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2016 ; 59
(3
): 199-206
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Retention of acetylcarnitine in chronic kidney disease causes insulin resistance
in skeletal muscle
#MMPMID27895387
Miyamoto Y
; Miyazaki T
; Honda A
; Shimohata H
; Hirayama K
; Kobayashi M
J Clin Biochem Nutr
2016[Nov]; 59
(3
): 199-206
PMID27895387
show ga
Insulin resistance occurs frequently in patients with chronic kidney disease.
However, the mechanisms of insulin resistance associated with chronic kidney
disease are unclear. It is known that an increase in the mitochondrial acetyl-CoA
(AcCoA)/CoA ratio causes insulin resistance in skeletal muscle, and this ratio is
regulated by carnitine acetyltransferase that exchanges acetyl moiety between CoA
and carnitine. Because excess acetyl moiety of AcCoA is excreted in urine as
acetylcarnitine, we hypothesized that retention of acetylcarnitine might be a
cause of insulin resistance in chronic kidney disease patients. Serum
acetylcarnitine concentrations were measured in chronic kidney disease patients,
and were significantly increased with reduction of renal function. The effects of
excess extracellular acetylcarnitine on insulin resistance were studied in
cultured skeletal muscle cells (C2C12 and human myotubes), and insulin-dependent
glucose uptake was significantly and dose-dependently inhibited by addition of
acetylcarnitine. The added acetylcarnitine was converted to carnitine via reverse
carnitine acetyltransferase reaction, and thus the AcCoA concentration and
AcCoA/CoA ratio in mitochondria were significantly elevated. The results suggest
that increased serum acetylcarnitine in CKD patients causes AcCoA accumulation in
mitochondria by stimulating reverse carnitine acetyltransferase reaction, which
leads to insulin resistance in skeletal muscle.