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Original research
Small intestinal metabolism is central to whole-body insulin resistance
  1. Giulia Angelini1,2,
  2. Serenella Salinari3,
  3. Lidia Castagneto-Gissey4,
  4. Alessandro Bertuzzi5,
  5. James Casella-Mariolo6,
  6. Sofie Ahlin7,
  7. Ivo Boskoski1,2,
  8. Melania Gaggini8,
  9. Marco Raffaelli1,2,
  10. Guido Costamagna1,2,
  11. Giovanni Casella4,
  12. Pier Luigi Marini6,
  13. Amalia Gastaldelli8,
  14. Stefan Bornstein9,10,
  15. Geltrude Mingrone1,2,9
  1. 1 Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
  2. 2 Università Cattolica del Sacro Cuore, Rome, Italy
  3. 3 Department of Computer, Control, and Management Engineering “Antonio Ruberti”, Universityof Rome “Sapienza”, Rome, Italy
  4. 4 Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy
  5. 5 CNR-Institute of Systems Analysis and Computer Science (IASI), Rome, Italy
  6. 6 Department of Surgery, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy
  7. 7 Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  8. 8 Cardiometabolic Risk Laboratory, Institute of Clinical Physiology, CNR, Pisa, Italy
  9. 9 Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK
  10. 10 Department of Medicine III, Universitätsklinikum Carl Gustav Carus an der Technischen, Universität Dresden, Dresden, Germany
  1. Correspondence to Professor Geltrude Mingrone, Internal Medicine, Universita Cattolica del Sacro Cuore, Rome 00168, Italy; geltrude.mingrone{at}unicatt.it

Abstract

Objective To assess the role of jejunum in insulin resistance in humans and in experimental animals.

Design Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.

We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.

In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling.

Results Whole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).

Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.

A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.

Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans.

Conclusion Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity.

Trial registration number NCT03111953.

  • small intestine
  • diabetes mellitus
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Footnotes

  • GA and SS are joint first authors.

  • SB and GM are joint senior authors.

  • Twitter @GiuliaAngelini7, @ivoboskoski

  • Contributors GM and GA designed the study. SS and AB performed the analysis of the data. GA and SA performed the study and acquired the data. LC-G, JC-M, IB, PLM, MR and GC performed the surgical procedures. AG and MG measured stable isotopes and revised the article. GM and GA wrote the manuscript. SB and GC revised and improved the manuscript.

  • Funding This study was founded by an internal grant from the Catholic University.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval The protocol was approved by the ethical committee of the Catholic University of Rome, Italy.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. The datasets generated during the current study are available from the corresponding author on reasonable request.

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