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Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K⁺_ATP channel-dependent pathway

Department of Medical Biochemistry and Genetics, Building 6.5, The Panum Institute, University of Copenhagen, 3C Blegdamsvej, DK-2200 Copenhagen N, Denmark

(Correspondence should be addressed to P Thams; Email: thams{at}imbg.ku.dk)

	Abstract

Top Abstract Introduction Materials and methods Results Discussion References

 
Objective: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K⁺ (K⁺_ATP) channel-dependent insulin secretion and in glucose amplification of K⁺_ATP channel-independent insulin secretion.

Methods: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay.

Results: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs–Ringer medium, the PKA inhibitors, H89 (10 µmol/l) and PKI 6–22 amide (30 µmol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion, but inhibited stimulation by the adenylyl cyclase activator, forskolin (10 µmol/l). In the presence of 60 mmol/l K⁺ and 250 µmol/l diazoxide, which stimulates maximum Ca²⁺ influx independently of K⁺_ATP channels, H89 (10 µmol/l) inhibited Ca²⁺-evoked insulin secretion, but failed to prevent glucose amplification of K⁺_ATP channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 µmol/l diazoxide, which cause modest Ca²⁺ influx, glucose amplification of K⁺_ATP channel-independent insulin secretion was observed without concomitant Ca²⁺ stimulation of PKA activity. In islets cultured at 16.7 mmol/l glucose, glucose (16.7 mmol/l)-induced insulin secretion in physiological Krebs–Ringer medium was augmented and now inhibited by H89 (10 µmol/l), implicating that culture at 16.7 mmol/l glucose may increase Ca²⁺-sensitive adenylyl cyclase activity and hence PKA activity. In accordance, Ca²⁺-evoked insulin secretion at 60 mmol/l K⁺ and 250 µmol/l diazoxide was improved, whereas glucose amplification of K⁺_ATP channel-independent insulin secretion was unaffected.

Conclusions: Glucose may activate PKA through triggering of the K⁺_ATP channel-dependent pathway. Glucose amplification of K⁺_ATP channel-independent insulin secretion, on the other hand, occurs by PKA-independent mechanisms.

	Introduction

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It is generally accepted that two signalling pathways may cooperate in glucose stimulation of insulin secretion from pancreatic ß-cells. These are the ATP-sensitive K⁺ (K⁺_ATP) channel-dependent and the K⁺_ATP channel-independent pathway. The K⁺_ATP channel-dependent pathway is mediated through an increase in the ATP:ADP ratio, closure of the cell surface K⁺_ATP channels, cell depolarization and opening of the voltage-sensitive Ca²⁺ channels and a rise in intracellular Ca²⁺, which then triggers glucose-induced insulin secretion. In addition, glucose also amplifies Ca²⁺-stimulated insulin secretion. This second pathway is now being recognized as the K⁺_ATP channel-independent but Ca²⁺-dependent pathway, because of its requirement for increased intracellular Ca²⁺. Whereas the second messengers involved in the K⁺_ATP channel-dependent pathway are well characterized, the underlying messengers involved in the K⁺_ATP channel-independent pathway are not yet known (1, 2).

At least five hypotheses regarding second messengers in K⁺_ATP channel-independent insulin secretion are currently considered: (i) Glucose may stimulate production of glutamate, which may sensitize the secretory machinery to Ca²⁺ (3). This mechanism is however disputed (4–6), and apparently a tenfold rise in glutamate does not stimulate insulin secretion (4). (ii) Glucose may induce an increase in cytosolic malonyl-CoA and consequently an increase in long-chain acyl-CoA in the cytosol, which may potentiate insulin release through, for example, activation of protein kinase C (PKC) (7). Lowering of malonyl-CoA with increased oxidation of long-chain acyl-CoA does not, however, affect glucose-induced insulin secretion (8, 9) and apparently long-chain acyl-CoA and glucose amplify secretion by differential mechanisms (10). (iii) Activation of protein acylation may be involved, since cerelunin, an inhibitor of acylation inhibits K⁺_ATP channel-independent insulin secretion (11, 12). Cerelunin, yet, may have non-specific effects and inhibits glucose metabolism (13). (iv) Glucose may activate hormone-sensitive lipase, which may increase long-chain acyl-CoA and diacylglycerol (14–17). In other studies, still, glucose-induced insulin secretion was unaffected by inhibition of hormone-sensitive lipase (18–20). (v) Changes in ATP concentrations may facilitate the K⁺_ATP channel-independent pathway (21), e.g. by activation of protein kinase A (PKA), which may constitute an ATP sensor in exocytosis (22, 23). In this way, cAMP and ATP may synergize in exocytosis, and indeed cAMP stimulation of K⁺_ATP channel-independent insulin secretion has been described as being dependent on glucose (24).

PKA modulates the activity of several cation channels in the ß-cell plasma membrane, leading to a transient increase in glucose-stimulated Ca²⁺ influx and elevation of cytosolic free Ca²⁺ concentration (25). In addition cAMP may modulate cytosolic Ca²⁺ through stimulation of Ca²⁺ mobilization from intracellular stores by PKA-dependent and PKA-independent mechanisms (26), the latter involving cAMP-regulated guanine nucleotide exchange factor II (cAMPGEFII) also termed exchange protein 2 activated by cAMP (Epac2) (27). More importantly, the cAMP/PKA pathway enhances glucose-stimulated insulin secretion at a distal site, beyond the elevation of cytosolic Ca²⁺. This distal site of cAMP action is thought to be responsible for most of the effect on secretion (28). Since these actions of cAMP/PKA are known to be glucose-dependent, cAMP appears to be a modulator of the pancreatic ß-cell signalling system, which in synergy with glucose may act to regulate ion channel activity and to sensitize the exocytotic machinery to Ca²⁺.

Apparently therefore, PKA could take a centre stage in glucose triggering and amplification of insulin secretion, since PKA both may stimulate K⁺_ATP channel-dependent insulin secretion by increasing Ca²⁺ influx/mobilization (25) and may stimulate K⁺_ATP channel-independent insulin secretion through activation of hormone-sensitive lipase (17), stimulation of Ca²⁺ uptake and ATP formation in mitochondria (26) and mediate distal effects of ATP in exocytosis (22, 23).

In contrast to the involvement of cAMP in the insulin response to G-protein-coupled receptor agonists like glucagon-like peptide-1 (GLP-1), the role of the cAMP/PKA pathway in glucose-stimulated insulin release has not been established. A function is supported by studies showing that cAMP levels are increased in ß-cells stimulated with glucose (29), and that overexpression of cAMP phosphodiesterase 3B reduces glucose-induced insulin secretion (30). Other studies, however, indicate that glucose-stimulated insulin release occurs efficiently regardless of ß-cell PKA activity (31, 32), and it has been suggested that even though cAMP can facilitate insulin release, it may not be necessary for glucose-stimulated insulin release (31, 32). Therefore, the role of cAMP in glucose-stimulated insulin secretion remains to be established.

In the present study, we have re-examined the role of the cAMP/PKA pathway in glucose stimulation of K⁺_ATP channel-dependent and K⁺_ATP channel-independent insulin secretion. It is demonstrated that glucose has a capacity to stimulate PKA in mouse islets. This effect is mediated by Ca²⁺ during triggering of the K⁺_ATP channel-dependent pathway. Glucose amplification by the K⁺_ATP channel-independent pathway, however, is not dependent on PKA and may therefore not represent amplification of PKA-stimulated exocytosis.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion References

 
Crude bacterial collagenase was obtained from Boehringer Mannheim. ¹²⁵I-labelled insulin and guinea-pig anti-insulin serum were from Novo Nordisk A/S (Bagsværd, Denmark). BSA, forskolin, 12-O-tetradecanoylphorbol 13-acetate (TPA), diazoxide and ouabain were from Sigma. H89 (N-(2-(( p-bromocinnamyl)amino)ethyl)-5-isoquinoline-sulphonamide), protein kinase inhibitor (PKI) 6–22 amide and calphostin C were from Calbiochem (San Diego, CA, USA). 8-CPT-cAMP (8-(4-chlorophenylthio)-adenosine-3^', 5^'-cyclic monophosphate) and 8-CPT-2^'-O-Me-cAMP (8-(4-chlorophenylthio)-2^'-O-methyladenosine-3^', 5^'-cyclic monophosphate) were from Biolog (Bremen, Germany). All other chemicals were of analytical grade.

Isolation and culture of islets

Islets were prepared by collagenase digestion of the pancreas of male albino mice (NMRI) (approximately 18–22 g body weight) fed ad libitum on a standard laboratory diet. Principles of laboratory animal care were followed. Islets were kept in tissue culture for 22–24 h in TCM 199 medium (1.26 mmol/l Ca²⁺, 5.5 mmol/l glucose) or when stated (0.26 mmol/l Ca²⁺, 5.5 or 16.7 mmol/l glucose) supplemented with 10% (v/v) newborn calf serum (Gibco), 20 mmol/l HEPES, 5 mmol/l NaHCO₃, 100 units penicillin/ml and 100 µg streptomycin/ml. PKI 6–22 amide was introduced during the 22–24 h culture period.

Insulin release

Insulin release from islets was determined by perifusion in a noncirculating system with beads of 0.25 ml Bio-Gel P2 (BioRad) as a supporting medium, as described previously (10). Twenty-five islets per chamber were perifused at 37 °C at a flow rate of 0.26 ml/min. The perifusion medium was Krebs–Ringer medium supplemented with 20 mmol/l HEPES, 5 mmol/l NaHCO₃, 2 mg BSA/ml and 3.3 mmol/l glucose. Islets were perifused for 45 min to obtain a basal release rate and then challenged with different insulin secretagogues and test agents for 60 min periods as indicated. The effluent medium was collected for periods of 5 or 10 min. Insulin was determined by radioimmunoassay. The rate of insulin release was expressed in nanograms per minute per 100 islets.

Miscellaneous

TPA, forskolin, diazoxide, H89 and calphostin C were added in a small volume of dimethyl sulphoxide (DMSO), final concentration 0.01–0.1%. Results are given as means±S.D. for n = 3–8 experiments in each condition as specified. Statistical evaluation of the data was made by ANOVA, followed by the Newman–Keuls test for multiple comparisons; not significant, P > 0.05. For statistical comparisons of the insulin data, the total release during the 60 min of stimulation was calculated.

	Results

Top Abstract Introduction Materials and methods Results Discussion References

 
Role of PKA in glucose-induced insulin secretion

In physiological Krebs–Ringer medium, the PKA inhibitor H89 (10 µmol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion in islets cultured at 5.5 mmol/l glucose, but appeared to inhibit amplification by forskolin (10 µmol/l) by approximately 27% (P < 0.05, n = 6) (Fig. 1a). Likewise, the PKA inhibitor PKI 6–22 amide (30 µmol/l) failed to affect glucose (16.7 mmol/l)-induced insulin secretion, but inhibited amplification by forskolin (10 µmol/l) by 39% (P < 0.05, n = 4) (Fig. 1b), suggesting that glucose per se does not activate PKA.

View larger version (23K): [in this window] [in a new window]   Figure 1 Effects of H89 and PKI 6–22 amide on glucose- and for-skolin-induced insulin secretion. (a) Islets were perifused with () or without (•) 10 µmol/l H89 (H8910) and with 16.7 mmol/l glucose (Gl16.7) and 10 µmol/l forskolin (Forsk10) as indicated. (b) Islets were cultured for 24 h with () or without (•) 30 µmol/l PKI 6–22 amide (PKI 6–22 amide30) and then perifused with 16.7 mmol/l glucose (Gl16.7) and 10 µmol/l forskolin (Forsk10) as indicated. Results are means± S.D. (n = 4–6).

View larger version (18K): [in this window] [in a new window]   Figure 2 Effects of 8-CPT-cAMP and 8-CPT-2'-O-Me-cAMP on glucose-induced insulin secretion. Islets were perifused at 16.7 mmol/l glucose (Gl16.7) and 250 µmol/l 8-CPT-cAMP (CPT-cAMP250) or 250 µmol/l 8-CPT-2'-O-Me-cAMP (CPT-MecAMP250) as indicated. , experiments in the absence of cAMP analogues (in panel b). Results are means± S.D. (n = 4–8).

In the presence of depolarizing K⁺ concentrations and diazoxide, which stimulates Ca²⁺ influx through voltage-sensitive Ca²⁺ channels and opens K⁺_ATP channels respectively, glucose amplification of insulin secretion is confined to an amplification of Ca²⁺-induced insulin secretion through the K⁺_ATP channel-independent pathway. At 60 mmol/l K⁺ and 250 µmol/l diazoxide, an increase in glucose from 3.3 to 16.7 mmol/l stimulated insulin secretion 2.94±0.88 (n = 6)-fold in the absence and 2.63±0.56 (n = 6)-fold in the presence of forskolin (10 µmol/l) (Fig. 3a). At 3.3 mmol/l glucose, H89 (10 µmol/l) led to an almost total abrogation of insulin secretion in the presence of 60 mmol/l K⁺ and 250 µmol/l diazoxide (P < 0.001, n = 4). This inhibition did not, however, prevent amplification of insulin secretion by glucose (16.7 mmol/l), which in the presence of H89 (10 µmol/l) still stimulated insulin secretion 2.25±0.83 (n = 6)-fold, suggesting that glucose stimulation of K⁺_ATP channel-independent insulin secretion may occur independently of PKA (Fig. 3b).

View larger version (23K): [in this window] [in a new window]   Figure 3 Effects of H89 on K+ATP channel-independent insulin secretion. Islets were perifused in the absence (a) or in the presence (b) of 10 µmol/l H89 (H8910) and at 60 mmol/l K+ + 250 µmol/l diazoxide (K+60 + Dz250) with 3.3 mmol/l glucose (Gl3.3, ) or 16.7 mmol/l glucose (Gl16.7, •) and 10 µmol/l forskolin (Forsk10) as indicated. Results are means± S.D. (n = 4–6).

So far these data suggest that glucose may stimulate PKA activity through the K⁺_ATP channel-dependent pathway and that glucose may amplify K⁺_ATP channel-independent insulin secretion by a PKA-independent mechanism. To evaluate further whether glucose stimulation of K⁺_ATP channel-independent insulin secretion also may proceed in the absence of concomitant activation of PKA by Ca²⁺, we looked for alternatives distinct from K⁺ depolarization for stimulation of the K⁺_ATP channel-independent pathway. In the presence of the Na⁺/K⁺-ATPase inhibitor, ouabain (1 mmol/l) and diazoxide (250 µmol/l), which cause modest membrane depolarization and Ca²⁺ influx (33, 34), glucose (16.7 mmol/l) increased insulin secretion (Fig. 4). H89 (10 µmol/l), however, failed to inhibit insulin secretion in this setting (n = 4) (Fig. 4), suggesting that glucose amplification of K⁺_ATP channel-independent insulin secretion may also occur independently of concomitant activation of the cAMP/PKA pathway.

View larger version (24K): [in this window] [in a new window]   Figure 4 Effects of glucose and H89 on ouabain-induced K+ATP channel-independent insulin secretion. Islets were perifused at 1 mmol/l ouabain + 250 µmol/l diazoxide (Ouabain1 + Dz250) and with 3.3 mmol/l glucose (Gl3.3, (), 16.7 mmol/l glucose (Gl16.7, •) or 16.7 mmol/l glucose +10 µmol/l H89 (H8910, ) as indicated. Results are means± S.D. (n = 4).

As outlined above, K⁺ depolarization per se appeared to activate the cAMP pathway (Fig. 3). As observed previously (10), maximum depolarization with 60 mmol/l K⁺ in the presence of 250 µmol/l diazoxide obliterates the stimulatory effect of the PKC activator TPA on insulin secretion (Fig. 5a and b). K⁺ (60 mmol/l) may not, however, stimulate adenylyl cyclase through activation of PKC, since the broad specific PKC inhibitor calphostin C (1 µmol/l), which inhibits TPA-stimulated insulin secretion (10), failed to inhibit insulin secretion at 3.3 or 16.7 mmol/l glucose (n = 3) (Fig. 5a and b). It is most likely, therefore, that K⁺ depolarization stimulates adenylyl cyclase activity through stimulation of Ca²⁺ influx.

View larger version (22K): [in this window] [in a new window]   Figure 5 Effects of calphostin C on K+ATP channel-independent insulin secretion. Islets were perifused with () or without (•) 1 µmol/l calphostin C (Calph1) and at 60 mmol/l K+ + 250 µmol/l diazoxide (K60 + + Dz250) with (a) 3.3 mmol/l glucose (Gl3.3) or (b) 16.7 mmol/l glucose (Gl16.7) and 0.16 µmol/l TPA (TPA0.16) as indicated. Results are means± S.D. (n = 3).

Culture of islets at stimulatory glucose concentrations has previously been shown to sensitize glucose-induced insulin secretion (35) and to increase adenylyl cyclase activity (36). In accordance, an increase from 5.5 to 16.7 mmol/l glucose during 24 h of pre-culture in TCM 199 medium (0.26 mmol/l Ca²⁺) amplified glucose-induced secretion in a way that was obliterated by H89 (10 µmol/l) (n = 6) (Fig. 6), demonstrating that glucose may sensitize insulin secretion through activation of adenylyl cyclase. Similar results were obtained after culture at 11 mmol/l glucose (results not shown).

View larger version (20K): [in this window] [in a new window]   Figure 6 Effects of H89 on glucose-induced insulin secretion in islets cultured at 16.7 mmol/l glucose. Islets were cultured for 24 h in TCM 199 medium (0.26 mmol/l Ca2+) supplemented with 5.5 mmol/l glucose () or 16.7 (•) mmol/l glucose and then perifused with 16.7 mmol/l glucose (Gl16.7) and 10 µmol/l forskolin (Forsk10) in (a) the absence or (b) the presence of 10 µmol/l H89 (H8910). Results are means± S.D. (n = 4–6).

View larger version (23K): [in this window] [in a new window]   Figure 7 Effects of glucose on K+ATP channel-independent insulin secretion in islets cultured at 16.7 mmol/l glucose. Islets were cultured for 24 h in TCM 199 medium (0.26 mmol/l Ca2+) supplemented with (a) 5.5 mmol/l glucose (Gl5.5) or (b) 16.7 mmol/l glucose (Gl16.7) and then perifused at 60 mmol/l K+ + 250 µmol/l diazoxide (K60+ + Dz250) with 3.3 mmol/l glucose (Gl3.3, ) or 16.7 mmol/l glucose (Gl16.7, •) and with 10 µmol/l forskolin (Forsk10) as indicated. Results are means± S.D. (n = 3).

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

Recent studies have suggested that cAMP not only activates PKA but also stimulates insulin secretion in islets by stimulation of cAMPGEFII (Epac2) (39, 40). Indeed cAMPGEFII has been shown to stimulate Ca²⁺ release from endoplasmic reticulum (40) and to cause a direct stimulation of exocytosis in ß-cells (41). According to the present experiments, however, cAMP-GEFs may only make a minor contribution to the overall effect of cAMP on exocytosis, since the membrane-permeable cAMPGEF-selective analogue 8-CPT-2'-O-Me-cAMP failed to affect the insulin secretion rate. Most probably, therefore, glucose stimulation of adenylyl cyclase activity stimulates insulin secretion mainly by virtue of the ability of cAMP to increase PKA activity.

In accordance with a previous study in mouse islets, where the cAMP antagonist adenosine-3', 5'-cyclic monophosphorothioate (Rp-cAMPS) was used (21), K⁺ depolarization per se appeared to activate the cAMP/PKA pathway. Thus glucose appears to stimulate PKA through triggering of the K⁺_ATP channel-dependent pathway of stimulated insulin release. In this way PKA may stimulate insulin secretion by modulation of Ca²⁺ handling (25) and through direct effects on exocytosis (28). In addition, PKA may activate hormone-sensitive lipase (17), leading to release of long-chain acyl-CoA, which may stimulate insulin secretion by means of protein acylation (11, 12) or by PKC activation (7), although the latter as demonstrated previously (10) and herein seems less likely.

Recently it has been suggested that PKA could constitute the ATP sensor in exocytosis of ß-cell granula (22, 23). PKA has previously been demonstrated to cause a direct stimulation of exocytosis in pancreatic ß-cells (28) and since ATP is considered a possible second messenger in glucose stimulation of K⁺_ATP channel-independent secretion (21), glucose might stimulate PKA activity and K⁺_ATP channel-independent secretion due to its ability to increase ATP in islet cells. Indeed one study demonstrated that forskolin stimulation of K⁺_ATP channel-independent insulin secretion was dependent on glucose and was obliterated in the absence of glucose (24), suggesting a possible significant interplay of glucose and PKA in amplification of K⁺_ATP channel-independent exocytosis. According to the present study, however, glucose stimulation of K⁺ _ATP channel-independent insulin secretion may not involve PKA activation and may even proceed without sizeable PKA activity. Thus glucose also stimulated insulin secretion via the K⁺_ATP channel-independent pathway in the presence of ouabain, which did not activate PKA.

In conclusion, therefore, the present study clearly demonstrates that glucose amplification K⁺_ATP channel-independent insulin secretion arises independently of PKA. Glucose has the capacity to stimulate PKA in islets. This activation, however, is accomplished through glucose triggering of K⁺_ATP channel-dependent insulin secretion.

	Acknowledgements

 
This work was supported by the Danish Diabetes Association and the A P Møller Foundation for the Advancement of Medical Science. The skilful technical assistance of Bente Vinther is highly appreciated.

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