Korean Diabetes J.  2010 Oct;34(5):274-283. 10.4093/kdj.2010.34.5.274.

Role of Pyruvate Dehydrogenase Kinase 4 in Regulation of Blood Glucose Levels

• Jeoung NH
• Harris RA

• KMID: 2029884
• DOI: http://doi.org/10.4093/kdj.2010.34.5.274

Abstract

In the well-fed state a relatively high activity of the pyruvate dehydrogenase complex (PDC) reduces blood glucose levels by directing the carbon of pyruvate into the citric acid cycle. In the fasted state a relatively low activity of the PDC helps maintain blood glucose levels by conserving pyruvate and other three carbon compounds for gluconeogenesis. The relative activities of the pyruvate dehydrogenase kinases (PDKs) and the opposing pyruvate dehydrogenase phosphatases determine the activity of PDC in the fed and fasted states. Up regulation of PDK4 is largely responsible for inactivation of PDC in the fasted state. PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis. In type 2 diabetes, up regulation of PDK4 also inactivates PDC, which promotes gluconeogenesis and thereby contributes to the hyperglycemia characteristic of this disease. When fed a high fat diet, wild type mice develop fasting hyperglycemia but PDK4 knockout mice remain euglycemic, proving that up regulation of PDK4 contributes to hyperglycemia in diabetes. These finding suggest PDK4 inhibitors might prove useful in the treatment of type 2 diabetes.

Keyword

Diabetes; Fasting; Glucose; Ketone bodies; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase; Steatosis

MeSH Terms

Animals
Blood Glucose
Carbon
Citric Acid Cycle
Diet, High-Fat
Fasting
Gluconeogenesis
Glucose
Homeostasis
Hyperglycemia
Ketone Bodies
Mice
Mice, Knockout
Oxidoreductases
Phosphoric Monoester Hydrolases
Phosphotransferases
Protein Kinases
Protein-Serine-Threonine Kinases
Pyruvate Dehydrogenase Complex
Pyruvic Acid
Up-Regulation
Blood Glucose
Carbon
Glucose
Ketone Bodies
Oxidoreductases
Phosphoric Monoester Hydrolases
Phosphotransferases
Protein Kinases
Protein-Serine-Threonine Kinases
Pyruvate Dehydrogenase Complex
Pyruvic Acid

Figure

• 

  Fig. 1 Regulation of the pyruvate dehydrogenase complex (PDC) and its kinases (PDKs) and phosphatases (PDPs). DCA, dichloroacetate.

• 

  Fig. 2 Current model for mechanism responsible for insulin resistance. FFA, free fatty acid; DAG, diacylglycerol; MCD, malonyl-CoA decarboxylase; ACC, acetyl-CoA carboxylase; TAG, triacylglycerol.

• 

  Fig. 3 Pathway of glyceroneogenesis from three carbon compounds. FFAs, free fatty acids; OAA, oxaloacetate; PEP, phosphoenolpyruvate.

• 

  Fig. 4 Effect of inhibition of PDK4 on the metabolic control of carbohydrate and fat. KBs, ketone bodies; FFAs, free fatty acids; Glc, glucose; Lac, lactate; Pyr, pyruvate; CAC, citric acid cycle.

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