Human Triglyceride-rich Lipoproteins Impair Glucose Metabolism and Insulin Signalling in L6 Skeletal Muscle Cells Independently of Non-esterified Fatty Acid Levels

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2005 Mar 5

PMID 15747109

Citations 13

Authors

M T Pedrini

M Kranebitter

A Niederwanger

S Kaser

J Engl

P Debbage

L A Huber

J R Patsch

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Elevated fasting and postprandial plasma levels of triglyceride-rich lipoproteins (TGRLs), i.e. VLDL/remnants and chylomicrons/remnants, are a characteristic feature of insulin resistance and are considered a consequence of this state. The aim of this study was to investigate whether intact TGRL particles are capable of inducing insulin resistance.

Methods: We studied the effect of highly purified TGRLs on glycogen synthesis, glycogen synthase activity, glucose uptake, insulin signalling and intramyocellular lipid (IMCL) content using fully differentiated L6 skeletal muscle cells.

Results: Incubation with TGRLs diminished insulin-stimulated glycogen synthesis, glycogen synthase activity, glucose uptake and insulin-stimulated phosphorylation of Akt and glycogen synthase kinase 3. Insulin-stimulated tyrosine phosphorylation of IRS-1, and IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase (PI3K) activity were not impaired by TGRLs, suggesting that these steps were not involved in the lipoprotein-induced effects on glucose metabolism. The overall observed effects were time- and dose-dependent and paralleled IMCL accumulation. NEFA concentration in the incubation media did not increase in the presence of TGRLs indicating that the effects observed were solely due to intact lipoprotein particles. Moreover, co-incubation of TGRLs with orlistat, a potent active-site inhibitor of various lipases, did not alter TGRL-induced effects, whereas co-incubation with receptor-associated protein (RAP), which inhibits interaction of TGRL particles with members of the LDL receptor family, reversed the TGRL-induced effects on glycogen synthesis and insulin signalling.

Conclusions/interpretation: Our data suggest that the accumulation of TGRLs in the blood stream of insulin-resistant patients may not only be a consequence of insulin resistance but could also be a cause for it.

Citing Articles

Native low-density lipoproteins are priming signals of the NLRP3 inflammasome/interleukin-1β pathway in human adipose tissue and macrophages.

Bissonnette S, Lamantia V, Ouimet B, Cyr Y, Devaux M, Rabasa-Lhoret R Sci Rep. 2023; 13(1):18848.

PMID: 37914804 PMC: 10620147. DOI: 10.1038/s41598-023-45870-1.

LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue.

Faraj M J Biomed Res. 2020; 34(4):251-259.

PMID: 32701068 PMC: 7386410. DOI: 10.7555/JBR.34.20190124.

Serotonin improves glucose metabolism by Serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells.

Al-Zoairy R, Pedrini M, Imran Khan M, Engl J, Tschoner A, Ebenbichler C Diabetol Metab Syndr. 2017; 9:1.

PMID: 28053672 PMC: 5209910. DOI: 10.1186/s13098-016-0201-1.

Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study.

Leon-Acuna A, Alcala-Diaz J, Delgado-Lista J, Torres-Pena J, Lopez-Moreno J, Camargo A Cardiovasc Diabetol. 2016; 15:68.

PMID: 27095446 PMC: 4837552. DOI: 10.1186/s12933-016-0380-y.

Plasma IL-1Ra: linking hyperapoB to risk factors for type 2 diabetes independent of obesity in humans.

Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Wassef H, Faraj M Nutr Diabetes. 2015; 5:e180.

PMID: 26417659 PMC: 4657760. DOI: 10.1038/nutd.2015.30.

References

Nordestgaard B, Wootton R, Lewis B . Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995; 15(4):534-42. DOI: 10.1161/01.atv.15.4.534. View

Daugherty A, Lange L, Sobel B, Schonfeld G . Aortic accumulation and plasma clearance of beta-VLDL and HDL: effects of diet-induced hypercholesterolemia in rabbits. J Lipid Res. 1985; 26(8):955-63. View

Canny J . A computational approach to edge detection. IEEE Trans Pattern Anal Mach Intell. 2011; 8(6):679-98. View

Koopman R, Schaart G, Hesselink M . Optimisation of oil red O staining permits combination with immunofluorescence and automated quantification of lipids. Histochem Cell Biol. 2001; 116(1):63-8. DOI: 10.1007/s004180100297. View

Simionescu N, Simionescu M . Cellular interactions of lipoproteins with the vascular endothelium: endocytosis and transcytosis. Targeted Diagn Ther. 1991; 5:45-95. DOI: 10.1201/9780203748831-3. View

Usui I, Takata Y, Imamura T, Morioka H, Sasaoka T, Sawa T . Fatty acid induced insulin resistance in rat-1 fibroblasts overexpressing human insulin receptors: impaired insulin-stimulated mitogen-activated protein kinase activity. Diabetologia. 1997; 40(8):894-901. DOI: 10.1007/s001250050765. View

Pan D, Lillioja S, Kriketos A, Milner M, Baur L, Bogardus C . Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997; 46(6):983-8. DOI: 10.2337/diab.46.6.983. View

Proctor S, Mamo J . Intimal retention of cholesterol derived from apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol. 2003; 23(9):1595-600. DOI: 10.1161/01.ATV.0000084638.14534.0A. View

Patsch J, Patsch W . Zonal ultracentrifugation. Methods Enzymol. 1986; 129:3-26. DOI: 10.1016/0076-6879(86)29059-x. View

10.

Herz J, Goldstein J, Strickland D, Ho Y, Brown M . 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991; 266(31):21232-8. View

11.

Proctor S, Mamo J . Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall--evidence that plaque cholesterol may be derived from post-prandial lipoproteins. Eur J Clin Invest. 1998; 28(6):497-503. DOI: 10.1046/j.1365-2362.1998.00317.x. View

12.

Boden G, Lebed B, Schatz M, Homko C, Lemieux S . Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001; 50(7):1612-7. DOI: 10.2337/diabetes.50.7.1612. View

13.

Proctor S, Pabla C, Mamo J . Arterial intimal retention of pro-atherogenic lipoproteins in insulin deficient rabbits and rats. Atherosclerosis. 2000; 149(2):315-22. DOI: 10.1016/s0021-9150(99)00341-x. View

14.

Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C . Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes. 2002; 51(5):1437-42. DOI: 10.2337/diabetes.51.5.1437. View

15.

Deeney J, Prentki M, Corkey B . Metabolic control of beta-cell function. Semin Cell Dev Biol. 2000; 11(4):267-75. DOI: 10.1006/scdb.2000.0175. View

16.

Schmitz-Peiffer C, Craig D, Biden T . Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem. 1999; 274(34):24202-10. DOI: 10.1074/jbc.274.34.24202. View

17.

Thamer C, Machann J, Bachmann O, Haap M, Dahl D, Wietek B . Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. J Clin Endocrinol Metab. 2003; 88(4):1785-91. DOI: 10.1210/jc.2002-021674. View

18.

Patsch W, Patsch J, Kostner G, Sailer S, BRAUNSTEINER H . Isolation of subfractions of human very low density lipoproteins by zonal ultracentrifugation. J Biol Chem. 1978; 253(14):4911-5. View

19.

Hara K, Yonezawa K, Sakaue H, Ando A, Kotani K, Kitamura T . 1-Phosphatidylinositol 3-kinase activity is required for insulin-stimulated glucose transport but not for RAS activation in CHO cells. Proc Natl Acad Sci U S A. 1994; 91(16):7415-9. PMC: 44411. DOI: 10.1073/pnas.91.16.7415. View

20.

Griffin M, Marcucci M, Cline G, Bell K, Barucci N, Lee D . Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999; 48(6):1270-4. DOI: 10.2337/diabetes.48.6.1270. View