Cited by 227Pancreatic function and diabetesCellular transport and secretionCalcium signaling and nucleotide metabolism

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A Subset of 50 Secretory Granules in Close Contact With l-Type Ca2+ Channels Accounts for First-Phase Insulin Secretion in Mouse β-Cells

Barg, Sebastian, Eliasson, Lena, Renström, Erik, Rorsman, Patrik·2002·Diabetes

DOI 10.2337/diabetes.51.2007.s74

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Abstract

Capacitance measurements were applied to mouse pancreatic beta-cells to elucidate the cellular mechanisms underlying biphasic insulin secretion. We report here that only 10,000 granules are immediately available for release. The releasable granules tightly associate with the voltage-gated alpha(1C) Ca(2+) channels, and it is proposed that the release of these granules accounts for first-phase insulin secretion. Subsequent replenishment of the releasable pool by priming of previously nonreleasable granules is required for second-phase insulin secretion. The latter reaction depends on intragranular acidification due to the concerted action of granular bafilomycin-sensitive v-type H(+)-ATPase and 4,4-diisothiocyanostilbene-2,2-disulfonate--blockable ClC-3 Cl(-) channels. Lowering the cytoplasmic ATP/ADP ratio prevents granule acidification, granule priming, and refilling of the releasable pool. The latter finding provides an explanation to the transient nature of insulin secretion elicited by, for example, high extracellular K(+) in the absence of metabolizable fuels.

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Self-citation
Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification
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Measuring Second Phase of Insulin Secretion by Components of Metabolic Syndrome
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“In this sense, with very little 1st ISEC, 2nd ISEC represents actually insulin storage in overt T2DM [9].”
Background
Arachidonic acid mobilizes Ca2+ from the endoplasmic reticulum and an acidic store in rat pancreatic β cells.
Yeung-Yam-Wah, V., Lee, A. K., & Tse, A. (2012) · Cell Calcium · doi:10.1016/j.ceca.2011.11.012 · Cited by 11
Sequential in vivo labeling of insulin secretory granule pools in INS - SNAP transgenic pigs
Kemter, E., Müller, A., Neukam, M., Ivanova, A., Klymiuk, N., Renner, S., Yang, K., Broichhagen, J., Kurome, M., Zakhartchenko, V., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2107665118 · Cited by 12
Electrical activity and exocytotic correlates of biphasic insulin secretion from β-cells of canine islets of Langerhans: Contribution of tuning two modes of Ca2+entry-dependent exocytosis to two modes of glucose-induced electrical activity
Misler, S., Zhou, Z., Dickey, A. S., Silva, A. M., Pressel, D. M., & Barnett, D. W. (2009) · Channels · doi:10.4161/chan.3.3.8972 · Cited by 17
OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion
Panagiotou, S., Tan, K.-W., Nguyen, P., Müller, A., Oqua, A. I., Tomas, A., Wendt, A., Eliasson, L., Tengholm, A., Solimena, M., et al. (2023) · bioRxiv · doi:10.1101/2023.02.22.529485 · Cited by 9
“A typical β-cell contains between 5000-15000 secretory granules (SGs) (Müller et al., 2021; Sato Tamiko, 1981), but only around 50-100 of these have the ability to fuse with the plasma membrane (Barg et al., 2002; Olofsson et al., 2002).”
BackgroundSelf-citation
The changing view of insulin granule mobility: From conveyor belt to signaling hub
Gaus, B., Brüning, D., Groß, S., Müller, M., & Rustenbeck, I. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.983152 · Cited by 10
“In fact, clustering and immobility have been repeatedly emphasized as central features of preexocytotic granules (31, 33, 55).”
Background
Biogenesis of the Insulin Secretory Granule in Health and Disease
Guest, P. C. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12668-1_2 · Cited by 15
Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell
Allen, J. G., & Tessem, J. S. (2022) · Cells · doi:10.3390/cells11131993 · Cited by 8
“Each insulin granule contains roughly 250,000 molecules of insulin and has a diameter of 250 nm [3].”
Background
The mechanisms of chromogranin B-regulated Cl− homeostasis
Jiang, Q., & Yadav, G. P. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220435 · Cited by 8
Observer-Independent Quantification of Insulin Granule Exocytosis and Pre-Exocytotic Mobility by TIRF Microscopy
Matz, M., Schumacher, K., Hatlapatka, K., Lorenz, D. A., Baumann, K., & Rustenbeck, I. (2013) · Microscopy and Microanalysis · doi:10.1017/s1431927613013767 · Cited by 8
“However, the observation that recently generated insulin granules are preferentially released ~Michael et al., 2007! suggests that the conventional view of granule transport as a unidirectional flow from the trans-Golgi network to the release sites ~e.g., Barg et al., 2002! lacks essential features.”
Background
Ca2+ homeostasis and exocytosis in carotid glomus cells: role of mitochondria.
Yan, L., Lee, A. K., Tse, F., & Tse, A. (2012) · Cell Calcium · doi:10.1016/j.ceca.2011.12.003 · Cited by 7
Unifying concepts in stimulus-secretion coupling in endocrine cells and some implications for therapeutics
Misler, S. (2009) · AJP Advances in Physiology Education · doi:10.1152/advan.90213.2008 · Cited by 9
“(stretch)-sensitive atrial myocytes (2); and K -sensitive zona glomerulosa cells of the adrenal cortex (3).”
BackgroundInfluential
Regulation of Insulin Granule Exocytosis
Renström, E., & Rorsman, P. (2008) · Springer eBooks · doi:10.1007/978-4-431-75452-7_9 · Cited by 7
Self-citation
Changes in granule mobility and age contribute to changes in insulin secretion after desensitization or rest
Gaus, B., Brüning, D., Hatlapatka, K., & Rustenbeck, I. (2021) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2021-002394 · Cited by 6
Increased fiber intake predicts the decrease in 2nd phase glucose-induced hyperinsulinemia following a hypocaloric diet in obese subjects
Provost, V., Lamantia, V., Bissonnette, S., Cyr, Y., & Faraj, M. (2019) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2019.01.014 · Cited by 8
Ca2+ clearance by plasmalemmal NCLX, Li+-permeable Na+/Ca2+ exchanger, is required for the sustained exocytosis in rat insulinoma INS-1 cells
Han, Y.-E., Ryu, S.-Y., Park, S.-H., Lee, K.-H., Lee, S., & Ho, W. (2015) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-015-1715-3 · Cited by 5
Calcium Current Inactivation Rather than Pool Depletion Explains Reduced Exocytotic Rate with Prolonged Stimulation in Insulin-Secreting INS-1 832/13 Cells
Pedersen, M. G., Salunkhe, V., Svedin, E., Edlund, A., & Eliasson, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103874 · Cited by 6
“of an immediately releasable pool (IRP) of granules located near Ca channels [8,10,11,13,14].”
Self-citation
Cell Swelling-induced Peptide Hormone Secretion
Štrbák, V. (2011) · Cellular Physiology and Biochemistry · doi:10.1159/000335849 · Cited by 5
Regulation of KATP channel by 17β-estradiol in pancreatic β-cells
Soriano, S., Ripoll, C., Fuentes, E., González, A., Alonso‐Magdalena, P., Ropero, A. B., Quesada, I., & Nadal, Á. (2011) · Steroids · doi:10.1016/j.steroids.2011.03.017 · Cited by 11
Phasic and tonic modes of depolarization-exocytosis coupling in β-cells of porcine islets of Langerhans
Misler, S., Silva, A. M., Barnett, D. W., & Dickey, A. S. (2009) · Channels · doi:10.4161/chan.3.2.7866 · Cited by 7
Conversion of glutamate into proline by the leucine analog BCH enhances biphasic insulin secretion in pancreatic β-cells
Gheibi, S., Cataldo, L. R., Ardalani, H., Nocquet, L., Spégel, P., Straub, S. G., Sharp, G. W. G., Fex, M., & Mulder, H. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108449 · Cited by 4
Sex-Specific Models to Predict Insulin Secretion and Sensitivity in Subjects with Overweight and Obesity
Beaudry, M., Bissonnette, S., Lamantia, V., Devaux, M., & Faraj, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076130 · Cited by 5
“The second phase represents a “reserve pool” of storage granules and produces a substantial and prolonged ISec that is larger than the first phase [16], as also demonstrated in this study (Supplementary Figure S1a,b).”
BackgroundResult
Measuring Exocytosis in Endocrine Tissue Slices
Klemen, M. S., Dolenšek, J., Stožer, A., & Rupnik, M. S. (2013) · Neuromethods · doi:10.1007/978-1-62703-676-4_7 · Cited by 7
“During these protocols, the holding potentials are transiently changed from resting membrane potential values to depolarized values for varying periods of time, ranging from a few to several hundreds of milliseconds [27–29].”
Background
Genetic ablation of synaptotagmin‐9 alters tomosyn‐1 function to increase insulin secretion from pancreatic β‐cells improving glucose clearance
Rahman, M. M., Pathak, A., Schueler, K. L., Alsharif, H. A., Michl, A. N., Alexander, J., Kim, J., & Bhatnagar, S. (2023) · The FASEB Journal · doi:10.1096/fj.202300291rr · Cited by 5
A Cellular Automaton Model as a First Model-Based Assessment of Interacting Mechanisms for Insulin Granule Transport in Beta Cells
Müller, M., Glombek, M., Powitz, J., Brüning, D., & Rustenbeck, I. (2020) · Cells · doi:10.3390/cells9061487 · Cited by 3
“With this procedure, the “Readily Releasable Pool” described in [71] and [13] is considered.”
Method
Insulin secretion kinetics from single islets reveals distinct subpopulations
Damodaran, R. G., Poussard, A., Côté, B., Andersen, P. L., & Vermette, P. (2018) · Biotechnology Progress · doi:10.1002/btpr.2632 · Cited by 4
“This secondary release is slow and sustained as long as glucose concentration remains high.(7,11,12)”
Background
Emptying the Pool: Modular Insulin Secretion From the Pancreas
Rizzo, M. A. (2016) · Diabetes · doi:10.2337/dbi15-0041 · Cited by 3
“This falls in line with estimates that a maximum of 5% of the insulin secretory granule pool can be mobilized in vitro (1).”
Background
Short-term impact of sugar consumption on hunger and ad libitum food intake in young women
Penaforte, F. R., Japúr, C. C., Pigatto, L. P., Chiarello, P. G., & Garcia, R. W. D. (2013) · Nutrition Research and Practice · doi:10.4162/nrp.2013.7.2.77 · Cited by 6
Molecular puzzle of insulin: structural assembly pathways and their role in diabetes
Urbaniak, E., Henry, S., Lalowski, M. M., & Borowiak, M. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1502469 · Cited by 11
Age-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic β-cells
Tsiaze, E. B., Huang, Y., Bombek, L. K., Yang, S., Jevšek, M., Seino, S., & Rupnik, M. S. (2012) · Open Journal of Molecular and Integrative Physiology · doi:10.4236/ojmip.2012.23008 · Cited by 5
The Role of the Cytoskeleton in Transport and Release of Insulin-Containing Granules by Pancreatic β-Cells
Goody, R. S., & Mannherz, H. G. (2010) · Springer eBooks · doi:10.1007/978-1-4419-6956-9_5 · Cited by 3
The Amount of Releasable Insulin Depends on Continuous Oxidative Phosphorylation
Tappe, C., Parambath, M., Reschke, J., & Rustenbeck, I. (2025) · Function · doi:10.1093/function/zqaf033 · Cited by 2
“13 , 14 Based on electrophysiological and ultrastructural data, these granules were termed the readily releasable pool.”
A minimal mathematical model to study insulin synthesis and secretion process
Paul, A., Kundu, J., & Chatterjee, S. (2023) · Applied Mathematical Modelling · doi:10.1016/j.apm.2023.06.012 · Cited by 2
Quantifying local heterogeneity of in vivo transport dynamics using stochastic scanning multiphoton multifocal microscopy and segmented spatiotemporal image correlation spectroscopy
Kim, H. Y., Jureller, J., Kuznetsov, A., Philipson, L., & Scherer, N. (2008) · SPIE BiOS · doi:10.1117/12.763300 · Cited by 2
Ion Channels and Insulin Secretion
Jacobson, D. A., & Philipson, L. H. (2008) · Springer eBooks · doi:10.1007/978-4-431-75452-7_6 · Cited by 6
Cyclin-Dependent Kinase 5 and Insulin Secretion
Bark, C., Rupnik, M. S., Jevšek, M., Mandic, S. A., & Berggren, P. (2008) · Springer eBooks · doi:10.1007/978-0-387-78887-6_11 · Cited by 1
“The sizes of SGs and SVs differ, with insulin granules being 5–10-fold larger in diameter, approximately 200–350 nm ( Barg et al., 2002 ).”
Background
Mitochondria – insulin granule crosstalk controls the early stages of granule maturationPreprint
Panagiotou, S., Mandal, K., Amini, S., Tan, K. W., Stephens, S. B., & Idevall‐Hagren, O. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.23.707428 · Cited by 1
“Mature IGs are stored in the cytoplasm and consist of two disJnct pools; the readily releasable pool which undergoes exocytosis upon sJmulaJon and the reserve pool, which is located deeper in the cytosol 6 .”
ADAM9 Genetic Variants and Their Role in Modulating Enzyme Activity in Diabetes and Metabolic Traits
Drobiova, H., Al‐Mulla, F., & Al-Temaimi, R. A. (2025) · Journal of Diabetes Research · doi:10.1155/jdr/5519447 · Cited by 1
“The main role of pancreatic b-cells is to produce and release insulin in a regulated manner to maintain blood glucose levels within normal ranges [59, 60].”
Membrane insertion of chromogranin B for granule maturation in regulated secretionPreprint
Yadav, G. P., Wang, H., Ouwendijk, J., Annamalai, M., Cross, S., Wang, Q., Hagan, D. W., Mathews, C. E., Phelps, E. A., Verkade, P., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2019.12.28.890053 · Cited by 1
Dielectrophoresis reveals stimulus-induced remodeling of insulin granule subpopulations
Archambeau, A. K., Korma, T., Deshmukh, A., Hayes, M. A., & White, K. L. (2026) · Biophysical Journal · doi:10.1016/j.bpj.2026.04.029
“Fractions 8–10 were identified as ISG-contain-ing fractions (Figure S5A) and were pooled and analyzed using a variety of biochemical and biophysical analyses (Figures 2B and S5).”
Dielectrophoresis Reveals Stimulus-Induced Remodeling of Insulin Granule Subpopulations
Archambeau, A., Korma, T., Deshmukh, A., Hayes, M. A., & White, K. L. (2025) · bioRxiv · doi:10.1101/2025.10.27.684914
Synaptotagmin-9 and Tomosyn-1 molecular complex regulates Stx1A SNAREs to inhibit insulin secretion from pancreatic β-cellsPreprint
Rahman, M. M., Pathak, A., Schueler, K. L., Alsharif, H. A., Michl, A. N., Alexander, J., Kim, J.-A., Chapman, E. R., & Bhatnagar, S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.20.513128
Prédicteurs de l’amélioration des facteurs de risques de diabète de type 2 suivant une diète hypocalorique
Provost, V. (2018) · doi:10.71781/26154
“Cet effet serait relié à une diminution de la production de chylomicrons et de VLDL ainsi qu’à une augmentation de la dégradation des lipoprotéines porteuses d’apoB-100 (86).”
Influential
Study of the insulin-sensitizing effect of myo-inositol in mouse : Evaluation of the nutritional interest of a myo-inositol supplementation
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“…constricted fusion pore (ca. 1,4 nm) allows diffusion of low-molecular weight compounds, such as Zn 2+ , ATP and GABA, into the extracellular space (Takahashi et al. 2002; Barg et al. 2002; Lindau and Alvarez de Toledo 2003; Tsuboi and Rutter 2003; MacDonald et al. 2006; Tsuboi et al. 2006) [Fig.”
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Cellular Fatty Acid Toxicity: Extrapolating Yeast Screens into Mammalian Models
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Authors: Barg, S., Eliasson, L., Renström, E., & Rorsman, P.
Affiliations: Lund University (SE)
From the Department of Molecular and Cellular Physiology, Institute of Physiology, Lund University, Lund, Sweden
ORCID: Barg, Sebastian
Eliasson, Lena
Rorsman, Patrik
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2002-02-01
Volume: 51
Issue: suppl_1
Pages: S74-S82
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.51.2007.s74
OpenAlex: W2050076638
Cited by: 227
References: 0
Citations by year: 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 4 · 2019: 10 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 14 · 2014: 6 · 2013: 8 · 2012: 14
FWCI: 3.18
Type: journal article
Language: en
Open access: closed
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Vetenskapsrådet
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords: insulin secretion, secretory granules, L-type calcium channels, first-phase insulin secretion, second-phase insulin secretion, pancreatic beta cells, V-ATPase, ClC-3 chloride channel, ATP/ADP ratio
MeSH terms: Insulin Secretion, Animals, Insulin, Islets of Langerhans, Calcium Channels, L-Type, Secretory Vesicles, Mice

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A Subset of 50 Secretory Granules in Close Contact With l-Type Ca2+ Channels Accounts for First-Phase Insulin Secretion in Mouse β-Cells

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