Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis
Open accessAbstract
How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function.
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GLUT2 neuronal knockout mice exhibit impaired GSIS, hyperglucagonemia, and decreased beta-cell proliferation and mass compared to controls.
“One study clearly demonstrated the importance of the nervous system’s ability to regulate islet beta-cell number and function: GLUT2 neuronal knockout mice exhibited impaired glucose-stimulated insulin secretion (GSIS), hyperglucagonemia, and decreased beta-cell proliferation and mass in comparison to controls.166”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [166]
Treatment of control mice with ganglionic blocker chlorisondamine reduced beta-cell proliferation rate by 50%, but in GLUT2 neuronal knockout mice, chlorisondamine did not further reduce proliferation rate.
“Importantly, treatment of the control mice with the ganglionic blocker chlorisondamine reduced the proliferation rate of beta-cells by 50%, but in GLUT2 neuronal knockout mice, chlorisondamine did not further reduce the proliferation rate.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [166]
Dysfunctional neuronal regulation of pancreatic islets may contribute to impaired GSIS, hyperglucagonemia, and decreased beta-cell proliferation and mass in T2D.
“T2D patients do not exhibit the cephalic phase of insulin secretion and based on the findings from studies it is possible that dysfunctional neuronal regulation of pancreatic islets contributes to the impaired GSIS, hyperglucagonemia, and decreased beta-cell proliferation and mass observed in this disease.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [166]
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BackgroundMarín‐Juez, R., Rovira, M., Crespo, D., van der Vaart, M., Spaink, H. P., & Planas, J. V. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.171 · Cited by 49 · see citing works
MicroRNA-21 promotes pancreatic β cell function through modulating glucose uptake
Liu, R., Liu, C., He, X., Sun, P., Zhang, B., Yang, H., Shi, W., & Ruan, Q. (2022) · Nature Communications · doi:10.1038/s41467-022-31317-0 · Cited by 48 · see citing works
Intestinal nutrient sensing and blood glucose control
Zietek, T., & Daniel, H. (2015) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000187 · Cited by 42 · see citing works
Postnatal β-Cell Proliferation and Mass Expansion Is Dependent on the Transcription Factor Nkx6.1
Taylor, B. L., Benthuysen, J. R., & Sander, M. (2014) · Diabetes · doi:10.2337/db14-0684 · Cited by 39 · see citing works
“Glucose has been identified as a systemic factor that stimulates b-cell proliferation (8,9), and recent studies suggest that glucose is a significant driver of early postnatal b-cell proliferation (10).”
BackgroundBrain glucose sensing, glucokinase and neural control of metabolism and islet function
Ogunnowo-Bada, E., Heeley, N., Brochard, L., & Evans, M. L. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12334 · Cited by 40 · see citing works
“Recent data suggest that, in addition to effects on insulin secretion, brain glucose sensing acting via pancreatic innervation may control β-cell mass [24].”
How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes?
Deem, J. D., Muta, K., Scarlett, J. M., Morton, G. J., & Schwartz, M. W. (2017) · Diabetes · doi:10.2337/dbi16-0067 · Cited by 39 · see citing works
“How are b-cells affected when the brain cannot sense glucose properly? On the basis of the brain-specific Glut2 deletion mouse model, the consequences include not only impaired cephalic and first-phase insulin secretion and glucose intolerance but also reduced b-cell mass and altered responsiveness to hypoglycemia (73…”
BackgroundExploring inter-organ crosstalk to uncover mechanisms that regulate β-cell function and mass
Shirakawa, J., Jesus, D. F. D., & Kulkarni, R. (2017) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2017.13 · Cited by 39 · see citing works
A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion
Picard, A., Soyer, J., Berney, X., Tarussio, D., Quenneville, S., Jan, M., Grouzmann, E., Burdet, F., Ibberson, M., & Thorens, B. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.041 · Cited by 35 · see citing works
Self-citationNeuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion.
Thorens, B. (2024) · Physiological Reviews · doi:10.1152/physrev.00038.2023 · Cited by 31 · see citing works
“This defect, together with the loss of vagally controlled fi rst-phase insulin secretion, induces a progressive development of glucose intolerance (107).”
BackgroundInfluentialSelf-citationThe autonomic nervous system regulates pancreatic β-cell proliferation in adult male rats
Moullé, V. S. F., Tremblay, C. C., Castell, A., Vivot, K., Éthier, M., Fergusson, G., Alquier, T., Ghislain, J. J., & Poitout, V. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00385.2018 · Cited by 32 · see citing works
Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus
Le, J., Chen, Y., Yang, W., Chen, L., & Ye, J. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.09.004 · Cited by 29 · see citing works
Neonatal pancreatic pericytes support β-cell proliferation
Epshtein, A., Rachi, E., Sakhneny, L., Mizrachi, S., Baer, D., & Landsman, L. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.07.010 · Cited by 30 · see citing works
Klf6 protects β-cells against insulin resistance-induced dedifferentiation
Dumayne, C., Tarussio, D., Sánchez-Archidona, A. R., Picard, A., Basco, D., Berney, X. P., Ibberson, M. R., & Thorens, B. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.02.001 · Cited by 26 · see citing works
“b-cell mass was measured by histomorphometry [21,23].”
Self-citationDuszka, K., Picard, A., Ellero‐Simatos, S., Chen, J., Defernez, M., Paramalingam, E., Pigram, A., Vanoaica, L., Canlet, C., Parini, P., et al. (2016) · Scientific Reports · doi:10.1038/srep36937 · Cited by 26 · see citing works
Self-citationQuenneville, S., Labouèbe, G., Basco, D., Metref, S., Viollet, B., Foretz, M., & Thorens, B. (2020) · Diabetes · doi:10.2337/db20-0577 · Cited by 25 · see citing works
“) with 6-h fasted mice, as previously described (26).”
MethodSelf-citationImaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective
Iozzo, P., & Guzzardi, M. A. (2019) · Endocrine Connections · doi:10.1530/ec-19-0348 · Cited by 24 · see citing works
Neuronal regulation of glucagon secretion and gluconeogenesis
Thorens, B. (2022) · Journal of Diabetes Investigation · doi:10.1111/jdi.13745 · Cited by 24 · see citing works
Self-citationInnervation modulates the functional connectivity between pancreatic endocrine cells
Yang, Y. H. C., Briant, L. J. B., Raab, C. A., Mullapudi, S. T., Maischein, H., Kawakami, K., & Stainier, D. Y. R. (2022) · eLife · doi:10.7554/elife.64526 · Cited by 23 · see citing works
“It has been proposed that glucose sensing neurons regulate early postnatal beta cell proliferation and maintenance of beta cell function ( Tarussio et al., 2014 ), and our data support the peri-islet localization of such neurons.”
Augustin, R., & Mayoux, E. (2014) · InTech eBooks · doi:10.5772/58325 · Cited by 23 · see citing works
Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase
Steinbusch, L. K. M., Picard, A., Bonnet, M. S., Basco, D., Labouèbe, G., & Thorens, B. (2016) · Diabetes · doi:10.2337/db15-1514 · Cited by 23 · see citing works
Self-citationFgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis
Picard, A., Metref, S., Tarussio, D., Dolci, W., Berney, X. P., Croizier, S., Labouèbe, G., & Thorens, B. (2021) · Diabetes · doi:10.2337/db20-1121 · Cited by 22 · see citing works
“Autonomic Nervous System Activity Recording The firing rates of the thoracic branch of both vagal and sympathetic nerves along the carotid artery were recorded as previously described (30,31).”
MethodSelf-citationAutophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity
Tutas, J., Tolve, M., Ozer, E., Ickert, L., Klein, I., Silverman, Q., Liebsch, F., Dethloff, F., Giavalisco, P., Endepols, H., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-024-01196-4 · Cited by 20 · see citing works
“Hence, we generated double KO mice with Slc2a2 inactivation by crossing previously described Slc2a2 floxed mice 62,63 with the ATG5 cKO mice (Fig.”
Self-citationMoullé, V. S. F. (2021) · Peptides · doi:10.1016/j.peptides.2021.170709 · Cited by 18 · see citing works
Strembitska, A., Labouèbe, G., Picard, A., Berney, X. P., Tarussio, D., Jan, M., & Thorens, B. (2022) · Nature Communications · doi:10.1038/s41467-022-33484-6 · Cited by 18 · see citing works
Self-citationHypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis
Ma, Y., Ratnasabapathy, R., Izzi‐Engbeaya, C. N., Nguyen‐Tu, M., Richardson, E., Hussain, S., Backer, I. D., Holton, C. M., Norton, M., Carrat, G., et al. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13359 · Cited by 17 · see citing works
Gervais, M., Labouèbe, G., Picard, A., Thorens, B., & Croizier, S. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000680 · Cited by 17 · see citing works
Self-citationBarahona, M. J., Langlet, F., Labouèbe, G., Croizier, S., Picard, A., Thorens, B., & García, M. D. L. Á. (2022) · Scientific Reports · doi:10.1038/s41598-022-22489-2 · Cited by 15 · see citing works
Self-citationBrain substrate metabolism and ß‐cell function in humans: A positron emission tomography study
Rebelos, E., Mari, A., Bucci, M., Honka, M., Hannukainen, J. C., Virtanen, K. A., Hirvonen, J., Nummenmaa, L., Heni, M., Iozzo, P., et al. (2020) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.136 · Cited by 14 · see citing works
da Luz, G., Frederico, M. J. S., Castro, A. J. G., Moraes, A. L. L., de Carvalho, F. K., Espíndola, L., Schmidt, É. C., Bouzon, Z. L., Pizzolatti, M. G., & Silva, F. R. M. B. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.04.027 · Cited by 14 · see citing works
“These results are in line with the pathways activated by nutraceuticals for insulin secretion by changing β-cell membrane potential, secretion of glucagon-like peptide 1 and glucose-induced insulin secretion [33,42] or, in a long-term effect, the stimulation on β-cell proliferation [43].”
ResultYang, M., Chen, Y., Vagionitis, S., Körtvely, E., Ueffing, M., Schmachtenberg, O., Hu, Z., Jiao, K., & Paquet‐Durand, F. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15533 · Cited by 13 · see citing works
Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production
Semplici, F., Mondragon, A., Macintyre, B., Madeyski-Bengston, K., Persson-kry, A., Barr, S., Ramne, A., Marley, A. E., McGinty, J., French, P. M. W., et al. (2016) · Diabetologia · doi:10.1007/s00125-016-4025-1 · Cited by 13 · see citing works
“The signalling pathways controlling glucagon secretion are less well defined and may involve a more dominant role for neural and hormonal control [13], as well as the cell-intrinsic actions of glucose.”
BackgroundSelf-citationDevelopment of the central nervous system
Cabej, N. R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85154-1.00003-5 · Cited by 12 · see citing works
Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes
Li, W. (2022) · Molecules · doi:10.3390/molecules27186117 · Cited by 10 · see citing works
“This effect appeared to be related to the restoration of glucose-stimulated insulin secretion and an increase in β-cell mass, suggesting that hypothalamic ceramides can regulate insulin secretion and even β-cell mass by inhibiting parasympathetic activity [96].”
BackgroundHypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS
Sato, K., Idelevich, A., Nagano, K., Rowe, G. C., Gori, F., & Baron, R. (2017) · Aging · doi:10.18632/aging.101157 · Cited by 8 · see citing works
Pancreatic Pericytes in Glucose Homeostasis and Diabetes
Landsman, L. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-11093-2_2 · Cited by 7 · see citing works
Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow
Lei, H., Preitner, F., Labouèbe, G., Rolf Gruetter, A., & Thorens, B. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18766743 · Cited by 6 · see citing works
Self-citationERRγ—A New Player in β Cell Maturation
Shirakawa, J., & Kulkarni, R. N. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.026 · Cited by 4 · see citing works
Kiba, T. (2025) · Cells · doi:10.3390/cells14171371 · Cited by 3 · see citing works
“Mice with glucose transporter type 2 (GLUT2) neuronal knockout demonstrated reduced insulin secretion (in response to glucose, elevated glucagon levels, and lower β -cell proliferation and mass compared to control mice [93]).”
Brain Nutrient Sensing: A Unifying Framework
Blouet, C., & Schwartz, G. J. (2025) · Annual Review of Physiology · doi:10.1146/annurev-physiol-042324-100329 · Cited by 1 · see citing works
“Conversely, impairments in brain glucose sensing, such as through the deletion of neuronal Glut2 or Gck, adversely affect peripheral glucose regulation (154; 155), suggesting a causal link between reduced brain glucose sensing and the development of dysfunctional glycemic control.”
Su, Q., Yuan, F., Li, X., Wang, X., Yang, K., Li, W., & Li, W. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.03.074 · Cited by 1 · see citing works
Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activityPreprint
Tutas, J., Tolve, M., Özer-Yildiz, E., Ickert, L., Klein, I., Hosseini, M., Liebsch, F., Dethloff, F., Gavalisco, P., Endepols, H., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.27.577372 · Cited by 1 · see citing works
Self-citationDétection cérébrale du glucose et homéostasie du glucose
Thorens, B., & Labouèbe, G. (2021) · Médecine des Maladies Métaboliques · doi:10.1016/j.mmm.2021.05.004
Self-citationPancreatic Brsk2 amplifies parasympathetic signals to promote type 2 diabetesPreprint
Xu, R., Wang, K., Yao, Z., Li, J., Pang, J., Zhou, Y., Wang, K., Liu, D., Zhang, Y., Sun, P. G., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.05.455219
Amouyal, C., Chen, S. P., Denom, J., Raho, I., Kassis, N., Diedisheim, M., Mifsud, F., Lallement, J., Georgiadou, E., Ibberson, M. R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.14.653935
“These results suggest that de novo ceramide synthesis in β-cells could regulate insulin secretion in vivo by modulation of the parasympathetic action through the regulation of a well-known receptor that controls insulin secretion [30].”
Self-citationRisk of dementia in diabetes mellitus: a mechanistic endeavor
Samanta, S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-33355-2.00029-3
Insulinorésistance musculaire : rôle du métabolisme des sphingolipides
Bandet, C. L. (2018) · theses.fr (ABES) · doi:10.70675/65c550d9z994bz4a63zb9c0z06c86e8645cd
- Authors
- Tarussio, D., Metref, S., Seyer, P., Mounien, L., Vallois, D., Magnan, C., Foretz, M., & Thorens, B.
- Affiliations
- University of Lausanne (CH)
- Institut de Génomique Fonctionnelle (FR)
- Aix-Marseille Université (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Thorens, Bernard
- Venue
- Journal of Clinical Investigation
- Published
- 2013-12-16
- Volume
- 124
- Issue
- 1
- Pages
- 413-424
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3871223
- OpenAlex
- W2107581350
- Cited by
- 71
- References
- 61
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 9 · 2016: 8 · 2015: 5 · 2014: 9
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (113525, 31003A, 128657)
- Université de Lausanne
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- GLUT2, beta-cell proliferation, beta-cell mass, glucose homeostasis, parasympathetic nerve activity, sympathetic activity, insulin secretion, glucagon secretion, impaired glucose tolerance, high-fat diet, postnatal development, ganglionic blockade, carbohydrate-free diet
- MeSH terms
- Insulin Secretion, Action Potentials, Animals, Autonomic Fibers, Preganglionic, Energy Metabolism, Female, Ganglia, Parasympathetic, Glucose, Homeostasis, Insulin, Male, Mice, Inbred C57BL, Pancreas, Glucose Intolerance, Mice, Knockout, Cell Proliferation, Insulin-Secreting Cells, Glucose Transporter Type 2, Mice, Mice, 129 Strain
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