Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels.

Clinical Department of Internal Medicine, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
Diabetologia (Impact Factor: 6.49). 05/2005; 48(4):756-66. DOI: 10.1007/s00125-005-1684-8
Source: PubMed

ABSTRACT 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.
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.
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.
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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fatty acid transport protein 6 (FATP6) is primarily expressed in the heart and seems to be involved in cardiac fatty acid uptake. Therefore, we investigated whether a variation in the 5'-untranslated region of the FATP6 gene is associated with features of the metabolic syndrome and signs of myocardial alteration or heart failure. A total of 755 male participants from a Metabolic Intervention Cohort Kiel were genotyped for the FATP6-7T>A polymorphism (rs2526246) and phenotyped for features of the metabolic syndrome. Participants underwent a glucose tolerance test and the postprandial assessment of metabolic variables after a standardised mixed meal. Left ventricular heart function was evaluated in fifty-four participants. Fasting (P = 0·01) and postprandial (P = 0·02) TAG concentrations were significantly lower in AA homozygotes when compared with wild-type carriers. Homozygosity of allele A was associated with significantly lower postprandial insulin concentrations after a glucose load and significantly lower systolic (P = 0·01) and diastolic (P = 0·01) blood pressure values compared with wild-type carriers. Accordingly, left ventricular heart mass was significantly lower in twenty-seven AA homozygotes in comparison with twenty-seven TT homozygotes, matched for BMI (P = 0·04). In conclusion, the effects of the FATP6 polymorphism on TAG are mediated by affluent dietary fat. The FATP6-7T>A polymorphism may protect from traits of the metabolic syndrome and CVD.
    The British journal of nutrition 09/2011; 107(10):1422-8. · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase Cepsilon was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappaB activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.
    Journal of Biological Chemistry 05/2007; 282(20):14807-15. · 4.65 Impact Factor
  • Conference Paper: On the YIG film filters
    [Show abstract] [Hide abstract]
    ABSTRACT: A new type of YIG film filter that consists of a microstrip line with a substrate of YIG films sandwiched between two dielectric slabs is proposed. The dispersion and transmission characteristics are calculated numerically. Sharp stopband characteristics were observed experimentally with a half-power bandwidth of 16.4 MHz. Alternatively, in the same line with an air gap a bandpass characteristic was observed with a quality factor of 430. These experimental results are compared with theory
    Microwave Symposium Digest, 1992., IEEE MTT-S International; 07/1992


Available from

Similar Publications