and other sulfonylureas has long been known to be markedly influenced by the prevailing concentration of glucose. The transient secretory response evoked by the drug alone becomes sustained and larger in the presence of the sugar (38). These differences can partially be attributed to the K+-ATP channel-independent action by which glucose increases the efficacy of Ca2+ on the secretory machinery (39). However, the present and other studies (40, 41, 42) indicate that an action on Ca2+ influx may also be important.

In conclusion, the regulation of ß-cell electrical activity by glucose cannot be explained only by a modulation of K+-ATP channel activity. If the other effects of glucose on the membrane potential are affected in ß-cells of type 2 diabetic patients, a treatment with sulfonylureas will imperfectly correct the defective triggering signal (Ca2+ influx) of insulin secretion.


   Acknowledgments
 
These studies were started at the I. Physiologisches Institut of the University of Saarland, where Prof. H. Meves provided me with facilities, and Mr. W. Schmeer provided skilled assistance. I thank M. Nenquin and S. Lagasse for secretarial and photographic help.


   Footnotes
 
1 This work was supported by Grant 3.4525.94 from the Fonds de la Recherche Scientifique Médicale (Brussels, Belgium) and Grant ARC 95/00–188 from the General Direction of Scientific Research of the French Community of Belgium. Back

Received September 24, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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