Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, ameliorates type 2 diabetes via reduced gluconeogenesis.

Abstract

AIMS:

Pyruvate dehydrogenase (PDH) catalyzes the decarboxylation of pyruvate to acetyl-CoA, which plays a key role in linking cytosolic glycolysis to mitochondria metabolism. PDH is physiologically inactivated by pyruvate dehydrogenase kinases (PDKs). Thus, activation of PDH via inhibiting PDK may lead to metabolic benefits. In the present study, we investigated the antidiabetic effect of PDK inhibition using dichloroacetate (DCA), a PDK inhibitor.

MAIN METHODS:

We evaluated the effect of single dose of DCA on plasma metabolic parameters in normal rats. Next, we investigated the antidiabetic effect of DCA in diabetic ob/ob mice. In addition, we performed in vitro assays to understand the effect and mechanism of action of DCA on gluconeogenesis in mouse myoblast cell line C2C12 and rat hepatoma cell line FaO.

KEY FINDINGS:

In normal rats, a single dose of DCA decreased the plasma level of pyruvate, the product of glycolysis, and the plasma glucose level only in the fasting state. Meanwhile, a single dose of DCA lowered the plasma glucose level, and a three-week treatment decreased the fructosamine level in diabetic ob/ob mice. In vitro experiments demonstrated concentration-dependent suppression of lactate production in C2C12 myotubes. In addition, DCA suppressed glucose production from pyruvate and lactate in FaO hepatoma cells. Thus, DCA-mediated restricted supply of gluconeogenic substrates from the muscle to liver, and direct suppression of hepatic gluconeogenesis might have contributed to its glucose-lowering effect in the current models.

SIGNIFICANCE:

PDK inhibitor may be considered as a potential antidiabetic agent harboring inhibitory effect on gluconeogenesis.

• Authors: Yuko Katayama, Yayoi Kawata, Yusuke Moritoh, Masanori Watanabe
• Journal: Heliyon (Heliyon) Vol. 8 Issue 2 Pg. e08889 (Feb 2022) ISSN: 2405-8440 [Print] England
• PMID: 35169648 (Publication Type: Journal Article)
• Copyright: © 2022 The Author(s).