38 results on '"Nenquin, Myriam"'
Search Results
2. In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions
- Author
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Henquin, Jean-Claude, Nenquin, Myriam, Sempoux, Christine, Guiot, Yves, Bellanne-Chantelot, Christine, Otonkoski, Timo, Lonlay, Pascale de, Nihoul-Fekete, Claire, and Rahier, Jacques
- Subjects
Gene mutations -- Health aspects -- Research ,Metabolic diseases -- Risk factors -- Genetic aspects -- Research ,Pancreas -- Physiological aspects -- Genetic aspects -- Research ,Health care industry - Abstract
Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic β cells. Dif-fuse forms of CHI (DiCHI), in which all β cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal β cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of β cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels., Introduction Congenital hyperinsulinism (CHI) is the major cause of persistent hypoglycemia in newborns and infants (1, 2). The underlying genetic etiology and biochemical mechanisms are multiple, resulting in heterogeneous clinical [...]
- Published
- 2011
- Full Text
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3. Metabolic amplifying pathway increases both phases of insulin secretion independently of [beta]-cell actin microfilaments
- Author
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Mourad, Nizar I., Nenquin, Myriam, and Henquin, Jean-Claude
- Subjects
Actin -- Genetic aspects ,Pancreatic beta cells -- Genetic aspects ,Insulin -- Health aspects ,Metabolomics -- Research ,Intermediate filament proteins -- Genetic aspects ,Biological sciences - Abstract
Two pathways control glucose-induced insulin secretion (IS) by [beta]-cells. The triggering pathway involves ATP-sensitive potassium (KATe) channel-dependent depolarization, [Ca.sup.2+] influx, and a rise in the cytosolic [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.c]), which triggers exocytosis of insulin granules. The metabolic amplifying pathway augments IS without further increasing [[[Ca.sup.2+]].sub.c]. The underlying mechanisms are unknown. Here, we tested the hypothesis that amplification implicates actin microfilaments. Mouse islets were treated with latrunculin B and cytochalasin B to depolymerize actin or jasplakinolide to polymerize actin. They were then perifused to measure [[[Ca.sup.2+]].sub.c] and IS. Metabolic amplification was studied during imposed steady elevation of [[[Ca.sup.2+]].sub.c] by tolbutamide or KCI or by comparing the magnitude of [[[Ca.sup.2+]].sub.c] and IS changes produced by glucose and tolbutamide. Both actin polymerization and depolymerization augmented IS triggered by all stimuli without increasing (sometimes decreasing) [[[Ca.sup.2+]].sub.c], which indicates a predominantly inhibitory function of microfilaments in exocytosis at a step distal to [[[Ca.sup.2+]].sub.c] increase. When [[[Ca.sup.2+]].sub.c] was elevated and controlled by KC1 or tolbutamide, the amplifying action of glucose was facilitated by actin depolymerization and unaffected by polymerization. Both phases of IS were larger in response to high-glucose than to tolbutamide in low-glucose, although triggering [[[Ca.sup.2+]].sub.c] was lower. This difference in IS, due to amplification, persisted when the IS rate was doubled by actin depolymerization or polymerization. In conclusion, metabolic amplification is rapid and influences the first as well as the second phase of IS. It is a late step of stimulus-secretion coupling, which does not require functional actin microfilaments and could correspond to acceleration of the priming process conferring release competence to insulin granules. biphasic insulin release; cytosolic calcium; exocytosis; insulin granules; pancreatic islets doi: 10.1152/ajpcell.00138.2010.
- Published
- 2010
4. Activators of PKA and Epac Distinctly Influence Insulin Secretion and Cytosolic Ca2+ in Female Mouse Islets Stimulated by Glucose and Tolbutamide
- Author
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Henquin, Jean-Claude and Nenquin, Myriam
- Published
- 2014
5. Glucose Stimulates Ca2+ Influx and Insulin Secretion in 2-Week-old β-Cells Lacking ATP-sensitive K+ Channels
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Szollosi, Andras, Nenquin, Myriam, Aguilar-Bryan, Lydia, Bryan, Joseph, and Henquin, Jean-Claude
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- 2007
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6. Congenital Hyperinsulinism Caused by Hexokinase I Expression or Glucokinase-Activating Mutation in a Subset of β-Cells
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Henquin, Jean-Claude, Sempoux, Christine, Marchandise, Joelle, Godecharles, Sebastien, Guiot, Yves, Nenquin, Myriam, and Rahier, Jacques
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- 2013
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7. cAMP-Mediated and Metabolic Amplification of Insulin Secretion Are Distinct Pathways Sharing Independence of β-Cell Microfilaments
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Mourad, Nizar I., Nenquin, Myriam, and Henquin, Jean-Claude
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- 2012
8. Glucose Controls Cytosolic Ca2+ and Insulin Secretion in Mouse Islets Lacking Adenosine Triphosphate-Sensitive K+ Channels Owing to a Knockout of the Pore-Forming Subunit Kir6.2
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Ravier, Magalie A., Nenquin, Myriam, Miki, Takashi, Seino, Susumu, and Henquin, Jean-Claude
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- 2009
9. Nutrient Control of Insulin Secretion in Isolated Normal Human Islets
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Henquin, Jean-Claude, Dufrane, Denis, and Nenquin, Myriam
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- 2006
10. In Vivo and In Vitro Glucose-Induced Biphasic Insulin Secretion in the Mouse: Pattern and Role of Cytoplasmic Ca2+ and Amplification Signals in β-Cells
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Henquin, Jean-Claude, Nenquin, Myriam, Stiernet, Patrick, and Ahren, Bo
- Published
- 2006
11. No evidence for a role of reverse Na+-Ca2+ exchange in insulin release from mouse pancreatic islets
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Garcia-Barrado, Maria-Jose, Gilon, Patrick, Sato, Yoshihiko, Nenquin, Myriam, and Henquin, Jean-Claude
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Calcium channels -- Physiological aspects ,Insulin -- Physiological aspects ,Mice -- Physiological aspects ,Islands of Langerhans -- Physiological aspects ,Biological sciences - Abstract
The role of calcium (Ca2+) currents in the initiation of insulin secretion in intact mouse pancreatic islets is investigated based on measurements of insulin release, cytoplasmic calcium concentration and B cell membrane potential. Data indicate that Ca2+ influx via reverse Na+-Ca2+ exchange has no effect on cytoplasmic calcium concentration. However, Ca2+ influx via voltage-dependent Ca2+ channels promote insulin release by increasing cytoplasmic calcium levels through removal of Na+.
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- 1996
12. SERCA3 Ablation Does Not Impair Insulin Secretion but Suggests Distinct Roles of Different Sarcoendoplasmic Reticulum Ca2+ Pumps for Ca2+ Homeostasis in Pancreatic β-cells
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Arredouani, Abdelilah, Guiot, Yves, Jonas, Jean-Christophe, Liu, Lynne H., Nenquin, Myriam, Pertusa, José A., Rahier, Jacques, Rolland, Jean-François, Shull, Gary E., Stevens, Martine, Wuytack, Frank, Henquin, Jean-Claude, and Gilon, Patrick
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- 2002
13. Signals and Pools Underlying Biphasic Insulin Secretion
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Henquin, Jean-Claude, Ishiyama, Nobuyoshi, Nenquin, Myriam, Ravier, Magalie A., and Jonas, Jean-Christophe
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- 2002
14. Inhibition of Protein Synthesis Sequentially Impairs Distinct Steps of Stimulus-secretion Coupling in Pancreatic β Cells*
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Garcia-Barrado, Maria-Jose, Ravier, Magalie A, Rolland, Jean-François, Gilon, Patrick, Nenquin, Myriam, and Henquin, Jean-Claude
- Published
- 2001
15. Tolbutamide and Diazoxide Influence Insulin Secretion by Changing the Concentration but Not the Action of Cytoplasmic Ca sup 2+ in beta-Cells
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Mariot, Pascal, Gilon, Patrick, Nenquin, Myriam, and Henquin, Jean-Claude
- Published
- 1998
16. Immaturity of insulin secretion by pancreatic islets isolated from one human neonate.
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Henquin, Jean‐claude and Nenquin, Myriam
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ISLANDS of Langerhans , *PANCREATIC beta cells , *CYCLIC adenylic acid , *FORSKOLIN , *PHYSIOLOGY ,NEWBORN infant health - Abstract
Abstract: Human β‐cells are functionally mature by the age of 1 year. The timeline and mechanisms of this maturation are unknown owing to the exceptional availability of testable tissue. Here, we report the first
in vitro study of insulin secretion by islets from a 5‐day‐old newborn. Glucose was inefficient alone, but induced insulin secretion, which was concentration‐dependent, showed a biphasic time‐course and was of similar magnitude as in infant islets when β‐cell cyclic adenosine monophosphate was raised by forskolin. Tolbutamide alone was effective in low glucose, but its effect was not augmented by high glucose. Metabolic amplification by glucose was thus inoperative, in contrast to amplification by cyclic adenosine monophosphate. Newborn islets showed high basal insulin secretion that could be inhibited by diazoxide or omission of CaCl2. Postnatal acquisition of functional maturity by human β‐cells implicates control of basal secretion and production of metabolic signals able to activate both triggering and amplifying pathways of insulin secretion. [ABSTRACT FROM AUTHOR]- Published
- 2018
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17. Disruption and stabilization of β-cell actin microfilaments differently influence insulin secretion triggered by intracellular Ca 2+ mobilization or store-operated Ca 2+ entry
- Author
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Henquin, Jean-Claude, Mourad, Nizar I., and Nenquin, Myriam
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- 2012
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18. Dynamics and Regulation of Insulin Secretion in Pancreatic Islets from Normal Young Children.
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Henquin, Jean-Claude and Nenquin, Myriam
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INSULIN regulation , *ISLANDS of Langerhans , *PEDIATRIC physiology , *TOLBUTAMIDE , *STIMULUS & response (Biology) , *FORSKOLIN - Abstract
Insulin secretion has only exceptionally been investigated in pancreatic islets from healthy young children. It remains unclear whether those islets behave like adult islets despite substantial differences in cellular composition and higher β-cell replication rates. Islets were isolated from 5 infants/toddlers (11–36 month-old) and perifused to characterize their dynamics of insulin secretion when subjected to various stimuli and inhibitors. Their insulin responses were compared to those previously reported for similarly treated adult islets. Qualitatively, infant islets responded like adult islets to stimulation by glucose, tolbutamide, forskolin (to increase cAMP), arginine and the combination of leucine and glutamine, and to inhibition by diazoxide and CaCl2 omission. This similarity included the concentration-dependency and biphasic pattern of glucose-induced insulin secretion, the dynamics of the responses to non-glucose stimuli and metabolic amplification of these responses. The insulin content was not different, but fractional insulin secretion rates were lower in infant than adult islets irrespective of the stimulus. However, the stimulation index was similar because basal secretion rates were also lower in infant islets. In conclusion, human β-cells are functionally mature by the age of one year, before expansion of their mass is complete. Their responsiveness (stimulation index) to all stimuli is not smaller than that of adult β-cells. Yet, under basal and stimulated conditions, they secrete smaller proportions of their insulin stores in keeping with smaller in vivo insulin needs during infancy. [ABSTRACT FROM AUTHOR]
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- 2016
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19. Dynamics of glucose-induced insulin secretion in normal human islets.
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Henquin, Jean-Claude, Dufrane, Denis, Kerr-Conte, Julie, and Nenquin, Myriam
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GLUCOSE ,ISLANDS of Langerhans ,PROINSULIN ,PEOPLE with diabetes ,ARGININE - Abstract
The biphasic pattern of glucose-induced insulin secretion is altered in type 2 diabetes. Impairment of the first phase is an early sign of β-cell dysfunction, but the underlying mechanisms are still unknown. Their identification through in vitro comparisons of islets from diabetic and control subjects requires characterization and quantification of the dynamics of insulin secretion by normal islets. When perifused normal human islets were stimulated with 15 mmol/l glucose (G15), the proinsulin/insulin ratio in secretory products rapidly and reversibly decreased (50%) and did not reaugment with time. Switching from prestimulatory G3 to G6-G30 induced biphasic insulin secretion with flat but sustained (2 h) second phases. Stimulation index reached 6.7- and 3.6-fold for the first and second phases induced by G10. Concentration dependency was similar for both phases, with half- maximal and maximal responses at G6.5 and G15, respectively. First-phase response to G15-G30 was diminished by short (30-60 min) prestimulation in G6 (vs. G3) and abolished by prestimulation in G8, whereas the second phase was unaffected. After 1-2 days of culture in G8 (instead of G5), islets were virtually unresponsive to G15. In both settings, a brief return to G3-G5 or transient omission of CaCl2 restored biphasic insulin secretion. Strikingly, tolbutamide and arginine evoked immediate insulin secretion in islets refractory to glucose. In conclusion, we quantitatively characterized the dynamics of glucose-induced insulin secretion in normal human islets and showed that slight elevation of prestimulatory glucose reversibly impairs the first phase, which supports the view that the similar impairment in type 2 diabetic patients might partially be a secondary phenomenon. [ABSTRACT FROM AUTHOR]
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- 2015
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20. Amplification of insulin secretion by acetylcholine or phorbol ester is independent of β-cell microfilaments and distinct from metabolic amplification
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Mourad, Nizar I., Nenquin, Myriam, and Henquin, Jean-Claude
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INSULIN , *GENE amplification , *ACETYLCHOLINE , *PHORBOL esters , *CYTOPLASMIC filaments , *PROTEIN kinase C - Abstract
Abstract: Insulin secretion (IS) triggered by β-cell [Ca2+]c is amplified by metabolic and receptor-generated signals. Diacylglycerol largely mediates acetylcholine (ACh) effects through protein-kinase C and other effectors, which can be directly activated by phorbol-ester (PMA). Using mouse islets, we investigated the possible role of microfilaments in ACh/PMA-mediated amplification of IS. PMA had no steady-state impact on actin microfilaments. Although ACh slightly augmented and PMA diminished glucose- and tolbutamide-induced increases in β-cell [Ca2+]c, both amplified IS in control islets and after microfilament disruption (latrunculin) or stabilization (jasplakinolide). Both phases of IS were larger in response to glucose than tolbutamide, although [Ca2+]c was lower. This difference in secretion, which reflects metabolic amplification, persisted in presence of ACh/PMA and was independent of microfilaments. Amplification of IS by ACh/PMA is thus distinct from metabolic amplification, but both pathways promote acquisition of release competence by insulin granules, which can access exocytotic sites without intervention of microfilaments. [Copyright &y& Elsevier]
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- 2013
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21. Disruption and stabilization of β-cell actin microfilaments differently influence insulin secretion triggered by intracellular Ca2+ mobilization or store-operated Ca2+ entry
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Henquin, Jean-Claude, Mourad, Nizar I., and Nenquin, Myriam
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ACTIN ,CYTOPLASMIC filaments ,GLUCOSE ,SULFONYLUREAS ,POTASSIUM ,INSULIN ,CALCIUM - Abstract
Abstract: Latrunculin depolymerizes and jasplakinolide polymerizes β-cell actin microfilaments. Both increase insulin secretion when Ca
2+ enters β-cells during depolarization by glucose, sulfonylureas or potassium. Mouse islets were held hyperpolarized with diazoxide, and stimulated with acetylcholine to test the role of microfilaments in insulin secretion triggered by intracellular Ca2+ mobilization and store-operated Ca2+ entry (SOCE). Jasplakinolide slightly attenuated Ca2+ mobilization and did not affect SOCE, but consistently inhibited the attending insulin secretion. Latrunculin did not affect Ca2+ changes induced by acetylcholine, but consistently increased insulin secretion, its effect being larger in response to Ca2+ entry than to Ca2+ mobilization. Microfilaments have thus a distinct impact on exocytosis of insulin granules depending on the source of triggering Ca2+ . [Copyright &y& Elsevier]- Published
- 2012
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22. Metabolic amplification of insulin secretion by glucose is independent of β-cell microtubules.
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Mourad, Nizar I., Nenquin, Myriam, and Henquin, Jean-Claude
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INSULIN , *SECRETION , *MICROTUBULES , *POTASSIUM channels , *EXOCYTOSIS , *CALCIUM channels - Abstract
Glucose-induced insulin secretion (IS) by β-cells is controlled by two pathways. The triggering pathway involves ATP-sensitive potassium (KATP) channel-dependent depolarization, Ca2+ influx, and rise in the cytosolic Ca2+ concentration ([Ca2+]c), which triggers exocytosis of insulin granules. The metabolic amplifying pathway augments IS without further increasing [Ca2+]c. After exclusion of the contribution of actin microfilaments, we here tested whether amplification implicates microtubule-dependent granule mobilization. Mouse islets were treated with nocodazole or taxol, which completely depolymerized and polymerized tubulin. They were then perifused to measure [Ca2+]c and IS. Metabolic amplification was studied during imposed steady elevation of [Ca2+]c by tolbutamide or KCl or by comparing [Ca2+]c and IS responses to glucose and tolbutamide. Nocodazole did not alter [Ca2+]c or IS changes induced by the three secretagogues, whereas taxol caused a small inhibition of IS that is partly ascribed to a decrease in [Ca2+]c. When [Ca2+]c was elevated and controlled by KCl or tolbutamide, the amplifying action of glucose was unaffected by microtubule disruption or stabilization. Both phases of IS were larger in response to glucose than tolbutamide, although triggering [Ca2+]c was lower. This difference, due to amplification, persisted in nocodazole- or taxol-treated islets, even when IS was augmented fourfold by microfilament disruption with cytochalasin B or latrunculin B. In conclusion, metabolic amplification rapidly augments first and second phases of IS independently of insulin granule translocation along microtubules. We therefore extend our previous proposal that it does not implicate the cytoskeleton but corresponds to acceleration of the priming process conferring release competence to insulin granules. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. Metabolic amplifying pathway increases both phases of insulin secretion independently of β-cell actin microfilaments.
- Author
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Mourad, Nizar I., Nenquin, Myriam, and Henquin, Jean-Claude
- Subjects
- *
GLUCOSE , *INSULIN , *ADENOSINE triphosphate , *CALCIUM ions , *ACTIN - Abstract
Two pathways control glucose-induced insulin secretion (IS) by β-cells. The triggering pathway involves ATP-sensitive potassium (KATP) channel-dependent depolarization, Ca2+ influx, and a rise in the cytosolic Ca2+ concentration ([Ca2+]c), which triggers exocytosis of insulin granules. The metabolic amplifying pathway augments IS without further increasing [Ca2+]c. The underlying mechanisms are unknown. Here, we tested the hypothesis that amplification implicates actin microfilaments. Mouse islets were treated with latrunculin B and cytochalasin B to depolymerize actin or jasplakinolide to polymerize actin. They were then perifused to measure [Ca2+]c and IS. Metabolic amplification was studied during imposed steady elevation of [Ca2+]c by tolbutamide or KCl or by comparing the magnitude of [Ca2+]c and IS changes produced by glucose and tolbutamide. Both actin polymerization and depolymerization augmented IS triggered by all stimuli without increasing (sometimes decreasing) [Ca2+]c, which indicates a predominantly inhibitory function of microfilaments in exocytosis at a step distal to [Ca2+]c increase. When [Ca2+]c was elevated and controlled by KCl or tolbutamide, the amplifying action of glucose was facilitated by actin depolymerization and unaffected by polymerization. Both phases of IS were larger in response to high-glucose than to tolbutamide in low-glucose, although triggering [Ca2+]c was lower. This difference in IS, due to amplification, persisted when the IS rate was doubled by actin depolymerization or polymerization. In conclusion, metabolic amplification is rapid and influences the first as well as the second phase of IS. It is a late step of stimulus-secretion coupling, which does not require functional actin microfilaments and could correspond to acceleration of the priming process conferring release competence to insulin granules. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
24. Glucose-induced Cytosolic pH Changes in β-Cells and Insulin Secretion Are Not Causally Related.
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Stiernet, Patrick, Nenquin, Myriam, Moulin, Pierre, Jonas, Jean-Christophe, and Henquin, Jean-Claude
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HYDROGEN-ion concentration , *REGULATION of secretion , *CELLULAR control mechanisms , *INSULIN , *CYTOSOL , *SODIUM , *HYDROGEN , *GLUCOSE - Abstract
The contribution of Na+/H+ exchange (achieved by NHE proteins) to the regulation of β-cell cytosolic pHc, and the role of pHc changes in glucose-induced insulin secretion are disputed and were examined here. Using real-time PCR, we identified plasmalemmal NHE1 and intracellular NHE7 as the two most abundant NHE isoforms in mouse islets. We, therefore, compared insulin secretion, cytosolic free Ca2+ ([Ca2+]c) and pHc in islets from normal mice and mice bearing an inactivating mutation of NHE1 (Slc9A1-swe/swe). The experiments were performed in HCO-3/CO2 or HEPES/NaOH buffers. PCR and functional approaches showed that NHE1 mutant islets do not express compensatory pH-regulating mechanisms. NHE1 played a greater role than HCO-3-dependent mechanisms in the correction of an acidification imposed by a pulse of NH4Cl. In contrast, basal pHc (in low glucose) and the alkalinization produced by high glucose were independent of NHE1. Dimethylamiloride, a classic blocker of Na+/H+ exchange, did not affect pHc but increased insulin secretion in NHE1 mutant islets, indicating unspecific effects. In control islets, glucose similarly increased [Ca2+]c and insulin secretion in HCO-3 and HEPES buffer, although pHc changed in opposite directions. The amplification of insulin secretion that glucose produces when [Ca2+]c is clamped at an elevated level by KCl was also unrelated to pHc and pHc changes. All effects of glucose on [Ca2+]c and insulin secretion proved independent of NHE1. In conclusion, NHE1 protects -cells against strong acidification, but has no role in stimulus-secretion coupling. The changes in pHc produced by glucose involve HCO-3-dependent mechanisms. Variations in β-cell pHc are not causally related to changes in insulin secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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25. Overnight Culture Unmasks Glucose-induced Insulin Secretion in Mouse Islets Lacking ATP-sensitive K+ Channels by Improving the Triggering Ca2+ Signal.
- Author
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Szollosi, Andras, Nenquin, Myriam, and Henquin, Jean-Claude
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GLUCOSE , *INSULIN , *ADENOSINE triphosphate , *OXIDATION , *CELLS - Abstract
A current model ascribes glucose-induced insulin secretion to the interaction of a triggering pathway (KATP channel-dependent Ca2+ influx and rise in cytosolic [Ca2+]c) and an amplifying pathway (KATP channel-independent augmentation of secretion without further increase of [Ca2+]c). However, several studies of sulfonylurea receptor 1 null mice (Sur1KO) failed to measure significant effects of glucose in their islets lacking KATP channels. We addressed this issue that challenges the model. Compared with controls, fresh Sur1KO islets showed slightly elevated basal [Ca2+]c and insulin secretion. In 15 mM glucose, the absolute rate of secretion was ~3-fold lower in Sur1KO than control islets, with only poor increase above base line. Overnight culture of Sur1KO islets in 10 mc glucose (not in 5 mM) augmented basal insulin secretion and considerably improved the response to 15 mM glucose, which reached higher values than in control islets, in which culture had little impact. Glucose stimulation during KCl depolarization showed that the amplifying pathway is functional in fresh and cultured Sur1KO islets. The differences in insulin secretion between fresh and cultured Sur1KO islets and between Sur1KO and control islets were not attributable to differences in insulin content, glucose oxidation rate, or synchronization of [Ca2+]c oscillations. The unmasking of glucose-induced insulin secretion in β-cells lacking KATP channels is paradoxically due to improvement in the production of a triggering signal (elevated [Ca2+]c). The results show that KATP channels are not the only transducer of glucose effects on [Ca2+]c in β-cells. They explain controversies in the literature and refute arguments raised against the model implicating an amplifying pathway in glucose-induced insulin secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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26. Glucose Stimulates Ca2+ Influx and Insulin Secretion in 2-Week-old β-CelIs Lacking ATP-sensitive K+ Channels.
- Author
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Szollosi, Andras, Nenquin, Myriam, Aguilar-Bryan, Lydia, Bryan, Joseph, and Henquin, Jean-Claude
- Subjects
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GLUCOSE , *INSULIN , *ADENOSINE triphosphate , *POTASSIUM channels , *CALCIUM channels - Abstract
In adult β-cells glucose-induced insulin secretion involves two mechanisms (a) a KATP channel-dependent Ca2+ influx and rise of cytosolic [Ca2+]c and (b) a KATP channel-independent amplification of secretion without further increase of [Ca2+]c. Mice lacking the high affinity sulfonylurea receptor (Sur1KO), and thus KATP channels, have been developed as a model of congenital hyperinsulinism. Here, we compared [Ca2+]c and insulin secretion in overnight cultured islets from 2-week-old normal and Sur1KO mice. Control islets proved functionally mature: the magnitude and biphasic kinetics of [Ca2+]c and insulin secretion changes induced by glucose, and operation of the amplifying pathway, were similar to adult islets. Sur1KO islets perifused with 1 mc glucose showed elevation of both basal [Ca2+]c and insulin secretion. Stimulation with 15 mM glucose produced a transient drop of [Ca2+]c followed by an overshoot and a sustained elevation, accompanied by a monophasic, 6-fold increase in insulin secretion, Glucose also increased insulin secretion when [Ca2+}c was clamped by KCl. When Sur1KO islets were cultured in 5 instead of 10 mM glucose, [Ca2+]c and insulin secretion were unexpectedly low in 1 mM glucose and increased following a biphasic time course upon stimulation by 15 mM glucose. This KATP channel-independent first phase [Ca2+]c rise was attributed to a Na+-, Cl--, and Na+-pump-independent depolarization of β-cells, leading to Ca2+ influx through voltage-dependent calcium channels. Glucose indeed depolarized Sur1KO islets under these conditions. It is suggested that unidentified potassium channels are sensitive to glucose and subserve the acute and long-term metabolic control of [Ca2+]c in β-cells without functional KATP channels. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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27. In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: pattern and role of cytoplasmic Ca2+ and amplification signals in beta-cells.
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Henquin J, Nenquin M, Stiernet P, Ahren B, Henquin, Jean-Claude, Nenquin, Myriam, Stiernet, Patrick, and Ahren, Bo
- Abstract
The mechanisms underlying biphasic insulin secretion have not been completely elucidated. We compared the pattern of plasma insulin changes during hyperglycemic clamps in mice to that of glucose-induced insulin secretion and cytosolic calcium concentration ([Ca(2+)](c)) changes in perifused mouse islets. Anesthetized mice were infused with glucose to clamp blood glucose at 8.5 (baseline), 11.1, 16.7, or 30 mmol/l. A first-phase insulin response consistently peaked at 1 min, and a slowly ascending second phase occurred at 16.7 and 30 mmol/l glucose. Glucose-induced insulin secretion in vivo is thus biphasic, with a similarly increasing second phase in the mouse as in humans. In vitro, square-wave stimulation from a baseline of 3 mmol/l glucose induced similar biphasic insulin secretion and [Ca(2+)](c) increases, with sustained and flat second phases. The glucose dependency (3-30 mmol/l) of both changes was sigmoidal with, however, a shift to the right of the relation for insulin secretion compared with that for [Ca(2+)](c). The maximum [Ca(2+)](c) increase was achieved by glucose concentrations, causing half-maximum insulin secretion. Because this was true for both phases, we propose that contrary to current concepts, amplifying signals are also implicated in first-phase glucose-induced insulin secretion. To mimic in vivo conditions, islets were stimulated with high glucose after being initially perifused with 8.5 instead of 3.0 mmol/l glucose. First-phase insulin secretion induced by glucose at 11.1, 16.7, and 30 mmol/l was decreased by approximately 50%, an inhibition that could not be explained by commensurate decreases in [Ca(2+)](c) or in the pool of readily releasable granules. Also unexpected was the gradually ascending pattern of the second phase, now similar to that in vivo. These observations indicated that variations in prestimulatory glucose can secondarily affect the magnitude and pattern of subsequent glucose-induced insulin secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
28. Both Triggering and Amplifying Pathways Contribute to Fuel-induced Insulin Secretion in the Absence of Sulfonylurea Receptor-1 in Pancreatic β-Cells.
- Author
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Nenquin, Myriam, Szollosi, Andras, Aguilar-Bryan, Lydia, Bryan, Joseph, and Henquin, Jean-Claude
- Subjects
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INSULIN , *PANCREATIC secretions , *HYPOGLYCEMIC agents , *HORMONES , *UREA , *PANCREATIC beta cells , *ISLANDS of Langerhans - Abstract
In normal β-cells glucose induces insulin secretion by activating both a triggering pathway (closure of KATP channels, depolarization, and rise in cytosolic [Ca2+]i) and an amplifying pathway (augmentation of Ca2+ efficacy on exocytosis). It is unclear if and how nutrients can regulate insulin secretion by β-cells lacking KATP channels (Sur1 knockout mice). We compared glucose-and amino acid-induced insulin secretion and [Ca2+]i changes in control and Sur1KO islets. In 1 mM glucose (non-stimulatory for controls), the triggering signal [Ca2+]i was high (loss of regulation) and insulin secretion was stimulated in Sur1KO islets. This "basal" secretion was decreased or increased by imposed changes in [Ca2+]i and was dependent on ATP production, indicating that both triggering and amplifying signals are involved. High glucose stimulated insulin secretion in Sur1KO islets, by an unsuspected, transient increase in [Ca2+]i and a sustained activation of the amplifying pathway. Unlike controls, Sur1KO islets were insensitive to diazoxide and tolbutamide, which rules out effects of either drug at sites other than KATP channels. Amino acids potently increased insulin secretion by Sur1KO islets through both a further electrogenic rise in [Ca2+]i and a metabolism-dependent activation of the amplifying pathway. After sulfonylurea blockade of their KATP channels, control islets qualitatively behaved like Sur1KO islets, but their insulin secretion rate was consistently lower for a similar or even higher [Ca2+]i. In conclusion, fuel secretagogues can control insulin secretion in β-cells without KATP channels, partly by an unsuspected influence on the triggering [Ca2+]i signal and mainly by the modulation of a very effective amplifying pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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29. SERCA3 ablation does not impair insulin secretion but suggests distinct roles of different sarcoendoplasmic reticulum Ca(2+) pumps for Ca(2+) homeostasis in pancreatic beta-cells.
- Author
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Arredouani, Abdelilah, Guiot, Yves, Jonas, Jean-Christophe, Liu, Lynne H., Nenquin, Myriam, Pertusa, José A., Rahier, Jacques, Rolland, Jean-François, Shull, Gary E., Stevens, Martine, Wuytack, Frank, Henquin, Jean-Claude, Gilon, Patrick, Pertusa, José A, and Rolland, Jean-François
- Subjects
ISLANDS of Langerhans ,ENDOPLASMIC reticulum - Abstract
Two sarcoendoplasmic reticulum Ca(2+)-ATPases, SERCA3 and SERCA2b, are expressed in pancreatic islets. Immunocytochemistry showed that SERCA3 is restricted to beta-cells in the mouse pancreas. Control and SERCA3-deficient mice were used to evaluate the role of SERCA3 in beta-cell cytosolic-free Ca(2+) concentration ([Ca(2+)](c)) regulation, insulin secretion, and glucose homeostasis. Basal [Ca(2+)](c) was not increased by SERCA3 ablation. Stimulation with glucose induced a transient drop in basal [Ca(2+)](c) that was suppressed by inhibition of all SERCAs with thapsigargin (TG) but unaffected by selective SERCA3 ablation. Ca(2+) mobilization by acetylcholine was normal in SERCA3-deficient beta-cells. In contrast, [Ca(2+)](c) oscillations resulting from intermittent glucose-stimulated Ca(2+) influx and [Ca(2+)](c) transients induced by pulses of high K(+) were similarly affected by SERCA3 ablation or TG pretreatment of control islets; their amplitude was increased and their slow descending phase suppressed. This suggests that, during the decay of each oscillation, the endoplasmic reticulum releases Ca(2+) that was pumped by SERCA3 during the upstroke phase. SERCA3 ablation increased the insulin response of islets to 15 mmol/l glucose. However, basal and postprandial plasma glucose and insulin concentrations in SERCA3-deficient mice were normal. In conclusion, SERCA2b, but not SERCA3, is involved in basal [Ca(2+)](c) regulation in beta-cells. SERCA3 becomes operative when [Ca(2+)](c) rises and is required for normal [Ca(2+)](c) oscillations in response to glucose. However, a lack of SERCA3 is insufficient in itself to alter glucose homeostasis or impair insulin secretion in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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30. Magnesium uptake by pancreatic islet cells is modulated by stimulators and inhibitors of the B-cell function.
- Author
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Henquin, Jean-Claude, Nenquin, Myriam, Awouters, Patricia, and Cogneau, Michel
- Subjects
- *
PANCREATIC secretions , *SUCROSE , *SUGARS , *GLUCOSE , *AMINO acids , *HYPOGLYCEMIC agents , *BIOCHEMISTRY - Abstract
28Mg2+ uptake by rat islets was measured during incubation with various stimulators or inhibitors of insulin release. D-Glucose induced a dose-dependent increase in 28Mg2+ uptake after 10 min or 120 min. The threshold concentration was around 6 mM and the maximum effect was observed with 15 - 20 mM glucose. After 120 min 28Mg2+ uptake was also stimulated by the metabolized sugars mannose, 7V-acetylglucosamine or glyceraldehyde, was unaffected by the non-metabolized or poorly metabolized L-glueose, galactose, 3-O-methylglucose, 2-deoxyglucose, fructose or mannoheptulose and was inhibited by glueosamine. The effect of glucose was markedly impaired by mannoheptulose, glueosamine, aminooxyacetate and NH4Cl, but was only partially decreased by D600 or diazoxide, which were ineffective in a glucose-free medium. Tolbutamide or KCl slightly increased 28Mg2+ uptake. Alanine, leucine alone or with glutamine, and ketoisocaproate also stimulated 28Mg2+ uptake, whereas arginine and lysine decreased it. These changes in 28Mg2+ uptake, brought about by various modifiers of the B-cell function, are thus similar but not identical to the changes in Ca2+ uptake, and are not the consequence insulin release. The stimulatory effect of glucose requires glucose metabolism by islet cells, but is only partially due to depolarization of the B-cell membrane. [ABSTRACT FROM AUTHOR]
- Published
- 1986
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31. Tolbutamide and diazoxide influence insulin secretion by changing the concentration but not the action of cytoplasmic Ca2+ in beta-cells.
- Author
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Mariot, Pascal, Gilon, Patrick, Nenquin, Myriam, Henquin, Jean-Claude, Mariot, P, Gilon, P, Nenquin, M, and Henquin, J C
- Subjects
TOLBUTAMIDE ,DIAZO compounds ,CALCIUM ,EXOCYTOSIS ,ISLANDS of Langerhans - Abstract
Sulfonylureas stimulate insulin secretion by blocking ATP-sensitive K+ channels (K+-ATP channels) of the beta-cell membrane, thereby causing depolarization, Ca2+ influx, and rise in cytoplasmic Ca2+ concentration ([Ca2+]i), whereas diazoxide inhibits insulin secretion by opening K+-ATP channels. It has been suggested recently that these drugs also respectively increase and decrease the efficacy of Ca2+ on exocytosis. This hypothesis was tested here with intact islets or single beta-cells from normal mice. Depolarizing islet cells by raising extracellular K+ from 4.8 to 15, 30, and 60 mmol/l progressively raised [Ca2+]i and stimulated insulin secretion. The magnitude of the [Ca2+]i rise produced by a subsequent addition of 100 micromol/l tolbutamide decreased as the concentration of K+ was increased. The effect on insulin secretion paralleled that on [Ca2+]i. Similarly, the magnitudes of the [Ca2+]i drop and of the inhibition of insulin secretion produced by 250 micromol/l diazoxide were inversely related to the concentration of K+. Either drug was effective on secretion only when it increased or decreased [Ca2+]i. Exocytosis of insulin granules from single, voltage-clamped beta-cells was also studied by measuring cell capacitance changes. In the perforated patch configuration, exocytosis was evoked by depolarizing pulses. Addition of tolbutamide to the extracellular medium did not affect the Ca2+ current and the resulting change in cell capacitance. In the whole-cell configuration, cell capacitance increased with the concentration of free Ca2+ in the solution diffusing from the pipette into the cell. It was markedly potentiated by cAMP, was inhibited by activation of alpha2-adrenoceptors with clonidine, and was strongly augmented by acetylcholine. In contrast, tolbutamide was ineffective whether applied intra- or extracellularly, at low or high free Ca2+, and with or without cAMP. Diazoxide also failed to interfere directly with exocytosis. These results indicate that tolbutamide and diazoxide affect insulin secretion by changing the concentration, not the action, of Ca2+ in beta-cells. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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32. Mechanisms of the stimulation of insulin release by saturated fatty acids. A study of palmitate effects in mouse beta-cells.
- Author
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Warnotte, Catherine, Gilon, Patrick, Nenquin, Myriam, Henquin, Jean-Claude, Warnotte, C, Gilon, P, Nenquin, M, and Henquin, J C
- Published
- 1994
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33. Pharmacological approach to understanding the control of insulin secretion in human islets.
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Henquin, Jean‐Claude, Dufrane, Denis, Gmyr, Valery, Kerr‐Conte, Julie, and Nenquin, Myriam
- Subjects
INSULIN ,PHARMACOLOGY ,GLUCOKINASE ,TOLBUTAMIDE ,DIAZOXIDE ,CYTOPLASMIC filaments ,LATRUNCULINS - Abstract
Aims To understand better the control of insulin secretion by human β cells and to identify similarities to and differences from rodent models. Methods Dynamic insulin secretion was measured in perifused human islets treated with pharmacological agents of known modes of action. Results Glucokinase activation ( Ro28-1675) lowered the glucose threshold for stimulation of insulin secretion to 1 mmol/ L ( G1), augmented the response to G3-G5 but not to G8-G15, whereas tolbutamide remained active in G20, which indicates that not all K
ATP channels were closed by high glucose concentrations. An almost 2-fold greater response to G15 than to supramaximal tolbutamide in G3 or to KCl+diazoxide in G15 vs G3 quantified the contribution of metabolic amplification to insulin secretion. Both disruption (latrunculin- B) and stabilization (jasplakinolide) of microfilaments augmented insulin secretion without affecting metabolic amplification. Tolbutamide-induced insulin secretion was consistently greater in G10 than G3, with a threshold at 1 and maximum at 10 µmol/ L tolbutamide in G10, vs 10 and 25 µmol/ L in G3. Sulphonylurea effects were thus clearly glucose-dependent. Insulin secretion was also increased by inhibiting K channels other than KATP channels: Kv or BK channels (tetraethylammonium), TASK-1 channels ( ML-365) and SK4 channels ( TRAM-34). Opening KATP channels with diazoxide inhibited glucose-induced insulin secretion with half maximum inhibitory concentrations of 9.6 and 24 µmol/ L at G7 and G15. Blockade of L-type Ca channels (nimodipine) abolished insulin secretion, whereas a blocker of T-type Ca channels ( NNC-55-0396) was ineffective at specific concentrations. Blockade of Na channels (tetrodotoxin) did not affect glucose-induced insulin secretion. Conclusions In addition to sharing a KATP channel-dependent triggering pathway and a metabolic amplifying pathway, human and rodent β cells were found to display more similarities than differences in the control of insulin secretion. [ABSTRACT FROM AUTHOR]- Published
- 2017
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34. Relative contribution of Ca 2+-dependent and Ca 2+-independent mechanisms to the regulation of insulin secretion by glucose
- Author
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Sato, Yoshihiko, Nenquin, Myriam, and Henquin, Jean-Claude
- Published
- 1998
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35. Stimulation of insulin release by benzoic acid derivatives related to the non-sulphonylurea moiety of glibenclamide: Structural requirements and cellular mechanisms
- Author
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Henquin, Jean-Claude, Garrino, Maria-Grazia, and Nenquin, Myriam
- Published
- 1987
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- View/download PDF
36. Insulin secretion in islets from mice with a double knockout for the dense core vesicle proteins islet antigen-2 (IA-2) and IA-2beta.
- Author
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Henquin JC, Nenquin M, Szollosi A, Kubosaki A, and Notkins AL
- Subjects
- Acetylcholine pharmacology, Amino Acids pharmacology, Animals, Arginine pharmacology, Autoantigens genetics, Autoantigens metabolism, Calcium metabolism, Cholinergic Agents pharmacology, Exocytosis physiology, Female, Glucose pharmacology, Insulin Secretion, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism, Mice, Mice, Knockout, Potassium Chloride pharmacology, Receptor-Like Protein Tyrosine Phosphatases, Class 8 metabolism, Insulin metabolism, Insulin-Secreting Cells physiology, Receptor-Like Protein Tyrosine Phosphatases, Class 8 genetics, Secretory Vesicles physiology
- Abstract
Islet antigen-2 (IA-2 or ICA 512) and IA-2beta (or phogrin) are major autoantigens in type 1 diabetes. They are located in dense core secretory vesicles including insulin granules, but their role in beta-cell function is unclear. Targeted disruption of either IA-2 or IA-2beta, or both, impaired glucose tolerance, an effect attributed to diminution of insulin secretion. In this study, we therefore characterized the dynamic changes in cytosolic Ca2+([Ca2+](c)) and insulin secretion in islets from IA-2/IA-2beta double knockout (KO) mice. High glucose (15 mM) induced biphasic insulin secretion in IA-2/IA-2beta KO islets, with a similar first phase and smaller second phase compared with controls. Since the insulin content of IA-2/IA-2beta KO islets was approximately 45% less than that of controls, fractional insulin secretion (relative to content) was thus increased during first phase and unaffected during second phase. This peculiar response occurred in spite of a slightly smaller rise in [Ca2+](c), could not be attributed to an alteration of glucose metabolism (NADPH fluorescence) and also was observed with tolbutamide. The dual control of insulin secretion via the K(ATP) channel-dependent triggering pathway and K(ATP) channel-independent amplifying pathway was unaltered in IA-2/IA-2beta KO islets, and so were the potentiations by acetylcholine or cAMP (forskolin). Intriguingly, amino acids, in particular the cationic arginine and lysine, induced larger fractional insulin secretion in IA-2/IA-2beta KO than control islets. In conclusion, IA-2 and IA-2beta are dispensable for exocytosis of insulin granules, but are probably more important for cargo loading and/or stability of dense core vesicles.
- Published
- 2008
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37. Overnight culture unmasks glucose-induced insulin secretion in mouse islets lacking ATP-sensitive K+ channels by improving the triggering Ca2+ signal.
- Author
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Szollosi A, Nenquin M, and Henquin JC
- Subjects
- ATP-Binding Cassette Transporters metabolism, Adenosine Triphosphate metabolism, Animals, Calcium metabolism, Cells, Cultured, Dose-Response Relationship, Drug, Insulin Secretion, Islets of Langerhans cytology, Mice, Mice, Knockout, Models, Biological, Multidrug Resistance-Associated Proteins metabolism, Potassium Channels metabolism, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sulfonylurea Receptors, Time Factors, Calcium Signaling genetics, Glucose pharmacology, Insulin metabolism, Islets of Langerhans metabolism, Multidrug Resistance-Associated Proteins deficiency, Potassium Channels deficiency, Sweetening Agents pharmacology
- Abstract
A current model ascribes glucose-induced insulin secretion to the interaction of a triggering pathway (K(ATP) channel-dependent Ca(2+) influx and rise in cytosolic [Ca(2+)](c)) and an amplifying pathway (K(ATP) channel-independent augmentation of secretion without further increase of [Ca(2+)](c)). However, several studies of sulfonylurea receptor 1 null mice (Sur1KO) failed to measure significant effects of glucose in their islets lacking K(ATP) channels. We addressed this issue that challenges the model. Compared with controls, fresh Sur1KO islets showed slightly elevated basal [Ca(2+)](c) and insulin secretion. In 15 mm glucose, the absolute rate of secretion was approximately 3-fold lower in Sur1KO than control islets, with only poor increase above base line. Overnight culture of Sur1KO islets in 10 mm glucose (not in 5 mm) augmented basal insulin secretion and considerably improved the response to 15 mm glucose, which reached higher values than in control islets, in which culture had little impact. Glucose stimulation during KCl depolarization showed that the amplifying pathway is functional in fresh and cultured Sur1KO islets. The differences in insulin secretion between fresh and cultured Sur1KO islets and between Sur1KO and control islets were not attributable to differences in insulin content, glucose oxidation rate, or synchronization of [Ca(2+)](c) oscillations. The unmasking of glucose-induced insulin secretion in beta-cells lacking K(ATP) channels is paradoxically due to improvement in the production of a triggering signal (elevated [Ca(2+)](c)). The results show that K(ATP) channels are not the only transducer of glucose effects on [Ca(2+)](c) in beta-cells. They explain controversies in the literature and refute arguments raised against the model implicating an amplifying pathway in glucose-induced insulin secretion.
- Published
- 2007
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38. The elevation of glutamate content and the amplification of insulin secretion in glucose-stimulated pancreatic islets are not causally related.
- Author
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Bertrand G, Ishiyama N, Nenquin M, Ravier MA, and Henquin JC
- Subjects
- Allosteric Site, Amino Acids, Cyclic pharmacology, Animals, Cells, Cultured, Dose-Response Relationship, Drug, Exocytosis, Female, Glucose metabolism, Hydrogen-Ion Concentration, Insulin Secretion, Male, Mice, Pancreas, Potassium metabolism, Potassium Chloride pharmacology, Protein Binding, Rats, Rats, Wistar, Time Factors, Tolbutamide pharmacology, Calcium metabolism, Glucose pharmacology, Glutamic Acid metabolism, Insulin metabolism
- Abstract
Glucose increases insulin secretion by raising cytoplasmic Ca(2+) ([Ca(2+)](i)) in beta-cells (triggering pathway) and augmenting the efficacy of Ca(2+) on exocytosis (amplifying pathway). It has been suggested that glutamate formed from alpha-ketoglutarate is a messenger of the amplifying pathway (Maechler, P., and Wollheim, C. B. (1999) Nature 402, 685-689). This hypothesis was tested with mouse islets depolarized with 30 mm KCl (+ diazoxide) or with a saturating concentration of sulfonylurea. Because [Ca(2+)](i) was elevated under these conditions, insulin secretion was stimulated already in 0 mm glucose. The amplification of secretion produced by glucose was accompanied by an increase in islet glutamate. However, glutamine (0.5-2 mm) markedly augmented islet glutamate without affecting insulin secretion, whereas glucose augmented secretion without influencing glutamate levels when these were elevated by glutamine. Allosteric activation of glutamate dehydrogenase by BCH (2-amino 2-norbornane carboxylic acid) lowered islet glutamate but increased insulin secretion. Similar insulin secretion thus occurred at very different cellular glutamate levels. Glutamine did not affect islet [Ca(2+)](i) and pH(i), whereas glucose and BCH slightly raised pH(i) and either slightly decreased (30 mm KCl) or increased (tolbutamide) [Ca(2+)](i). The general dissociation between changes in islet glutamate and insulin secretion refutes a role of beta-cell glutamate in the amplification of insulin secretion by glucose.
- Published
- 2002
- Full Text
- View/download PDF
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