In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion

Article Article scientifique Article In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion eng 2025-09-01 author Zhou Yan Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland. 931387 author Baez Nicolas Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland. 877084 Département de physiologie cellulaire et métabolisme (PHYME) author Fu Tingting Department of Quantum Matter Physics, Laboratory of Advanced Technology, University of Geneva, Geneva, Switzerland. 403338 Département de physique de la matière quantique (FIMAC) author Brun Thierry 0000-0002-1659-4283 Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland. 24644 Structure enseignement (ENSI) author Maechler Pierre 0000-0002-2005-1433 Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland. Electronic address: Pierre.Maechler@unige.ch. 76515 Département de physiologie cellulaire et métabolisme (PHYME) 110661 10.1016/j.jbc.2025.110661 40902975 0021-9258 https://www.sciencedirect.com/science/article/pii/S002192582502513X Upon glucose stimulation, metabolic pathways of pancreatic beta-cells promptly adapt metabolite levels inducing insulin secretion fine-tuned by mitochondrial glutamate dehydrogenase (GDH). Although well described in vitro, these responses cannot yet be captured in vivo due to the intrinsic nature of the islets scattered throughout the pancreas. Tested first in vitro, glutamate precursor glutamine enhanced glucose-stimulated insulin secretion without eliciting oxidative catabolism, as opposed to glucose. Then, to be as close as possible to the in vivo state, we collected the pancreas of mouse models in fasted versus fed states and at the peak of a glucose tolerance test, immediately followed by snap freezing before in situ analysis of metabolic pathways. On the same series of pancreatic cryosections, islets were identified by dithizone beta-cell staining for metabolic analyses combining spatial in situ redox enzymatic assay with targeted metabolomics using time-of-flight secondary ion MS high-resolution imaging. Direct measurements in cryopreserved pancreatic sections of control and beta-cell specific GDH knockout mice showed tight coupling between glycolysis and mitochondrial pathways favored by low lactate dehydrogenase activity and strong succinate dehydrogenase velocity. In response to regular feeding, intra-islet glutamate and glutamine levels were elevated, an effect dependent on beta-cell GDH. Acute in vivo glucose stimulation increased both alanine and glutamate intra-islet levels. Lack of beta-cell GDH abrogated the rise in glutamate and reduced insulin secretion without impacting alanine levels. Overall, the hallmark of in vivo beta-cell stimulation was a strong mitochondrial activity and GDH-dependent elevation of glutamate required for the full development of insulin secretion. Beta-cell Glutamate dehydrogenase Insulin secretion Metabolomics Pancreatic islet Dewey 612 Dewey 500.2 Swiss National Science Foundation An integrated multi-organ analysis of glutamate dehydrogenase 192486 CH Projects 134 Département de physiologie cellulaire et métabolisme 21C 33 Département de physique de la matière quantique 131 false 402 Mitochondries et métabolisme énergétique 671 The Journal of biological chemistry 28a3d85b-7a67-4d53-8828-98f482434e83 Article (Accepted version) Public In_press-Zhou_et_al.pdf 36122603 application/pdf CC BY-4.0 dac51202e4fb38fba6a06bf88db4862cd78a112c3843dc1403cc6c13adcdd7d6 001f7268-dc16-47bb-a2e0-129ad9643e4f Supplemental data Public 1-s2.0-S002192582502513X-mmc1.pdf 1535022 application/pdf edd7e994b7d6a1d16af8cf93983aba73e859525af8e8cf5505a97fc6fe4844b8 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté des sciences / Section de physique / Département de physique de la matière quantique

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In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion	The Journal of biological chemistry			2025	39	18

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