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.

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

“…Increased levels of short and middle ACs in the diabetic cohort with CKD may be explained by alterations in the expression or activity of FAO enzymes aside CPT1A(3) as short and middle ACs may derive from long chain ACs incomplete fatty acid oxidation (22). Further, the systemic clearance of ACs may be differentially impaired in this population, also impacting on their biodistribution (23,24).…”

Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan

“…Several studies have shown elevation of serum acetylcarnitine in humans and animals with different kidney diseases 38–41 . Accumulation of acetylcarnitine in patients with CKD may lead to the inhibition of carnitine acetyltransferase activity and mitochondrial dysfunction in skeletal muscles by shifting there are action in the opposite direction 42 . Our current study demonstrated that the serum acetylcarnitine level was significantly increased with reduction of renal function in patients with CKD.…”

Maternal Restricted- and Over-Feeding During Gestation Result in Distinct Lipid and Amino Acid Metabolite Profiles in the Longissimus Muscle of the Offspring

“…Further, acetyl carnitine concentration was increased in patients with impaired glucose tolerance or type 2 diabetes and was positively correlated with increased body fat and waist to hip ratio (Mai et al, 2013; Abu Bakar and Sarmidi, 2017). Insulin dependent uptake of 2-deoxyglucose in cultured myotubes was inhibited by the acetyl carnitine in a dose dependent manner, suggesting that acetyl carnitine contributes to insulin resistance in skeletal muscle (Miyamoto et al, 2016). Further, in myotubes with increased mitochondrial dysfunction (induced by Antimycin A), acyl carnitine metabolites were increased, potentially due to incomplete beta oxidation by the mitochondria (Abu Bakar and Sarmidi, 2017).…”