Glutamate Acts as a Key Signal Linking Glucose Metabolism to Incretin/cAMP Action to Amplify Insulin Secretion
Open accessAbstract
Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Glutamate may be co-released with insulin from human β-cells.
“Similarly, Vglut2 (SLC17A6) is expressed in human β-cells ((68) and glutamate may therefore be co-released with insulin from β-cells (205).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [205]
The Results section on glutamate transport into insulin granules reports that β-cell insulin granules can accumulate glutamate, and the Discussion links granular glutamate to insulin-granule exocytosis. This supports the possibility behind the claim, but the paper does not show glutamate being co-released with insulin from human β-cells; the experiments described here use cell lines and animal islets. Page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nauck, M. A., Heimesaat, M. M., Orskov, C., Holst, J. J., Ebert, R., & Creutzfeldt, W. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116186 · Cited by 1,651 · see citing works
Li, D.-Q., Jing, X., Salehi, A., Collins, S. C., Hoppa, M. B., Rosengren, A. H., Zhang, E., Lundquist, I., Olofsson, C. S., Mörgelin, M., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.011 · Cited by 50 · cited 1× · see citing works
“TheCl flux through the chloride transport protein ClC-3 in the insulin granule membrane has been shown to be required for GIIS (Li et al., 2009).”
BackgroundSelf-citation
Flagged first, then by citations
Research works printed but not linked: 59
- Ahrén B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes Nat. Rev. Drug Discov. 8 2009 369 385 19365392
- Aspinwall C.A. Brooks S.A. Kennedy R.T. Lakey J.R. Effects of intravesicular H+ and extracellular H+ and Zn2+ on insulin secretion in pancreatic beta cells J. Biol. Chem. 272 1997 31308 31314 9395458
- Bai L. Zhang X. Ghishan F.K. Characterization of vesicular glutamate transporter in pancreatic α - and β -cells and its regulation by glucose Am. J. Physiol. Gastrointest. Liver Physiol. 284 2003 G808 G814 12444014
- Bellocchio E.E. Reimer R.J. Fremeau R.T. Jr. Edwards R.H. Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter Science 289 2000 957 960 10938000
- Bertrand G. Ishiyama N. Nenquin M. Ravier M.A. Henquin J.C. The elevation of glutamate content and the amplification of insulin secretion in glucose-stimulated pancreatic islets are not causally related J. Biol. Chem. 277 2002 32883 32891 12087106
- Bos J.L. Epac proteins: multi-purpose cAMP targets Trends Biochem. Sci. 31 2006 680 686 17084085
- Brisson G.R. Malaisse-Lagae F. Malaisse W.J. The stimulus-secretion coupling of glucose-induced insulin release. VII. A proposed site of action for adenosine-3′,5′-cyclic monophosphate J. Clin. Invest. 51 1972 232 241 4333019 PMC302121
- Brozzi F. Lajus S. Diraison F. Rajatileka S. Hayward K. Regazzi R. Molnár E. Váradi A. MyRIP interaction with MyoVa on secretory granules is controlled by the cAMP-PKA pathway Mol. Biol. Cell 23 2012 4444 4455 22993210 PMC3496617
- Carobbio S. Frigerio F. Rubi B. Vetterli L. Bloksgaard M. Gjinovci A. Pournourmohammadi S. Herrera P.L. Reith W. Mandrup S. Maechler P. Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis J. Biol. Chem. 284 2009 921 929 19015267
- Casimir M. Lasorsa F.M. Rubi B. Caille D. Palmieri F. Meda P. Maechler P. Mitochondrial glutamate carrier GC1 as a newly identified player in the control of glucose-stimulated insulin secretion J. Biol. Chem. 284 2009 25004 25014 19584051 PMC2757205
- Cataland S. Crockett S.E. Brown J.C. Mazzaferri E.L. Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man J. Clin. Endocrinol. Metab. 39 1974 223 228 4423791
- Charles M.A. Fanska R. Schmid F.G. Forsham P.H. Grodsky G.M. Adenosine 3′,5′-monophosphate in pancreatic islets: glucose-induced insulin release Science 179 1973 569 571 4346825
- Delmeire D. Flamez D. Hinke S.A. Cali J.J. Pipeleers D. Schuit F. Type VIII adenylyl cyclase in rat beta cells: coincidence signal detector/generator for glucose and GLP-1 Diabetologia 46 2003 1383 1393 13680124
- Drucker D.J. The biology of incretin hormones Cell Metab. 3 2006 153 165 16517403
- Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes Lancet 368 2006 1696 1705 17098089
- Dyachok O. Idevall-Hagren O. Sågetorp J. Tian G. Wuttke A. Arrieumerlou C. Akusjärvi G. Gylfe E. Tengholm A. Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion Cell Metab. 8 2008 26 37 18590690
- Eliasson L. Ma X. Renström E. Barg S. Berggren P.O. Galvanovskis J. Gromada J. Jing X. Lundquist I. Salehi A. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells J. Gen. Physiol. 121 2003 181 197 12601083 PMC2217330
- Eto K. Tsubamoto Y. Terauchi Y. Sugiyama T. Kishimoto T. Takahashi N. Yamauchi N. Kubota N. Murayama S. Aizawa T. Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion Science 283 1999 981 985 9974390
- Gammelsaeter R. Coppola T. Marcaggi P. Storm-Mathisen J. Chaudhry F.A. Attwell D. Regazzi R. Gundersen V. A role for glutamate transporters in the regulation of insulin secretion PLoS ONE 6 2011 e22960 21853059 PMC3154915
- Goto Y. Kakizaki M. Masaki N. Spontaneous diabetes produced by selective breeding of normal Wistar rats Proc. Jpn. Acad. 51 1975 80 85
- Gras C. Herzog E. Bellenchi G.C. Bernard V. Ravassard P. Pohl M. Gasnier B. Giros B. El Mestikawy S. A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons J. Neurosci. 22 2002 5442 5451 12097496 PMC6758212
- Grill V. Cerasi E. Activation by glucose of adenyl cyclase in pancreatic islets of the rat FEBS Lett. 33 1973 311 314 4353994
- Henquin J.C. Triggering and amplifying pathways of regulation of insulin secretion by glucose Diabetes 49 2000 1751 1760 11078440
- Holst J.J. The physiology of glucagon-like peptide 1 Physiol. Rev. 87 2007 1409 1439 17928588
- Holst J.J. Knop F.K. Vilsbøll T. Krarup T. Madsbad S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes Diabetes Care 34 Suppl 2 2011 S251 S257 21525464 PMC3632188
- Høy M. Maechler P. Efanov A.M. Wollheim C.B. Berggren P.O. Gromada J. Increase in cellular glutamate levels stimulates exocytosis in pancreatic beta-cells FEBS Lett. 531 2002 199 203 12417312
- Iwasaki M. Minami K. Shibasaki T. Miki T. Miyazaki J. Seino S. Establishment of new clonal pancreatic β-cell lines (MIN6-K) useful for study of incretin/cyclic adenosine monophosphate signaling J. Diabetes Investig. 1 2010 137 142 PMC4008005 24843422
- Kanno T. Ma X. Barg S. Eliasson L. Galvanovskis J. Göpel S. Larsson M. Renström E. Rorsman P. Large dense-core vesicle exocytosis in pancreatic beta-cells monitored by capacitance measurements Methods 33 2004 302 311 15183179
- Kreymann B. Williams G. Ghatei M.A. Bloom S.R. Glucagon-like peptide-1 7-36: a physiological incretin in man Lancet 2 1987 1300 1304 2890903
- Kubota A. Maeda H. Kanamori A. Matoba K. Jin Y. Minagawa F. Obana M. Iemitsu K. Ito S. Amamiya H. Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients J. Diabetes Investig. 3 2012 503 509 PMC4015429 24843615
- MacDonald M.J. Evidence for the malate aspartate shuttle in pancreatic islets Arch. Biochem. Biophys. 213 1982 643 649 6462111
- MacDonald M.J. Fahien L.A. Glutamate is not a messenger in insulin secretion J. Biol. Chem. 275 2000 34025 34027 10967090
- Maechler P. Wollheim C.B. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis Nature 402 1999 685 689 10604477
- Matsubara T. Mita A. Minami K. Hosooka T. Kitazawa S. Takahashi K. Tamori Y. Yokoi N. Watanabe M. Matsuo E. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue Cell Metab. 15 2012 38 50 22225875
- Naito S. Ueda T. Adenosine triphosphate-dependent uptake of glutamate into protein I-associated synaptic vesicles J. Biol. Chem. 258 1983 696 699 6130088
- Omote H. Miyaji T. Juge N. Moriyama Y. Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport Biochemistry 50 2011 5558 5565 21612282
- Ostenson C.G. Khan A. Abdel-Halim S.M. Guenifi A. Suzuki K. Goto Y. Efendic S. Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat Diabetologia 36 1993 3 8 8436249
- Peyot M.L. Gray J.P. Lamontagne J. Smith P.J. Holz G.G. Madiraju S.R. Prentki M. Heart E. Glucagon-like peptide-1 induced signaling and insulin secretion do not drive fuel and energy metabolism in primary rodent pancreatic β-cells PLoS ONE 4 2009 e6221 19593440 PMC2704866
- Polonsky K.S. Given B.D. Hirsch L.J. Tillil H. Shapiro E.T. Beebe C. Frank B.H. Galloway J.A. Van Cauter E. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus N. Engl. J. Med. 318 1988 1231 1239 3283554
- Porte D. Jr. Banting lecture 1990. Beta-cells in type II diabetes mellitus Diabetes 40 1991 166 180 1991568
- Prentki M. Matschinsky F.M. Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion Physiol. Rev. 67 1987 1185 1248 2825225
- Rorsman P. Renström E. Insulin granule dynamics in pancreatic beta cells Diabetologia 46 2003 1029 1045 12879249
- Roseth S. Fykse E.M. Fonnum F. Uptake of L-glutamate into rat brain synaptic vesicles: effect of inhibitors that bind specifically to the glutamate transporter J. Neurochem. 65 1995 96 103 7790899
- Saeed A.I. Sharov V. White J. Li J. Liang W. Bhagabati N. Braisted J. Klapa M. Currier T. Thiagarajan M. TM4: a free, open-source system for microarray data management and analysis Biotechniques 34 2003 374 378 12613259
- Seino S. Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis Physiol. Rev. 85 2005 1303 1342 16183914
- Seino Y. Fukushima M. Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences J. Diabetes Investig. 1 2010 8 23 PMC4020673 24843404
- Seino S. Shibasaki T. Minami K. Dynamics of insulin secretion and the clinical implications for obesity and diabetes J. Clin. Invest. 121 2011 2118 2125 21633180 PMC3104758
- Shibasaki T. Takahashi H. Miki T. Sunaga Y. Matsumura K. Yamanaka M. Zhang C. Tamamoto A. Satoh T. Miyazaki J. Seino S. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP Proc. Natl. Acad. Sci. USA 104 2007 19333 19338 18040047 PMC2148290
- Siegel E.G. Creutzfeldt W. Stimulation of insulin release in isolated rat islets by GIP in physiological concentrations and its relation to islet cyclic AMP content Diabetologia 28 1985 857 861 2417905
- Song W.J. Seshadri M. Ashraf U. Mdluli T. Mondal P. Keil M. Azevedo M. Kirschner L.S. Stratakis C.A. Hussain M.A. Snapin mediates incretin action and augments glucose-dependent insulin secretion Cell Metab. 13 2011 308 319 21356520 PMC3053597
- Sugawara K. Shibasaki T. Mizoguchi A. Saito T. Seino S. Rab11 and its effector Rip11 participate in regulation of insulin granule exocytosis Genes Cells 14 2009 445 456 19335615
- Susini S. Roche E. Prentki M. Schlegel W. Glucose and glucoincretin peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic β(INS-1) cells FASEB J. 12 1998 1173 1182 9737720
- Takamori S. Rhee J.S. Rosenmund C. Jahn R. Identification of differentiation-associated brain-specific phosphate transporter as a second vesicular glutamate transporter (VGLUT2) J. Neurosci. 21 2001 RC182 11698620 PMC6762262
- Uehara S. Jung S.K. Morimoto R. Arioka S. Miyaji T. Juge N. Hiasa M. Shimizu K. Ishimura A. Otsuka M. Vesicular storage and secretion of L-glutamate from glucagon-like peptide 1-secreting clonal intestinal L cells J. Neurochem. 96 2006 550 560 16336630
- Vetterli L. Carobbio S. Pournourmohammadi S. Martin-Del-Rio R. Skytt D.M. Waagepetersen H.S. Tamarit-Rodriguez J. Maechler P. Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase Mol. Biol. Cell 23 2012 3851 3862 22875990 PMC3459861
- Weir G.C. Mojsov S. Hendrick G.K. Habener J.F. Glucagonlike peptide I (7-37) actions on endocrine pancreas Diabetes 38 1989 338 342 2645190
- Xie X.S. Stone D.K. Racker E. Determinants of clathrin-coated vesicle acidification J. Biol. Chem. 258 1983 14834 14838 6140265
- Xie X.S. Crider B.P. Stone D.K. Isolation and reconstitution of the chloride transporter of clathrin-coated vesicles J. Biol. Chem. 264 1989 18870 18873 2572598
- Yasuda T. Shibasaki T. Minami K. Takahashi H. Mizoguchi A. Uriu Y. Numata T. Mori Y. Miyazaki J. Miki T. Seino S. Rim2α determines docking and priming states in insulin granule exocytosis Cell Metab. 12 2010 117 129 20674857
Cited by
Sorted by citations
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Self-citationBalboa, D., Barsby, T., Lithovius, V., Saarimäki-Vire, J., Omar-Hmeadi, M., Dyachok, O., Montaser, H., Lund, P.-E., Yang, M., Ibrahim, H., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01219-z · Cited by 433 · see citing works
Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function
Rowlands, J., Heng, J., Newsholme, P., & Carlessi, R. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00672 · Cited by 302 · see citing works
The incretin system in healthy humans: The role of GIP and GLP-1
Holst, J. J. (2019) · Metabolism · doi:10.1016/j.metabol.2019.04.014 · Cited by 248 · see citing works
First-phase insulin secretion: can its evaluation direct therapeutic approaches?
Di Giuseppe, G., Ciccarelli, G., Soldovieri, L., Capece, U., Cefalo, C. M. A., Moffa, S., Nista, E. C., Brunetti, M., Cinti, F., Gasbarrini, A., et al. (2023) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2023.02.001 · Cited by 46 · see citing works
- Authors
- Gheni, G., Ogura, M., Iwasaki, M., Yokoi, N., Minami, K., Nakayama, Y., Harada, K., Hastoy, B., Wu, X., Takahashi, H., Kimura, K., Matsubara, T., Hoshikawa, R., Hatano, N., Sugawara, K., Shibasaki, T., Inagaki, N., Bamba, T., Mizoguchi, A., Fukusaki, E., Rorsman, P., & Seino, S.
- Affiliations
- Kobe University (JP)
- Kyoto University (JP)
- The University of Osaka (JP)
- Mie University (JP)
- Churchill Hospital (GB)
- Corresponding author
- Seino, Susumu
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 9
- Issue
- 2
- Pages
- 661-673
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4536302
- OpenAlex
- W2090433349
- Cited by
- 156
- References
- 2
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 13 · 2023: 9 · 2022: 18 · 2021: 19 · 2020: 6 · 2019: 14 · 2018: 10 · 2017: 21 · 2016: 11 · 2015: 16 · 2014: 1
- FWCI
- 15.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kobe University Repository Kernel (Kobe University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Core Research for Evolutional Science and Technology
- Canadian Institutes of Health Research
- Ministry of Education, Culture, Sports, Science and Technology
- Wellcome Trust
- Japan Science and Technology Agency
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glutamate, insulin secretion, incretins, cAMP signaling, glucose metabolism, malate-aspartate shuttle, pancreatic beta cells, insulin granules, glucose homeostasis, diabetes mellitus, obesity, PKA signaling, metabolomics
- MeSH terms
- Cyclic AMP, Animals, Cells, Cultured, Cytoplasm, Exocytosis, Glucose, Insulin, Male, Signal Transduction, Rats, Wistar, Cyclic AMP-Dependent Protein Kinases, Glutamic Acid, Secretory Vesicles, Cell Line, Tumor, Insulin-Secreting Cells, Mice, Rats, Incretins, Metabolome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
