Knocking out PDK2 and PDK4 lowers fasting blood glucose levels, increases insulin sensitivity, and greatly improves glucose tolerance

Abstract

The pyruvate dehydrogenase complex (PDC) is a regulatory site for glucose oxidation in mammals. PDC is regulated by phosphorylation by PDC kinases. PDK2 is constitutively expressed but less responsive to physiological changes than PDK4. Basal expression of PDK4 is lower than PDK2 but greatly increased by fasting and diabetes. PDK2/PDK4 double knockout (K2/K4-DoKo) mice were produced to test their importance for glucose homeostasis. K2/K4-DoKo mice are viable, grow normally, and have normal blood glucose levels in the fed state. Overnight fasting induces lower blood levels of glucose (60 ± 2 vs. 36 ± 1 mg/dl), lower lactate (2.39 ± 0.05 vs. 1.39 ± 0.22 mmol/L), lower alanine (0.22 ± 0.03 vs. 0.11 ± 0.02 mmol/L), lower pyruvate, higher 3-hydroxybutyrate, higher acetoacetate, higher lactate to pyruvate ratios, and lower 3-hydroxybutyrate to acetoacetate ratios. Glycerol, free fatty acids, and triacylglycerols are not affected. Glucose tolerance is remarkably better in the K2/K4-DoKo mice. Insulin levels are lower throughout glucose tolerance test in K2/K4-DoKo mice. Insulin sensitivity determined by response to insulin injection is greater in the K2/K4-DoKo mice. Knocking out PDK2 and PDK4 causes much higher PDC activity in tissues which promotes oxidation of three carbon compounds and limits their availability for gluconeogenesis. Ketone bodies are elevated because greater PDC activity inhibits ketone body oxidation in peripheral tissues and promotes ketone body synthesis from pyruvate in the liver. Fatty acid levels are not increased because lipolysis in adipose tissue is inhibited by 3-hydroxybutyrate. PDK2 and PDK4 are important determinants of the blood levels of glucose and are therefore potential targets for the treatment of diabetes. Supported by DK47844