New insights into pancreatic β-cell metabolic signaling in insulin secretion

1996 ◽  
Vol 134 (3) ◽  
pp. 272-286 ◽  
Author(s):  
Marc Prentki
Keyword(s):  
Insulin Secretion ◽  
Cell Signaling ◽  
Insulin Release ◽  
Cell Activation ◽  
Cell Metabolism ◽  
Second Messengers ◽  
Acid Oxidation ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Metabolic Signaling

Prentki M. New insights into pancreatic β-cell metabolic signaling in insulin secretion. Eur J Endocrinol 1996;134:272–86. ISSN 0804–4643 In recent years, it has become apparent that second messengers and factors other than ATP, metabolically sensitive KATP+ channels and Ca2+ play essential roles in nutrient-induced insulin release. This paper reviews the evidence in support of several new concepts and hypotheses in the field of β-cell signaling. These include in particular that: a rise in cytosolic Ca2+ is not sufficient to explain the kinetics and extent of secretion induced by glucose: variations in ADP, rather than ATP, regulate β-cell metabolism and the KATP+ channel; anaplerosis (the replenishment of the citric acid cycle with intermediates) is essential for β-cell activation; a shift from fatty acid oxidation to esterification is an important event in β-cell signaling; malonyl-CoA and long chain acyl-CoA esters may act as metabolic coupling factors; glycolytic oscillations underlie, in part, oscillations in electrical activity, cytosolic Ca2+ and insulin release. A metabolic model of fuel sensing that integrates the mode of action of all classes of nutrient secretagogues is proposed. Marc Prentki, Department of Nutrition, University of Montreal, CP6128, Succ, Centre-Ville, Montreal, PQ H3C3J7, Canada

scholarly journals Hypoxylonol F Isolated from Annulohypoxylon annulatum Improves Insulin Secretion by Regulating Pancreatic β-cell Metabolism

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 335 ◽  
Author(s):  
Dahae Lee ◽  
Buyng Su Hwang ◽  
Pilju Choi ◽  
Taejung Kim ◽  
Youngseok Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Peroxisome Proliferator ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Stimulated Insulin Secretion

Insulin plays a key role in glucose homeostasis and is hence used to treat hyperglycemia, the main characteristic of diabetes mellitus. Annulohypoxylon annulatum is an inedible ball-shaped wood-rotting fungus, and hypoxylon F is one of the major compounds of A. annulatum. The aim of this study is to evaluate the effects of hypoxylonol F isolated from A. annulatum on insulin secretion in INS-1 pancreatic β-cells and demonstrate the molecular mechanisms involved. Glucose-stimulated insulin secretion (GSIS) values were evaluated using a rat insulin ELISA kit. Moreover, the expression of proteins related to pancreatic β-cell metabolism and insulin secretion was evaluated using Western blotting. Hypoxylonol F isolated from A. annulatum was found to significantly enhance glucose-stimulated insulin secretion without inducing cytotoxicity. Additionally, hypoxylonol F enhanced insulin receptor substrate-2 (IRS-2) levels and activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1). Our findings showed that A. annulatum and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells. This suggests that A. annulatum can be used as a therapeutic agent to treat diabetes.

scholarly journals Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets

2012 ◽  
Vol 214 (3) ◽  
pp. 301-311 ◽  
Author(s):  
Mauricio da Silva Krause ◽  
Aline Bittencourt ◽  
Paulo Ivo Homem de Bittencourt ◽  
Neville H McClenaghan ◽  
Peter R Flatt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Cell Metabolism ◽  
Redox Status ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Upstream Kinase ◽  
Mouse Islets

Interleukin-6 (IL6) has recently been reported to promote insulin secretion in a glucagon-like peptide-1-dependent manner. Herein, the direct effects of IL6 (at various concentrations from 0 to 1000 pg/ml) on pancreatic β-cell metabolism, AMP-activated protein kinase (AMPK) signaling, insulin secretion, nitrite release, and redox status in a rat clonal β-cell line and mouse islets are reported. Chronic insulin secretion (in μg/mg protein per 24 h) was increased from 128.7±7.3 (no IL6) to 178.4±7.7 (at 100 pg/ml IL6) in clonal β-cells and increased significantly in islets incubated in the presence of 5.5 mM glucose for 2 h, from 0.148 to 0.167±0.003 ng/islet. Pretreatment with IL6 also induced a twofold increase in basal and nutrient-stimulated insulin secretion in subsequent 20 min static incubations. IL6 enhanced both glutathione (GSH) and glutathione disulphide (GSSG) by nearly 20% without changing intracellular redox status (GSSG/GSH). IL6 dramatically increased iNOS expression (byca. 100-fold) with an accompanying tenfold rise in nitrite release in clonal β-cells. Phosphorylated AMPK levels were elevated approximately twofold in clonal β-cells and mouse islet cells. Calmodulin-dependent protein kinase kinase levels (CaMKK), an upstream kinase activator of AMPK, were also increased by 50% after IL6 exposure (in β-cells and islets). Our data have demonstrated that IL6 can stimulate β-cell-dependent insulin secretion via direct cell-based mechanisms. AMPK, CaMKK (an upstream kinase activator of AMPK), and the synthesis of nitric oxide appear to alter cell metabolism to benefit insulin secretion. In summary, IL6 exerts positive effects on β-cell signaling, metabolism, antioxidant status, and insulin secretion.

Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic β-cells

2008 ◽  
Vol 36 (5) ◽  
pp. 955-958 ◽  
Author(s):  
Deirdre Keane ◽  
Philip Newsholme
Keyword(s):  
Arachidonic Acid ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Metabolism ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. In the present review, we focus on exogenous and endogenous effects of NEFAs, including the polyunsaturated fatty acid, arachidonic acid (or its metabolites generated from cyclo-oxygenase activity), on β-cell metabolism, and have explored the outcomes with respect to β-cell insulin secretion.

Extracellular calcium influx activates adenylate cyclase 1 and potentiates insulin secretion in MIN6 cells

2013 ◽  
Vol 450 (2) ◽  
pp. 365-373 ◽  
Author(s):  
Tetsuya Kitaguchi ◽  
Manami Oya ◽  
Yoshiko Wada ◽  
Takashi Tsuboi ◽  
Atsushi Miyawaki
Keyword(s):  
Insulin Secretion ◽  
Adenylate Cyclase ◽  
Calcium Influx ◽  
Second Messengers ◽  
Pcr Analysis ◽  
Intracellular Camp ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Small Interference Rna ◽  
Min6 Cells

Intracellular cAMP and Ca2+ are important second messengers that regulate insulin secretion in pancreatic β-cells; however, the molecular mechanism underlying their mutual interaction for exocytosis is not fully understood. In the present study, we investigated the interplay between intracellular cAMP and Ca2+ concentrations ([cAMP]i and [Ca2+]i respectively) in the pancreatic β-cell line MIN6 using total internal reflection fluorescence microscopy. For measuring [cAMP]i, we developed a genetically encoded yellow fluorescent biosensor for cAMP [Flamindo (fluorescent cAMP indicator)], which changes fluorescence intensity with cAMP binding. Application of high-KCl or glucose to MIN6 cells induced the elevation of [cAMP]i and exocytosis. Furthermore, application of an L-type Ca2+ channel agonist or ionomycin to induce extracellular Ca2+ influx evoked the elevation of [cAMP]i, whereas application of carbachol or thapsigargin, which mobilize Ca2+ from internal stores, did not evoke the elevation of [cAMP]i. We performed RT (reverse transcription)–PCR analysis and found that Ca2+-sensitive Adcy1 (adenylate cyclase 1) was expressed in MIN6 cells. Knockdown of endogenous ADCY1 by small interference RNA significantly suppressed glucose-induced exocytosis and the elevation of both [cAMP]i and [Ca2+]i. Taken together, the findings of the present study demonstrate that ADCY1 plays an important role in the control of pancreatic β-cell cAMP homoeostasis and insulin secretion.

scholarly journals ATP is an essential autocrine factor for pancreatic β‐cell signaling and insulin secretion

2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Sebastian Hauke ◽  
Jona Rada ◽  
Gergely Tihanyi ◽  
Danny Schilling ◽  
Carsten Schultz
Keyword(s):  
Insulin Secretion ◽  
Cell Signaling ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Autocrine Factor

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

scholarly journals Functional MR Microimaging of Pancreatic β-Cell Activation

2006 ◽  
Vol 15 (2) ◽  
pp. 195-203 ◽  
Author(s):  
Barjor Gimi ◽  
Lara Leoni ◽  
Jose Oberholzer ◽  
Mark Braun ◽  
Jose Avila ◽  
...  
Keyword(s):  
Cell Activation ◽  
Pancreatic Β Cell ◽  
Β Cell

scholarly journals Reducing Glucokinase Activity Restores Endogenous Pulsatility and Enhances Insulin Secretion in Islets From db/db Mice

Endocrinology ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 3747-3760 ◽  
Author(s):  
Ishrat Jahan ◽  
Kathryn L Corbin ◽  
Avery M Bogart ◽  
Nicholas B Whitticar ◽  
Christopher D Waters ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Opposite Effect ◽  
Glucose Sensing ◽  
Β Cell ◽  
Left Shift ◽  
Low Glucose ◽  
Mouse Islets ◽  
Secretion Rates

Abstract An early sign of islet failure in type 2 diabetes (T2D) is the loss of normal patterns of pulsatile insulin release. Disruptions in pulsatility are associated with a left shift in glucose sensing that can cause excessive insulin release in low glucose (relative hyperinsulinemia, a hallmark of early T2D) and β-cell exhaustion, leading to inadequate insulin release during hyperglycemia. Our hypothesis was that reducing excessive glucokinase activity in diabetic islets would improve their function. Isolated mouse islets were exposed to glucose and varying concentrations of the glucokinase inhibitor d-mannoheptulose (MH) to examine changes in intracellular calcium ([Ca2+]i) and insulin secretion. Acutely exposing islets from control CD-1 mice to MH in high glucose (20 mM) dose dependently reduced the size of [Ca2+]i oscillations detected by fura-2 acetoxymethyl. Glucokinase activation in low glucose (3 mM) had the opposite effect. We then treated islets from male and female db/db mice (age, 4 to 8 weeks) and heterozygous controls overnight with 0 to 10 mM MH to determine that 1 mM MH produced optimal oscillations. We then used 1 mM MH overnight to measure [Ca2+]i and insulin simultaneously in db/db islets. MH restored oscillations and increased insulin secretion. Insulin secretion rates correlated with MH-induced increases in amplitude of [Ca2+]i oscillations (R2 = 0.57, P < 0.01, n = 10) but not with mean [Ca2+]i levels in islets (R2 = 0.05, not significant). Our findings show that correcting glucose sensing can restore proper pulsatility to diabetic islets and improved pulsatility correlates with enhanced insulin secretion.

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