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Propofol (Diprivan®) and Intralipid® Exacerbate Insulin Resistance in Type-2 Diabetic Hearts by Impairing GLUT4 Trafficking


Lou, Phing-How; Lucchinetti, Eliana; Zhang, Liyan; Affolter, Andreas; Gandhi, Manoj; Zhakupova, Assem; Hersberger, Martin; Hornemann, Thorsten; Clanachan, Alexander S; Zaugg, Michael (2015). Propofol (Diprivan®) and Intralipid® Exacerbate Insulin Resistance in Type-2 Diabetic Hearts by Impairing GLUT4 Trafficking. Anesthesia and Analgesia, 120(2):329-340.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:February 2015
Deposited On:12 Mar 2015 08:27
Last Modified:14 Feb 2018 08:56
Publisher:Lippincott Williams & Wilkins
ISSN:0003-2999
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1213/ANE.0000000000000558
PubMed ID:25437926

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