title: Retention of acetylcarnitine in chronic kidney disease causes insulin resistance in skeletal muscle.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan.
authors.forename: Homare
authors.initials: H
authors.lastname: Shimohata
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hirayama
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ami, Inashiki, Ibaraki 300-0395, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
keywords: acetylcarnitine; chronic kidney disease; insulin resistance; mitochondria; skeletal muscle