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Gisela Drews - One of the best experts on this subject based on the ideXlab platform.
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tgr5 activation promotes Stimulus Secretion Coupling of pancreatic β cells via a pka dependent pathway
Diabetes, 2019Co-Authors: Jonas Maczewsky, Martina Düfer, Julia Kaiser, Anne Gresch, Felicia Gerst, Peter Krippeitdrews, Gisela DrewsAbstract:The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in β-cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine β-cell function by TGR5 activation. Both a Gαs inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted Stimulus-Secretion Coupling (SSC). OLA reduced KATP current and elevated current through Ca2+ channels. Accordingly, in mouse and human β-cells, TGR5 ligands increased the cytosolic Ca2+ concentration by stimulating Ca2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counterregulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide 3-kinase did not prevent stimulating effects of OLA. Involvement of exchange protein directly activated by cAMP 2 (Epac2) or farnesoid X receptor (FXR2) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local glucagon-like peptide 1 (GLP-1) Secretion from α-cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in β-cells stimulates insulin Secretion via an AC/cAMP/PKA-dependent pathway, which is supposed to interfere with SSC by affecting KATP and Ca2+ currents and thus membrane potential.
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ATP mediates a negative autocrine signal on Stimulus-Secretion Coupling in mouse pancreatic β-cells
Endocrine, 2018Co-Authors: Cita Bauer, Peter Krippeit-drews, Martina Düfer, Julia Kaiser, Jelena Sikimic, Gisela DrewsAbstract:The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin Secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal. We evaluated whether extracellular ATP interferes with the Ca2+-mediated negative feedback mechanism that regulates oscillatory activity of β-cells. To experimentally uncover the Ca2+-induced feedback we applied a high extracellular Ca2+ concentration. Under this condition ATP (100 µM) inhibited glucose-evoked oscillations of electrical activity and hyperpolarized the membrane potential. Furthermore, ATP acutely increased the interburst phase of Ca2+ oscillations and reduced the current through L-type Ca2+ channels. Accordingly, ATP (500 µM) decreased glucose-induced insulin Secretion. The ATP effect was not mimicked by AMP, ADP, or adenosine. The use of specific agonists and antagonists and mice deficient of large conductance Ca2+-dependent K+ channels revealed that P2X, but not P2Y receptors, and Ca2+-dependent K+ channels are involved in the underlying signaling cascade induced by ATP. The effectiveness of ATP to interfere with parameters of Stimulus-Secretion Coupling is markedly reduced at low extracellular Ca2+ concentration. It is suggested that extracellular ATP which is co-secreted with insulin in a pulsatile manner during glucose-stimulated exocytosis provides a negative feedback signal driving β-cell oscillations in co-operation with Ca2+ and other signals.
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Mitochondrial succinate dehydrogenase is involved in Stimulus-Secretion Coupling and endogenous ROS formation in murine beta cells
Diabetologia, 2015Co-Authors: Armin Edalat, Philipp Schulte-mecklenbeck, Cita Bauer, Sabrina Undank, Peter Krippeit-drews, Gisela Drews, Martina DüferAbstract:Aims/hypothesis Generation of reduction equivalents is a prerequisite for nutrient-stimulated insulin Secretion. Mitochondrial succinate dehydrogenase (SDH) fulfils a dual function with respect to mitochondrial energy supply: (1) the enzyme is part of mitochondrial respiratory chains; and (2) it catalyses oxidation of succinate to fumarate in the Krebs cycle. The aim of our study was to elucidate the significance of SDH for beta cell Stimulus-Secretion Coupling (SSC).
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Glitazones exert multiple effects on β-cell Stimulus-Secretion Coupling.
Molecular pharmacology, 2012Co-Authors: Martina Düfer, Armin Edalat, Peter Krippeit-drews, Katja Noack, Gisela DrewsAbstract:Earlier studies suggest that glitazones exert beneficial effects in patients with type 2 diabetes by directly affecting insulin Secretion of β -cells, besides improving the effectiveness of insulin in peripheral tissues. The effects of glitazones on Stimulus-Secretion Coupling (SSC) are poorly understood. We tested the influence of troglitazone and pioglitazone on different parameters of SSC, including insulin Secretion (radioimmunoassay), cell membrane potential, various ion currents (patch-clamp), mitochondrial membrane potential (ΔΨ), and cytosolic Ca 2+ concentration (fluorescence). Troglitazone exerted stimulatory, inhibitory, or no effects on insulin Secretion depending on the drug and glucose concentration. It depolarized the ΔΨ, thus lowering ATP production, which resulted in opening of ATP-dependent K + channels (K ATP channels) and reduced insulin Secretion. However, it also exerted direct inhibitory effects on K ATP channels that can explain enhanced insulin Secretion. Troglitazone also inhibited the currents through voltage-dependent Ca 2+ and K + channels. Pioglitazone was less effective than troglitazone on all parameters tested. The effects of both glitazones were markedly reduced in the presence of bovine serum albumin. Glitazones exert multiple actions on β -cell SSC that have to be considered as undesired side effects because the influence of these compounds on β -cells is not controllable. The final effect on insulin Secretion depends on many parameters, including the actual glucose and drug concentration, protein binding of the drug, and the drug by itself. Troglitazone and pioglitazone differ in their influence on SSC. It can be assumed that the effects of pioglitazone on β -cells are negligible under in vivo conditions.
John A. Williams - One of the best experts on this subject based on the ideXlab platform.
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Multiple inhibitory effects of genistein on Stimulus-Secretion Coupling in rat pancreatic acini
American Journal of Physiology-gastrointestinal and Liver Physiology, 1994Co-Authors: Rui-dong Duan, David I. Yule, A. C. C. Wagner, John A. WilliamsAbstract:Genistein, a tyrosine kinase inhibitor, inhibited cholecystokinin (CCK)-induced maximal amylase release from rat pancreatic acini by 18, 31, and 46% at concentrations of 100, 300, and 750 microM, respectively, after 30 min preincubation. Genistein similarly decreased amylase release stimulated by bombesin but not that stimulated by secretin or vasoactive intestinal peptide. The steps of Stimulus-Secretion Coupling affected by genistein were further evaluated. We found genistein dose dependently suppressed CCK-as well as NaF-induced polyphosphoinositide hydrolysis with a 50% inhibitory concentration of 380 and 400 microM, respectively, but only slightly suppressed the increase of intracellular Ca2+ concentration in response to either low or high concentrations of CCK. Genistein at 300 microM also decreased incorporation of [3H]inositol into phosphatidylinositol 4,5-bisphosphate. Most strikingly, 300 microM genistein inhibited Ca(2+)-stimulated amylase release by 85% in streptolysin O-permeabilized acini and thapsigargin-stimulated amylase release by 69% in intact acini. Daidzein, the inactive analogue of genistein, had no effect on any of the above parameters. Genistein, up to 750 microM, did not affect amylase release in response to phorbol ester. To relate these inhibitory effects of genistein to its inhibition of tyrosine phosphorylation, Western blotting was performed with an anti-phosphotyrosine monoclonal antibody. Genistein at 100 microM partly and at 300 microM completely inhibited CCK-induced tyrosine phosphorylation. In conclusion, genistein inhibits amylase release at multiple stages of Stimulus-Secretion Coupling. These effects most likely involve both tyrosine kinase-dependent and -independent mechanisms.
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Effects of okadaic acid indicate a role for dephosphorylation in pancreatic Stimulus-Secretion Coupling.
American Journal of Physiology-cell Physiology, 1992Co-Authors: Andreas C.c. Wagner, Matthew J. Wishart, David I. Yule, John A. WilliamsAbstract:Okadaic acid completely inhibits phosphatase 2A at nanomolar concentrations, while complete inhibition of type 1 phosphatases occurs at 1 microM. Phosphatase 2B is significantly inhibited only at concentrations > 1 microM. In rat pancreatic acini, 1 microM okadaic acid shifted the cholecystokinin (CCK) dose-response curve for stimulating amylase release to the right without reducing maximal Secretion. At 3 microM, okadaic acid inhibited maximal CCK-induced amylase release to 78 +/- 7% of control, whereas the inactive analogue 1-Nor-okadaone had no effect. Three lines of evidence indicate that this inhibition by okadaic acid occurs at a late step in Stimulus-Secretion Coupling: 1) intracellular Ca2+ signaling in response to agonist stimulation was not appreciably altered by okadaic acid; 2) stimulation with phorbol ester plus thapsigargin (thus by-passing receptor activation), which gave 85 +/- 4% of maximal CCK-induced amylase release, was inhibited 66 +/- 4% by 3 microM okadaic acid; and 3) Ca(2+)-induced amylase Secretion in streptolysin O-permeabilized cells was also reduced by 85 +/- 7%. Two-dimensional polyacrylamide gel electrophoresis of 32P-labeled acini and autoradiography demonstrated that okadaic acid dose dependently increased overall protein phosphorylation. Correspondingly, okadaic acid also led to an inhibition of CCK-induced dephosphorylation. These results show that okadaic acid inhibits pancreatic acinar Secretion at a step after generation of intracellular messengers and indicate a role for protein dephosphorylation in Stimulus-Secretion Coupling.
P Johnson - One of the best experts on this subject based on the ideXlab platform.
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nicotinic acid adenine dinucleotide phosphate naadp and endolysosomal two pore channels modulate membrane excitability and Stimulus Secretion Coupling in mouse pancreatic β cells
Journal of Biological Chemistry, 2015Co-Authors: Abdelilah Arredouani, Margarida Ruas, Stephan C Collins, Raman Parkesh, Frederick Clough, Toby Pillinger, George Coltart, Katja Rietdorf, Andrew Royle, P JohnsonAbstract:Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca2+ action potentials due to the activation of voltage-dependent Ca2+ channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2+ release from intracellular stores during Stimulus-Secretion Coupling in primary mouse pancreatic β cells. NAADP-regulated Ca2+ release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca2+ from the endolysosomal system, resulting in localized Ca2+ signals. We show here that NAADP-mediated Ca2+ release from endolysosomal Ca2+ stores activates inward membrane currents and depolarizes the β cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during Stimulus-response Coupling. Selective pharmacological inhibition of NAADP-evoked Ca2+ release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca2+ signals, and insulin Secretion. Our findings implicate NAADP-evoked Ca2+ release from acidic Ca2+ storage organelles in Stimulus-Secretion Coupling in β cells.
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Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells
Journal of Biological Chemistry, 2015Co-Authors: Abdelilah Arredouani, Margarida Ruas, Raman Parkesh, Frederick Clough, Toby Pillinger, George Coltart, Katja Rietdorf, Andrew Royle, Stephan Collins, P JohnsonAbstract:Pancreatic beta cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca(2+) action potentials due to the activation of voltage-dependent Ca(2+) channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca(2+) release from intracellular stores during Stimulus-Secretion Coupling in primary mouse pancreatic beta cells. NAADP-regulated Ca(2+) release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca(2+) from the endolysosomal system, resulting in localized Ca(2+) signals. We show here that NAADP-mediated Ca(2+) release from endolysosomal Ca(2+) stores activates inward membrane currents and depolarizes the beta cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during Stimulus-response Coupling. Selective pharmacological inhibition of NAADP-evoked Ca(2+) release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca(2+) signals, and insulin Secretion. Our findings implicate NAADP-evoked Ca(2+) release from acidic Ca(2+) storage organelles in Stimulus-Secretion Coupling in beta cells.
Claes-göran Östenson - One of the best experts on this subject based on the ideXlab platform.
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Peptidergic regulation of maturation of the Stimulus-Secretion Coupling in fetal islet beta cells.
Pancreas, 2000Co-Authors: Åke Sjöholm, E Sandberg, Claes-göran Östenson, Suad EfendicAbstract:The Stimulus-Secretion Coupling of the insulin-producing pancreatic islet beta cell is subject to functional maturation during fetal life. We studied the maturation of a glucose-responsive insulin release from fetal rat islets and specifically investigated the impact of peptidergic regulation. To this end, islets were isolated from 21-day-old fetal rats and maintained for 7 days in tissue culture at 3.3 or 11.1 mM glucose and various supplements. In islets cultured in low glucose, acutely raising the ambient glucose concentration to 16.7 mM evoked a modest stimulation of short-term insulin release that was more pronounced in islets maintained in high glucose. Moreover, the insulin content was much higher in islets cultured in high than in low glucose. Culture with growth hormone (GH) markedly amplified both basal and stimulated short-term insulin Secretion from islets maintained in either low or high glucose. Additionally, GH significantly elevated the insulin content in islets maintained in low glucose. Transforming growth factor alpha (TGF-alpha) increased basal, but not glucose-stimulated, insulin release and insulin content in islets cultured in low glucose. Gastrin, expressed in islets during fetal life, did not affect basal or glucose-stimulated insulin release, or insulin content, in islets maintained in either low or high glucose. The addition of gastrin to TGF-alpha did not affect the results obtained with the latter peptide. Gastrin-releasing peptide failed to influence basal or glucose-responsive insulin secretory rates, and insulin content, at either glucose concentration during culture. The somatostatin analog Sandostatin (octreotide acetate) neither influenced basal nor stimulated short-term insulin release at any glucose concentration present during culture, whereas the hormone significantly decreased the insulin content of islets cultured in high glucose. Pancreastatin, produced by porcine islet beta and delta cells, failed to influence basal or glucose-responsive insulin secretory rates, and islet insulin content, at either glucose concentration during culture. Culture with gastric inhibitory peptide (GIP) or glucagon-like peptide I (GLP-1), two proposed incretins, did not affect short-term insulin Secretion in response to 3.3 or 16.7 mM glucose irrespective of the ambient glucose concentration during culture. To the contrary, GLP-1, but not GIP, increased the content of insulin in islets cultured in low glucose. We conclude that islet beta-cell differentiation and functional maturation of the Stimulus-Secretion Coupling can be modulated in vitro in fetal rat pancreatic tissue by peptidergic regulation and glycemic stimulation. We suggest that GH and TGF-alpha stimulate, while somatostatin, through paracrine interaction, may inhibit, these processes. These effectors may be of regulatory significance in the in vivo development of glucose-sensitive beta cells, and defects in these mechanisms may result in glucose intolerance in adult subjects.
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Islet Amyloid Polypeptide Regulates Multiple Steps in Stimulus-Secretion Coupling of β Cells in Rat Pancreatic Islets
Pancreas, 2000Co-Authors: Feng Wang, Johan Permert, Claes-göran ÖstensonAbstract:Islet amyloid polypeptide (IAPP) is produced in pancreatic beta cells. Intraislet function of IAPP is still uncertain. In the present study, we investigated effects of IAPP and somatostatin on Stimulus-Secretion Coupling of beta cells in isolated rat pancreatic islets. Insulin Secretion induced by 22.2 mM glucose was increased by an IAPP antiserum (0.1%) or an IAPP antagonist (IAPP8-37, 10 microM). Pretreatment of islets with pertussis toxin (PTX) abolished the stimulating effect of IAPP8-37 on glucose-induced insulin Secretion. In contrast, IAPP antiserum and IAPP8-37 did not change insulin Secretion induced by 30 mM KCl. Somatostatin (1 nM) inhibited insulin Secretion induced by 22.2 mM glucose, 10 mM L-arginine, 25 microM forskolin, and 200 microM carbachol. IAPP (10 microM) enhanced the inhibitory effect of somatostatin on insulin Secretion induced by L-arginine or forskolin. PTX pretreatment abolished the effects of somatostatin and IAPP on arginine-induced insulin Secretion. In conclusion, IAPP regulates multiple steps in signal transductions of beta cells. The effects of IAPP on beta cells are mediated by PTX-sensitive regulatory G proteins.
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Regulation of in vitro maturation of Stimulus-Secretion Coupling in fetal rat islet β-cells
Endocrine, 2000Co-Authors: Åke Sjöholm, E Sandberg, Claes-göran Östenson, Suad EfendicAbstract:We have studied the maturation of a glucose-responsive insulin release from fetal rat islets, and specifically investigated the impact of nutrients, α-adrenoceptors, imidazoline receptors, and cyclic adenosine monophosphate (cAMP). Islets were isolated from 21-d-old fetal rats and maintained for 7 d in tissue culture at 3.3 or 11.1 mM glucose and various supplements. Culture in the presence of the nonglucidic nutrient α-ketoisocaproic acid (KIC), markedly enhanced both basal and stimulated insulin release from islets cultured at either low or high glucose. Additionally, KIC significantly elevated the insulin content of islets maintained in low glucose, whereas it slightly lowered it is islets cultured at high glucose. Culture with phentolamine, an antagonist of α-adrenergic and imidazoline receptors, markedly amplified both basal and glucose-stimulated insulin Secretion when added with islets cultured in either low or high glucose. By contrast, the pure α2-adrenoreceptor antagonist benextramine had no such effects. Addition to culture media of a membrane-permeant agonist (Sp-cAMP[S]) or antagonist (Rp-cAMP[S]) of cAMP-dependent protein kinases types I and II failed to influence basal or glucose-responsive insulin secretory rates at either glucose concentration during culture as well as islet insulin content. In conclusion, islet β-cell differentiation and functional maturation of the Stimulus-Secretion Coupling can be accelerated in vitro in fetal rat pancreatic tissue by nutrient stimulation, and by interference with imidazoline receptors, whereas cAMP seems virtually ineffective in this respect. These effectors may be of regulatory significance in the vivo development of glucose-sensitive β-cells.
Martina Düfer - One of the best experts on this subject based on the ideXlab platform.
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tgr5 activation promotes Stimulus Secretion Coupling of pancreatic β cells via a pka dependent pathway
Diabetes, 2019Co-Authors: Jonas Maczewsky, Martina Düfer, Julia Kaiser, Anne Gresch, Felicia Gerst, Peter Krippeitdrews, Gisela DrewsAbstract:The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in β-cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine β-cell function by TGR5 activation. Both a Gαs inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted Stimulus-Secretion Coupling (SSC). OLA reduced KATP current and elevated current through Ca2+ channels. Accordingly, in mouse and human β-cells, TGR5 ligands increased the cytosolic Ca2+ concentration by stimulating Ca2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counterregulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide 3-kinase did not prevent stimulating effects of OLA. Involvement of exchange protein directly activated by cAMP 2 (Epac2) or farnesoid X receptor (FXR2) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local glucagon-like peptide 1 (GLP-1) Secretion from α-cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in β-cells stimulates insulin Secretion via an AC/cAMP/PKA-dependent pathway, which is supposed to interfere with SSC by affecting KATP and Ca2+ currents and thus membrane potential.
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ATP mediates a negative autocrine signal on Stimulus-Secretion Coupling in mouse pancreatic β-cells
Endocrine, 2018Co-Authors: Cita Bauer, Peter Krippeit-drews, Martina Düfer, Julia Kaiser, Jelena Sikimic, Gisela DrewsAbstract:The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin Secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal. We evaluated whether extracellular ATP interferes with the Ca2+-mediated negative feedback mechanism that regulates oscillatory activity of β-cells. To experimentally uncover the Ca2+-induced feedback we applied a high extracellular Ca2+ concentration. Under this condition ATP (100 µM) inhibited glucose-evoked oscillations of electrical activity and hyperpolarized the membrane potential. Furthermore, ATP acutely increased the interburst phase of Ca2+ oscillations and reduced the current through L-type Ca2+ channels. Accordingly, ATP (500 µM) decreased glucose-induced insulin Secretion. The ATP effect was not mimicked by AMP, ADP, or adenosine. The use of specific agonists and antagonists and mice deficient of large conductance Ca2+-dependent K+ channels revealed that P2X, but not P2Y receptors, and Ca2+-dependent K+ channels are involved in the underlying signaling cascade induced by ATP. The effectiveness of ATP to interfere with parameters of Stimulus-Secretion Coupling is markedly reduced at low extracellular Ca2+ concentration. It is suggested that extracellular ATP which is co-secreted with insulin in a pulsatile manner during glucose-stimulated exocytosis provides a negative feedback signal driving β-cell oscillations in co-operation with Ca2+ and other signals.
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Mitochondrial succinate dehydrogenase is involved in Stimulus-Secretion Coupling and endogenous ROS formation in murine beta cells
Diabetologia, 2015Co-Authors: Armin Edalat, Philipp Schulte-mecklenbeck, Cita Bauer, Sabrina Undank, Peter Krippeit-drews, Gisela Drews, Martina DüferAbstract:Aims/hypothesis Generation of reduction equivalents is a prerequisite for nutrient-stimulated insulin Secretion. Mitochondrial succinate dehydrogenase (SDH) fulfils a dual function with respect to mitochondrial energy supply: (1) the enzyme is part of mitochondrial respiratory chains; and (2) it catalyses oxidation of succinate to fumarate in the Krebs cycle. The aim of our study was to elucidate the significance of SDH for beta cell Stimulus-Secretion Coupling (SSC).
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Glitazones exert multiple effects on β-cell Stimulus-Secretion Coupling.
Molecular pharmacology, 2012Co-Authors: Martina Düfer, Armin Edalat, Peter Krippeit-drews, Katja Noack, Gisela DrewsAbstract:Earlier studies suggest that glitazones exert beneficial effects in patients with type 2 diabetes by directly affecting insulin Secretion of β -cells, besides improving the effectiveness of insulin in peripheral tissues. The effects of glitazones on Stimulus-Secretion Coupling (SSC) are poorly understood. We tested the influence of troglitazone and pioglitazone on different parameters of SSC, including insulin Secretion (radioimmunoassay), cell membrane potential, various ion currents (patch-clamp), mitochondrial membrane potential (ΔΨ), and cytosolic Ca 2+ concentration (fluorescence). Troglitazone exerted stimulatory, inhibitory, or no effects on insulin Secretion depending on the drug and glucose concentration. It depolarized the ΔΨ, thus lowering ATP production, which resulted in opening of ATP-dependent K + channels (K ATP channels) and reduced insulin Secretion. However, it also exerted direct inhibitory effects on K ATP channels that can explain enhanced insulin Secretion. Troglitazone also inhibited the currents through voltage-dependent Ca 2+ and K + channels. Pioglitazone was less effective than troglitazone on all parameters tested. The effects of both glitazones were markedly reduced in the presence of bovine serum albumin. Glitazones exert multiple actions on β -cell SSC that have to be considered as undesired side effects because the influence of these compounds on β -cells is not controllable. The final effect on insulin Secretion depends on many parameters, including the actual glucose and drug concentration, protein binding of the drug, and the drug by itself. Troglitazone and pioglitazone differ in their influence on SSC. It can be assumed that the effects of pioglitazone on β -cells are negligible under in vivo conditions.
