Production of reactive oxygen species – a possible cause of postoperative insulin resistance
Prosjekt
- Prosjektnummer
- SFP1044-12
- Ansvarlig person
- Øivind Irtun
- Institusjon
- Universitetssykehuset Nord-Norge HF
- Prosjektkategori
- Ph.d.-stipend
- Helsekategori
- Metabolic and endocrine
- Forskningsaktivitet
- 5. Treatment Development
Rapporter
MAIN CONCLUSIONS
1. An impairment in pyruvate dehydrogenase activity after surgery, along with reduced pyruvate oxidation, while no overall impairment of maximal ADP stimulated respiration in mitochondria, in line with normal activity of ETC complexes.
2. Mitochondria in both skeletal muscle and liver express increased capacity for ROS release after surgery.
3. A single morning dose CHO load is sufficient to diminish peripheral insulin resistance in the immediate phase after surgery. The beneficial effect of CHO loading could be prescribed to reduced circulating free fatty acids (FFAs).
4. A perioperative infusion of GLP-1 prevents development of peripheral insulin resistance after surgery, most likely through indirect mechanisms on skeletal muscle glucose uptake.
5. GLP-1 augment the suppressing effect of insulin on EGR, both in normal-sensitive subjects, and during postoperative insulin resistance.
Karbohydrat-loading før kirurgisk intervensjon reduserer postoperativ insulin resistens. Dette minsker igjen postoperativ katabolisme og reduserer også komplikasjonsfrekvensen. Vi har vist at en enkel dose karbohydratrik drikk 2 timer før kirurgisk inngrep er nok til å redusere den postoperative insulinresistensen. Det er derfor innlysende at preoperativ karbohydratrik væske bør være standard behandling før alle større kirurgiske inngrep.
Glucagon-like peptid (GLP-1) er et neuropeptide og incretin derivert fra transcripsjonsproduktet av proglucagon genet. Hovedkilde for GLP-1 i periferien er intestinal L celler som sekrerer GLP-1 som et tarm-hormon.
GLP-1 er et potent antihyperglycemisk hormon som inkluderer ß-cellene i pankreas til å utskille insulin som respons til hyperglykemi. Altså, redusere den postoperative insulinresistens. I våre studier viste vi at perioperativ infusjon av GLP-1 reduserte dannelsen av perifer insulinresistens etter kirurgi. Dette skjer sannsynligvis indirekte via skjelettmuskel-glukose opptak. Humane studier bør etter hvert utføres for å se om infusjon av GLP-1 også her reduserer postoperativ insulinresistens.
Postoperativ insulinresistens gir økt morbiditet hos pasienter. Videre forsinker det rekonvalesensen.
Årsaken til den postoperative insulinresistens er kun delvis kartlagt. I dette doktorgrads studie har vi sett på og kartlagt mulige mekanismer som er medvirkende. Vi har kartlagt noen mekanismer som er medvirkende i denne prosessen.Postoperativ insulinresistens medfører økt morbiditet og forlenget rekonvalesens hos pasienter etter kirurgi. Man ser de samme mekanismene hos pasienter etter større traumer. Vi har tidligere etablert en grisemodell på kirurgisk forskningslaboratorium ved Universitetet i Tromsø. Denne modellen har vi nå brukt i dette doktorgradsarbeidet. Artikkelen "Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance" Hagve M, Gjessing PF, Fuskevåg OM, Larsen TS, Irtun Ø. ble publisert i PhysAm J Physiol Endocrinol Metab. 2015 Apr 15;308(8):E613-20.
Dette året har vi gjennomført nok et studie som har resultert i artikkelen: "A perioperative infusion of glucagon like peptide 1 (GLP-1) diminishes peripheral insulin resistance after surgical trauma in pigs" Martin Hagve, Petter Fosse Gjessing, Mikal Jakob Hole, Ole Martin Fuskevåg, Tom-Erik Mollnes, Terje S. Larsen, and Øivind Irtun. Dette arbeidet er nå under innsendelse for publisering. .
After surgery, the development of an acute insulin resistance has been identified as a negative factor associated with increased morbidity and hospital stay, but the physiological and molecular mechanisms underlying this condition are not fully elucidated.
We assessed the change in mitochondrial functions with special focus on pyruvate oxidation capacity, enzyme activities, levels of ROS release and uncoupling in skeletal muscle and liver mitochondria during this state.Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by D-6,6-2H2-glucose infusion and hyperinsulinemic-euglycemic step-clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (~34%, P<0.01), while hepatic insulin sensitivity remained unchanged. Subsarcolemmal (SSM) and intramyofibrillar (IFM) mitochondria isolated from skeletal muscle showed a postoperative decline in ADP stimulated respiration (VADP) for pyruvate (~61%, P<0.05 and ~40%, P<0.001, respectively), while VADP for glutamate and palmitoyl-L-carnitine (PC) was unchanged. Mitochondrial leak respiration (Voligo) with PC was increased in SSM (1.9-fold, P<0.05) and IFM (2.5-fold, P<0.05) indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (~32%, P<0.01) and positively correlated to the decline in peripheral insulin sensitivity (R=0.748, P<0.05). All other measured enzyme activities was unchanged. No changes were observed in mitochondrial function in liver. Mitochondrial H2O2 and O2•- emission was measured spectrofluorometrically and H2O2 was increased in both SSM, IFM and liver mitochondria (~2.3-fold, ~2.5-fold and ~2.3-fold, respectively, all P<0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arise in the postoperative phase along with increased ROS emission suggesting a link between mitochondrial function and development of acute postoperative insulin resistance.
Vitenskapelige artikler
Hagve M, Gjessing PF, Hole MJ, Jansen, KM, Fuskevåg OM, Mollness TE, Larsen TS, Irtun Ø.
Perioperative infusion of glucagon like peptide-1 prevents peripheral insulin resistance after surgical trauma.
Submitted
Deltagere
- Øivind Irtun Prosjektleder
- Tom Eirik Mollnes Prosjektdeltaker
- Terje Larsen Prosjektdeltaker
- Ole-Martin Fuskevåg Prosjektdeltaker
- Petter Fosse Gjessing Prosjektdeltaker
- Martin Iversen Hagve Doktorgradsstipendiat
- Martin Hagve Doktorgradsstipendiat
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
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