title: Propofol (Diprivan®) and Intralipid® exacerbate insulin resistance in type-2 diabetic hearts by impairing GLUT4 trafficking.
abstract: BACKGROUND
  The IV anesthetic, propofol, when administered as fat emulsion-based formulation (Diprivan) promotes insulin resistance, but the direct effects of propofol and its solvent, Intralipid, on cardiac insulin resistance are unknown.
  
  
  METHODS
  Hearts of healthy and type-2 diabetic rats (generated by fructose feeding) were aerobically perfused for 60 minutes with 10 μM propofol in the formulation of Diprivan or an equivalent concentration of its solvent Intralipid (25 μM) ± insulin (100 mU•L). Glucose uptake, glycolysis, and glycogen metabolism were measured using [H]glucose. Activation of Akt, GSK3β, AMPK, ERK1/2, p38MAPK, S6K1, JNK, protein kinase Cθ (PKCθ), and protein kinase CCβII (PKCβII) was determined using immunoblotting. GLUT4 trafficking and phosphorylations of insulin receptor substrate-1 (IRS-1) at Ser307(h312), Ser1100(h1101), and Tyr608(hTyr612) were measured. Mass spectrometry was used to determine acylcarnitines, phospholipids, and sphingolipids.
  
  
  RESULTS
  Diprivan and Intralipid reduced insulin-induced glucose uptake and redirected glucose to glycogen stores in diabetic hearts. Reduced glucose uptake was accompanied by lower GLUT4 trafficking to the sarcolemma. Diprivan and Intralipid inactivated GSK3β but activated AMPK and ERK1/2 in diabetic hearts. Only Diprivan increased phosphorylation of Akt(Ser473/Thr308) and translocated PKCθ and PKCβII to the sarcolemma in healthy hearts, whereas it activated S6K1 and p38MAPK and translocated PKCβII in diabetic hearts. Furthermore, only Diprivan phosphorylated IRS-1 at Ser1100(h1101) in healthy and diabetic hearts. JNK expression, phosphorylation of Ser307(h312) of IRS-1, and PKCθ expression and translocation were increased, whereas GLUT4 expression was reduced in insulin-treated diabetic hearts. Phosphatidylglycerol, phosphatidylethanolamine, and C18-sphingolipids accumulated in Diprivan-perfused and Intralipid-perfused diabetic hearts.
  
  
  CONCLUSIONS
  Propofol and Intralipid promote insulin resistance predominantly in type-2 diabetic hearts.
authors.affiliation: From the *Department of Anesthesiology and Pain Medicine and Department of Pharmacology, University of Alberta, Edmonton, Canada; †Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada; ‡Department of Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland; §Department of Pharmacology, University of Alberta, Edmonton, Canada; and ‖Department of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Phing-How
authors.initials: PH
authors.lastname: Lou
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Andreas
authors.initials: A
authors.lastname: Affolter
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.forename: Assem
authors.initials: A
authors.lastname: Zhakupova
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
mesh_terms: D018686:Anesthetics, Intravenous / Q000633:toxicity*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism*; D004655:Emulsions / Q000633:toxicity; D005217:Fat Emulsions, Intravenous / Q000633:toxicity*; D005632:Fructose; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007333:Insulin Resistance; D008297:Male; D010743:Phospholipids / Q000633:toxicity*; D015742:Propofol / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013024:Soybean Oil / Q000633:toxicity*
chemical_list: D018686:Anesthetics, Intravenous; D004655:Emulsions; D005217:Fat Emulsions, Intravenous; D051275:Glucose Transporter Type 4; D010743:Phospholipids; C495694:Slc2a4 protein, rat; C545823:soybean oil, phospholipid emulsion; D005632:Fructose; D013024:Soybean Oil; D006003:Glycogen; D002950:Citrate (si)-Synthase; D005947:Glucose; D015742:Propofol