Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects
Veterans Affairs San Diego Healthcare System and Department of Medicine, University of California, San Diego, La Jolla, California 92093 Submitted 31 October 2003 ; accepted in final form 6 April 2003 We examined the regulation of free fatty acid (FFA, palmitate) uptake into skeletal muscle cells of...
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Veröffentlicht in: | American journal of physiology: endocrinology and metabolism 2003-08, Vol.285 (2), p.E354-E362 |
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Zusammenfassung: | Veterans Affairs San Diego Healthcare System and Department of Medicine,
University of California, San Diego, La Jolla, California 92093
Submitted 31 October 2003
; accepted in final form 6 April 2003
We examined the regulation of free fatty acid (FFA, palmitate) uptake into
skeletal muscle cells of nondiabetic and type 2 diabetic subjects. Palmitate
uptake included a protein-mediated component that was inhibited by phloretin.
The protein-mediated component of uptake in muscle cells from type 2 diabetic
subjects (78 ± 13 nmol · mg protein - 1
· min - 1 ) was reduced compared with that in
nondiabetic muscle (150 ± 17, P < 0.01). Acute insulin
exposure caused a modest (16 ± 5%, P < 0.025) but
significant increase in protein-mediated uptake in nondiabetic muscle. There
was no significant insulin effect in diabetic muscle (+19 ± 19%,
P = not significant). Chronic (4 day) treatment with a series of
thiazolidinediones, troglitazone (Tgz), rosiglitazone (Rgz), and pioglitazone
(Pio) increased FFA uptake. Only the phloretin-inhibitable component was
increased by treatment, which normalized this activity in diabetic muscle
cells. Under the same conditions, FFA oxidation was also increased by
thiazolidinedione treatment. Increases in FFA uptake and oxidation were
associated with upregulation of fatty acid translocase (FAT/CD36) expression.
FAT/CD36 protein was increased by Tgz (90 ± 22% over control), Rgz (146
± 42%), and Pio (111 ± 37%, P < 0.05 for all 3)
treatment. Tgz treatment had no effect on fatty acid transporter protein-1 and
membrane-associated plasmalemmal fatty acid-binding protein mRNA expression.
We conclude that FFA uptake into cultured muscle cells is, in part, protein
mediated and acutely insulin responsive. The basal activity of FFA uptake is
impaired in type 2 diabetes. In addition, chronic thiazolidinedione treatment
increased FFA uptake and oxidation into cultured human skeletal muscle cells
in concert with upregulation of FAT/CD36 expression. Increased FFA uptake and
oxidation may contribute to lower circulating FFA levels and reduced insulin
resistance in skeletal muscle of individuals with type 2 diabetes following
thiazolidinedione treatment.
fatty acid transporters; fatty acid translocase; free fatty acid utilization; troglitazone; rosiglitazone; pioglitazone
Address for reprint requests and other correspondence: R. R. Henry, VA San
Diego Healthcare System (9111G), 3350 La Jolla Village Dr., San Diego, CA
92161 (E-mail:
rrhenry{at}vapop.ucs |
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ISSN: | 0193-1849 1522-1555 |
DOI: | 10.1152/ajpendo.00491.2001 |