In Muscle-Specific Lipoprotein Lipase−Overexpressing Mice, Muscle Triglyceride Content Is Increased Without Inhibition of Insulin-Stimulated Whole-Body and Muscle-Specific Glucose Uptake
- Peter J. Voshol12,
- Miek C. Jong1,
- Vivian E.H. Dahlmans1,
- Dagmar Kratky3,
- Sanja Levak-Frank4,
- Rudolf Zechner3,
- Johannes A. Romijn2 and
- Louis M. Havekes12
- 1TNO-Prevention and Health, Division VBO, Leiden, the Netherlands
- 2Department of Endocrinology and Metabolic Diseases, Leiden University Medical Centre, Leiden, the Netherlands
- 3Institute of Molecular Biology, Biochemistry, and Microbiology, University of Graz, Graz, Austria
- 4Institute of Medical Biochemistry and Medical Molecular Biology, University of Graz, Graz, Austria
Abstract
In patients with type 2 diabetes, a strong correlation between accumulation of intramuscular triclycerides (TGs) and insulin resistance has been found. The aim of the present study was to determine whether there is a causal relation between intramuscular TG accumulation and insulin sensitivity. Therefore, in mice with muscle-specific overexpression of human lipoprotein lipase (LPL) and control mice, muscle TG content was measured in combination with glucose uptake in vivo, under hyperinsulinemic-euglycemic conditions. Overexpression of LPL in muscle resulted in accumulation of TGs in skeletal muscle (85.5 ± 33.3 vs. 25.7 ± 23.1 μmol/g tissue in LPL and control mice, respectively; P < 0.05). During the hyperinsulinemic clamp study, there were no differences in plasma glucose, insulin, and FFA concentrations between the two groups. Moreover, whole-body, as well as skeletal muscle, insulin-mediated glucose uptake did not differ between LPL-overexpressing and wild-type mice. Surprisingly, whole-body glucose oxidation was decreased by ∼60% (P < 0.05), whereas nonoxidative glucose disposal was increased by ∼50% (P < 0.05) in LPL-overexpressing versus control mice. In conclusion, overexpression of human LPL in muscle increases intramuscular TG accumulation, but does not affect whole-body or muscle-specific insulin-mediated uptake, findings that argue against a simple causal relation between intramuscular TG content and insulin resistance.
Footnotes
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Address correspondence and reprint requests to Dr. Peter J. Voshol, TNO-Prevention and Health, Division VBO, Zernikedreef 9, NL-2333 CK Leiden, The Netherlands. E-mail: pj.voshol{at}pg.tno.nl.
Received for publication 14 March 2001 and accepted in revised form 10 August 2001.
AGAT, acylglycerol-3-phosphate acyltransferase; 2-DG, 2-deoxy-d-[1-14C]glucose; 2-DG-P, 2-DG-6-phosphate; EGP, endogenous glucose production; FFA, free fatty acid; LPL, lipoprotein lipase; PBS, phosphate-buffered saline; TG, triglyceride.
