The Changes in Adenine Nucleotides Measured in Glucose-stimulated Rodent Islets Occur in β Cells but Not in α Cells and Are Also Observed in Human Islets
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Glucose metabolism by pancreatic beta and alpha cells is essential for stimulation of insulin secretion and inhibition of glucagon secretion. Studies using rodent islets have suggested that the ATP/ADP ratio serves as second messenger in beta cells. This study compared the effects of glucose on glucose oxidation ([U-14C]glucose) and adenine nucleotides (luminometric method) in purified rat alpha and beta cells. The rate of glucose oxidation at 1 mM glucose was higher in beta than alpha cells (4.5-fold, i.e. approximately 2-fold after normalization for cell size). It was more strongly stimulated by 10 mM glucose in beta cells (9-fold) than in alpha cells (5-fold). At 1 mM glucose, ATP levels were similar in both cell types, which corresponds to an approximately 2-fold higher concentration in alpha cells ( approximately 6.5 mM) than in beta cells ( approximately 3 mM). In beta cells, glucose dose-dependently increased ATP and decreased ADP levels, causing a rise in the ATP/ADP ratio from 2.4 to 11.6 at 1 and 10 mM, respectively. In alpha cells, glucose did not affect ATP and ADP levels, and the ATP/ADP ratio remained stable around 7.5. In human islets, the ATP/ADP ratio progressively increased between 1 and 10 mM glucose. In duct cells, which often contaminate human islet preparations, an increase in the ATP/ADP ratio sometimes occurred between 1 and 3 mM glucose. In conclusion, the present observations establish that the regulation of glucagon secretion by glucose does not involve changes in alpha cell adenine nucleotides and further support the role of the ATP/ADP ratio in the control of insulin secretion.
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Biochemical measurements of [ATP]i in purified rat β-cells suggest ATP is ~2 mM under basal conditions and rises to 4 mM when glucose is increased to 10 mM.
“These values are in broad agreement with biochemical measurements of [ATP]i in purified rat β-cells which suggest ATP is ~2 mM under basal conditions and rises to 4 mM when glucose is increased to 10 mM (142) (see v).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [142]
The Discussion reports that ATP concentration in purified rat β-cells rose when glucose increased from 1 to 10 mM, supporting the direction of the claim. But it calculates a rise from approximately 3 to 7 mM, not 2 to 4 mM, and cautions that these values do not exactly represent cytoplasmic concentrations. (LLM, conf=0.88)
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“It has been estimated that ATP concentration inside the -cell is already higher than 1 mm at low glucose (27), suggesting that the fraction of closed KATP channels in -cells may actually exceed 93%.”
BackgroundLee, B., Miles, P. D. G., Vargas, L., Luan, P., Glasco, S., Kushnareva, Y., Kornbrust, E. S., Grako, K. A., Wollheim, C. B., Maechler, P., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.4.965 · Cited by 73 · see citing works
Stronger control of ATP/ADP by proton leak in pancreatic β-cells than skeletal muscle mitochondria
Affourtit, C., & Brand, M. D. (2006) · Biochemical Journal · doi:10.1042/bj20051280 · Cited by 71 · see citing works
Hinke, S. A., Hellemans, K., & Schuit, F. C. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.064881 · Cited by 70 · see citing works
“1978), and in the ATP/ADP ratio (Detimary et al. 1998); in concert an anabolic flux called cataplerosis (Farfari et al.”
BackgroundSelf-citationde Marchi, U., Thévenet, J., Hermant, A., Dioum, E., & Wiederkehr, A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.513184 · Cited by 68 · see citing works
“In the pancreatic beta cell, after nutrient stimulation the phosphorylation potential is even elevated despite an augmented energy demand (7, 28, 29, 35).”
BackgroundSubmembrane ATP and Ca2+kinetics in α-cells: unexpected signaling for glucagon secretion
Li, J., Yu, Q., Ahooghalandari, P., Gribble, F. M., Reimann, F. M., Tengholm, A., & Gylfe, E. (2015) · The FASEB Journal · doi:10.1096/fj.14-265918 · Cited by 67 · see citing works
Adenine nucleotide regulation in pancreatic β-cells: modeling of ATP/ADP-Ca2+interactions
Fridlyand, L. E., Ma, L., & Philipson, L. H. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00595.2004 · Cited by 66 · see citing works
“In contrast to -cells, no increase in the [ATP]/[ADP] value was found in purified rat -cells following an increase in [Glc] (18).”
Complexin I regulates glucose-induced secretion in pancreatic β-cells
Abderrahmani, A., Niederhäuser, G., Plaisance, V., Roehrich, M.-E., Lenain, V., Coppola, T., Regazzi, R., & Waeber, G. (2004) · Journal of Cell Science · doi:10.1242/jcs.01041 · Cited by 65 · see citing works
Quesada, I., Todorova, M. G., & Soria, B. (2006) · Biophysical Journal · doi:10.1529/biophysj.105.069906 · Cited by 63 · see citing works
Schwanstecher, C., Neugebauer, B., Schulz, M., & Schwanstecher, M. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s363 · Cited by 62 · see citing works
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“It has been shown that α cells contain many KATP channels and already have a high ATP/ADP ratio in the absence of glucose (32, 33).”
BackgroundAMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells
Leclerc, I., Sun, G., Morris, C., Fernández‐Millán, E., Nyirenda, M., & Rutter, G. A. (2010) · Diabetologia · doi:10.1007/s00125-010-1929-z · Cited by 54 · see citing works
“Hence, glucose-induced changes in total adenine nucleotide levels were difficult to demonstrate in FACS-purified rat alpha cells [38].”
Martens, G. A., Vervoort, A., de Casteele, M. V., Stangé, G. M., Hellemans, K., Thi, H. V. V., Schuit, F. C., & PIPELEERS, D. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700083200 · Cited by 58 · see citing works
Self-citationMarchand, S. L., & Piston, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047084 · Cited by 57 · see citing works
“6A, [1]), that would lead to greater ATP concentrations in a-cells, as reported in [33].”
BackgroundCellular Origin of Hexokinase in Pancreatic Islets
Schuit, F. C., Moens, K., Heimberg, H., & PIPELEERS, D. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32803 · Cited by 58 · see citing works
Self-citationPharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
Martin, G. M., Chen, P., Devaraneni, P. K., & Shyng, S. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00386 · Cited by 52 · see citing works
Yang, J., Wong, R., Park, M., Wu, J., Cook, J. R., York, D. A., Deng, S., Markmann, J. F., Naji, A., Wolf, B. A., et al. (2006) · PubMed · Cited by 54 · see citing works
Koeslag, J. H., Saunders, P. T., & Terblanche, E. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.037895 · Cited by 53 · see citing works
“Variations in glucose concentrations from 1 to 10 mmol l_1 therefore do not result in changes in ADP/ATP ratio in fluorescence-activated cellsorter-purified a-cells (Heimberg et al. 1995; Detimary et al. 1998).”
BackgroundNutrient regulation of glucagon secretion: involvement in metabolism and diabetes
Marroquí, L., Alonso‐Magdalena, P., Merino, B., Fuentes, E., Nadal, Á., & Quesada, I. (2014) · Nutrition Research Reviews · doi:10.1017/s0954422414000031 · Cited by 55 · see citing works
“differences existing between both islet cell types((32)).”
Yang, J., Wong, R., Park, M., Wu, J., Cook, J. R., York, D. A., Deng, S., Markmann, J. F., Naji, A., Wolf, B. A., et al. (2006) · Diabetes · doi:10.2337/diabetes.55.01.06.db05-0938 · Cited by 54 · see citing works
Xia, F., Leung, Y., Gaisano, G., Gao, X., Chen, Y., Fox, J. E. M., Bhattacharjee, A., Wheeler, M. B., Gaisano, H. Y., & Tsushima, R. G. (2007) · Endocrinology · doi:10.1210/en.2006-1296 · Cited by 54 · see citing works
The Flaws and Future of Islet Volume Measurements
Huang, H.-H., Harrington, S., & Stehno‐Bittel, L. (2018) · Cell Transplantation · doi:10.1177/0963689718779898 · Cited by 53 · see citing works
Transduction of Human Islets with Pseudotyped Lentiviral Vectors
Kobinger, G., Deng, S., Louboutin, J., Vatamaniuk, M., Matschinsky, F., Markmann, J., Raper, S., & Wilson, J. M. (2004) · Human Gene Therapy · doi:10.1089/104303404772680010 · Cited by 84 · see citing works
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“When the concentration of glucose increases, islet cell metabolism accelerates [27e29], and the ratio of cytosolic ATP to ADP augments in a concentration-dependent manner [29,30], which closes KATP channels in the b-cell membrane [10,31].”
BackgroundSelf-citationNucleotide Sensitivity of Pancreatic ATP-Sensitive Potassium Channels and Type 2 Diabetes
Schwanstecher, C., & Schwanstecher, M. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s358 · Cited by 49 · see citing works
“It has not been proven that adenine nucleotides are the main or sole regulators of the KATP channel in intact -cells, but the variations of channel activity in patches with fluctuation of nucleotide concentrations around the physiological values (30) and evidence that the cytosolic ATP-to-ADP ratio changes over a wide…”
BackgroundTrites, M. J., & Clugston, R. D. (2019) · Lipids in Health and Disease · doi:10.1186/s12944-019-1151-z · Cited by 48 · see citing works
Glucose-dependent docking and SNARE protein-mediated exocytosis in mouse pancreatic alpha-cell
Andersson, S. A., Pedersen, M. G., Vikman, J., & Eliasson, L. (2011) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-011-0979-5 · Cited by 46 · see citing works
“Escalating glucose concentrations results in a concentration-dependent acceleration of glucose metabolism in both alpha- and beta-cells [8].”
Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion
Watts, M., & Sherman, A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.4504 · Cited by 45 · see citing works
“Some studies report no change (23,36), but others show an increase in ATP with glucose (6,37,38).”
BackgroundA pathway model of glucose-stimulated insulin secretion in the pancreatic β-cell
Maheshvare, M. D., Raha, S., König, M., & Pal, D. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1185656 · Cited by 43 · see citing works
“Detimary, 1998 (55) 9852040 ATP, ADP, ATP+ADP, ATP/ADP Wistar rats”
Fast and cAMP-Sensitive Mode of Ca2+-Dependent Exocytosis in Pancreatic β-Cells
Kasai, H., Suzuki, T., Liu, T., Kishimoto, T. E., & Takahashi, N. K. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s19 · Cited by 42 · see citing works
Physiological characterization of the human EndoC-βH1 β-cell line
Gurgul-Convey, E., Kaminski, M. T., & Lenzen, S. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.05.072 · Cited by 41 · see citing works
Mitochondrial metabolism and dynamics in pancreatic beta cell glucose sensing
Rutter, G. A., Sidarala, V., Kaufman, B. A., & Soleimanpour, S. A. (2023) · Biochemical Journal · doi:10.1042/bcj20230167 · Cited by 39 · see citing works
Quantal ATP release in rat β-cells by exocytosis of insulin-containing LDCVs
Karanauskaite, J., Hoppa, M. B., Braun, M., Galvanovskis, J., & Rorsman, P. (2008) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-008-0610-6 · Cited by 37 · see citing works
“Pancreatic β-cells contain 4 fmol of ATP per cell [22] of which 30% is stored in the ∼10,000 insulincontaining secretory granules [14].”
BackgroundSaito, T., Okada, S., Yamada, E., Ohshima, K., Shimizu, H., Shimomura, K., Sato, M., Pessin, J. E., & Mori, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305114200 · Cited by 37 · see citing works
Zaborska, K. E., Dadi, P. K., Dickerson, M. T., Nakhe, A. Y., Thorson, A. S., Schaub, C. M., Graff, S. M., Stanley, J. E., Kondapavuluru, R. S., Denton, J. S., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101056 · Cited by 32 · see citing works
“However, glucose-induced ATP production in a-cells is significantly lower than in b-cells [34,69] and the ATP/ADP ratio is much higher in a-cells compared to b-cells under low-glucose conditions [15].”
BackgroundDoliba, N. M., Wehrli, S. L., Vatamaniuk, M. Z., Qin, W. D., Buettger, C. W., Collins, H. W., & Matschinsky, F. M. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00282.2006 · Cited by 36 · see citing works
“Measurements of intracellular ATP concentration ([ATP]i) in purified rat -cells suggest that [ATP]i is 2 mmol/l (2 pmol/10(3) cells) in the absence of glucose and increases to 4 mmol/l cells ( 4 pmol/10(3) cells) when glucose is raised to 10 mmol/l (8).”
BackgroundRavier, M. A., Eto, K., Jonkers, F. C., Nenquin, M., Kadowaki, T., & Henquin, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.3.1587 · Cited by 36 · see citing works
Self-citationCharacterization of Islet Preparations
Colton, C. K., Papas, K. K., Pisania, A., Rappel, M. J., Powers, D. E., O’Neil, J. J., Omer, A., Weir, G. C., & Bonner‐Weir, S. (2007) · Elsevier eBooks · doi:10.1016/b978-012369415-7/50007-7 · Cited by 35 · see citing works
Leucine Culture Reveals That ATP Synthase Functions as a Fuel Sensor in Pancreatic β-Cells
Yang, J., Wong, R., Wang, X., Moibi, J. A., Hessner, M. J., Greene, S. R., Wu, J., Sukumvanich, S. S., Wolf, B. A., & Gao, Z. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405309200 · Cited by 35 · see citing works
Aggarwal, S., Giri, S., Ribnicky, D., Burk, D. H., Karki, N., & Wang, M. S. Q. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.05.003 · Cited by 34 · see citing works
“Further, since β cells have glucose-sensing property, the glucose–induced changes in energy state of β cells and are associated with insulin release (Detimary et al., 1998; Detimary et al., 1995).”
The Shifting Landscape of KAtpChannelopathies and the Need for ‘Sharper’ Therapeutics
Kharade, S. V., Nichols, C. G., & Denton, J. S. (2016) · Future Medicinal Chemistry · doi:10.4155/fmc-2016-0005 · Cited by 34 · see citing works
Grubelnik, V., Markovič, R., Lipovšek, S., Leitinger, G., Gosak, M., Dolenšek, J., Valladolid-Acebes, I., Berggren, P.-O., Stožer, A., Perc, M., et al. (2020) · Royal Society Open Science · doi:10.1098/rsos.191171 · Cited by 32 · see citing works
“Additionally, the values of JGPDH are comparable with experimentally measured values at 1 and 10 mM glucose [34,36].”
BackgroundMethodContribution of Mitochondria to Insulin Secretion by Various Secretagogues
Ježek, P., Holendová, B., Jabůrek, M., Dlasková, A., & Plecitá‐Hlavatá, L. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0113 · Cited by 32 · see citing works
“With isolated rat PIs, elevations from resting 2 mM up to insulin-stimulating 4 mM [ATP] (at 10 mM [glucose]) were found (43), while AC50 at *3 mM was reported for the total ATP rise and 50% KATP closure in mouse PIs, not correlating with AC50 of*12 mM for GSIS (210).”
MethodAn adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells
Schulze, D., Düfer, M., Wieringa, B., Krippeit‐Drews, P., & Drews, G. (2007) · Diabetologia · doi:10.1007/s00125-007-0742-9 · Cited by 32 · see citing works
“The bulk ATP concentration in beta cells ranges between 3 and 5 mmol/l at high glucose concentration [1–3].”
BackgroundEffects of Glucose and Amino Acids on Free ADP in βHC9 Insulin-Secreting Cells
Ronner, P., Naumann, C. M., & Friel, E. (2001) · Diabetes · doi:10.2337/diabetes.50.2.291 · Cited by 32 · see citing works
Metabolic regulation of glucagon secretion
Armour, S. L., Stanley, J. E., Cantley, J., Dean, E. D., & Knudsen, J. G. (2023) · Journal of Endocrinology · doi:10.1530/joe-23-0081 · Cited by 30 · see citing works
Anello, M., Spampinato, D., Piro, S., Purrello, F., & Rabuazzo, A. M. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00320.2003 · Cited by 30 · see citing works
“In particular, the increase of the ATP-to-ADP (ATP/ADP) ratio tightly associates to glucose-induced insulin granules release (1, 6, 7).”
BackgroundDiderichsen, P. M., & Göpel, S. (2006) · Journal of Biological Physics · doi:10.1007/s10867-006-9013-0 · Cited by 30 · see citing works
“Studies on dispersed α-cells indicate that the ATP/ADP ratio remains unaffected by glucose [9].”
Piro, S., Rabuazzo, A. M., Renis, M., & Purrello, F. (2012) · PubMed · doi:10.3275/7866 · Cited by 29 · see citing works
Phosphocreatine as a determinant of KATP channel activity in pancreatic β-cells
Krippeit-Drews, P., Backer, M., Düfer, M., & Drews, G. (2003) · Pflügers Archiv · doi:10.1007/s00424-002-0975-x · Cited by 22 · see citing works
“The ATP concentration in the b-cell is estimated to be high in the range of 3 to 5 mM [3, 9].”
BackgroundLu, Y., Xu, J., Li, Y., Wang, R., Dai, C., Zhang, B., Zhang, X., Xu, L., Tao, Y., Han, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.ade8647 · Cited by 28 · see citing works
Intercellular Communication in the Islet of Langerhans in Health and Disease
Ng, X. W., Chung, Y. H., & Piston, D. W. (2021) · Comprehensive physiology · doi:10.1002/cphy.c200026 · Cited by 39 · see citing works
Spégel, P., Andersson, L. E., Storm, P., Sharoyko, V. V., Göhring, I., Rosengren, A. H., & Mulder, H. (2015) · Endocrinology · doi:10.1210/en.2014-1391 · Cited by 25 · see citing works
“Notably, the coupling of cytosolic and mitochondrial metabolism has been shown to be much less efficient in the than in the -cell (35, 36).”
BackgroundAnello, M., Ucciardello, V., Piro, S., Patanè, G., Frittitta, L., Calabrese, V., Stella, A. M. G., Vigneri, R., Purrello, F., & Rabuazzo, A. M. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.5.e1082 · Cited by 25 · see citing works
“Because ADP may antagonize the effect of ATP on KATP 1 channels (24), and the ATP-to-ADP ratio plays a critical role and tightly regulates glucose-induced insulin release in both rodent (8) and human islets (7), these alterations may be the cause of the reduced insulin secretion in islets chronically exposed to high l…”
BackgroundChapter 17 Glucose, Regulator of Survival and Phenotype of Pancreatic Beta Cells
Martens, G. A., & PIPELEERS, D. G. (2009) · Vitamins and hormones · doi:10.1016/s0083-6729(08)00617-1 · Cited by 24 · see citing works
Self-citation
- Authors
- Detimary, P., Dejonghe, S., Ling, Z., Pipeleers, D., Schuit, F., & Henquin, J.-C.
- Affiliations
- UCLouvain (BE)
- Vrije Universiteit Brussel (BE)
- Corresponding author
- Henquin, Jean-Claude
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-12
- Volume
- 273
- Issue
- 51
- Pages
- 33905-33908
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2023149007
- Cited by
- 159
- References
- 38
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 8 · 2022: 2 · 2021: 7 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 9 · 2014: 13 · 2013: 8 · 2012: 6
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion)
- Funders
- Fédération Wallonie-Bruxelles
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- adenine nucleotides, ATP/ADP ratio, pancreatic beta cells, alpha cells, glucose oxidation, insulin secretion, glucagon secretion, second messengers, human islets, duct cells
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Adult, Animals, Cells, Cultured, Glucose, Glycolysis, Humans, Islets of Langerhans, Kinetics, Male, Middle Aged, Species Specificity, Rats, Wistar, Rats
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