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A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice
- Source :
- EBioMedicine, Vol 58, Iss, Pp 102895-(2020), EBioMedicine, EBioMedicine, Elsevier, 2020, 58, pp.102895. ⟨10.1016/j.ebiom.2020.102895⟩, EBioMedicine, 2020, 58, pp.102895. ⟨10.1016/j.ebiom.2020.102895⟩
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- Background Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. Methods We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca2+-imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. Findings EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. Interpretation Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. Funding European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Societe Francophone du Diabete, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030–188447), Fondation de l'Avenir.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
endocrine system
[SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery
Bariatric Surgery
lcsh:Medicine
Inflammation
Type 2 diabetes
[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery
ob/ob mouse
General Biochemistry, Genetics and Molecular Biology
1117 Public Health and Health Services
03 medical and health sciences
0302 clinical medicine
Diabetes mellitus
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
medicine
media_common.cataloged_instance
Medicine [Science]
European union
media_common
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Bariatric surgery
geography
lcsh:R5-920
geography.geographical_feature_category
microRNA
business.industry
Insulin secretion
Diabetes
lcsh:R
1103 Clinical Sciences
Beta cell function
General Medicine
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
medicine.disease
Islet
3. Good health
Surgery
030104 developmental biology
Lipotoxicity
030220 oncology & carcinogenesis
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Beta cell
medicine.symptom
business
lcsh:Medicine (General)
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....c83d3183810cb27d20f9b918f57b50a4