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* TNO Prevention and Health, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands
Division of Haematology/Oncology, Cornell University, New York, NY 14850
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
** Department of Endocrinology and Diabetes, Leiden University Medical Center, Leiden, The Netherlands
Department of Cardiology and General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
1 To whom correspondence should be addressed. e-mail: pj.voshol{at}pg.tno.nl
CD36 (fatty acid translocase) is involved in high-affinity peripheral fatty acid uptake. Mice lacking CD36 exhibit increased plasma free fatty acid and triglyceride (TG) levels and decreased glucose levels. Studies in spontaneous hypertensive rats lacking functional CD36 link CD36 to the insulin-resistance syndrome. To clarify the relationship between CD36 and insulin sensitivity in more detail, we determined insulin-mediated whole-body and tissue-specific glucose uptake in CD36-deficient (CD36-/-) mice. Insulin-mediated whole-body and tissue-specific glucose uptake was measured by D-[3H]glucose and 2-deoxy-D-[1-3H]glucose during hyperinsulinemic clamp in CD36-/- and wild-type control littermates (CD36+/+) mice. Whole-body and muscle-specific insulin-mediated glucose uptake was significantly higher in CD36-/- compared with CD36+/+ mice. In contrast, insulin completely failed to suppress endogenous glucose production in CD36-/- mice compared with a 40% reduction in CD36+/+ mice. This insulin-resistant state of the liver was associated with increased hepatic TG content in CD36-/- mice compared with CD36+/+ mice (110.9 ± 12.0 and 68.9 ± 13.6 µg TG/mg protein, respectively). Moreover, hepatic activation of protein kinase B by insulin, measured by Western blot, was reduced by 54%.
Our results show a dissociation between increased muscle and decreased liver insulin sensitivity in CD36-/- mice.
Abbreviations: CD36-/-, CD36-deficient; CD36+/+, wild-type control littermates; 2-DG, 2-deoxy-D-[1-3H]glucose; FFA, free fatty acid; SHR, spontaneous hypertensive rat; TG, triglyceride; VLDLr, VLDL receptor
Supplementary key words fatty acid transport • glucose metabolism • hepatic steatosis • hyperinsulinemic clamp
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