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Knocking out pyruvate dehydrogenase kinase 4 lowers blood glucose by altering fuel selection in peripheral tissues

Activity of the pyruvate dehydrogenase complex (PDC) is strongly inhibited by phosphorylation in the fasted state and by diabetes. An important component of the mechanism, greater pyruvate dehydrogenase kinase 4 (PDK4) activity due to increased expression, was investigated with PDK4‐knockout (PDK4‐KO) mice. Mice that lack PDK4 exhibit modestly lower fasting blood glucose and improved glucose tolerance. Activity state of PDC (% of complex dephosphorylated and active) is greater in heart, skeletal muscle, and kidney but not the liver of fasted PDK4‐KO mice. Concentrations of the intermediates of the gluconeogenic pathway are reduced in the liver of PDK4‐KO mice, consistent with a reduced rate of gluconeogenesis due to a substrate supply limitation. The blood concentrations of gluconeogenic substrates are reduced in PDK4‐KO mice, consistent with reduced formation in peripheral tissues. Lactate, pyruvate, and alanine are formed at slower rates by isolated muscle preparations from PDK4‐KO mice as a consequence of increased oxidation of glucose to CO2, reduced glycolysis, and a greater rate of glycogen synthesis. Catabolism of branched‐chain amino acids (BCAAs) is reduced in muscle preparations at the level of transamination with α‐ketoglutarate, consistent with the importance of BCAAs as a major source of amino groups for alanine synthesis. Fasting induces higher blood levels of free fatty acids in PDK4‐KO mice than in normal mice. This is explained by a slower rate of fatty acid oxidation in the muscle of PDK4‐KO mice, a consequence of increased rates of glucose and pyruvate oxidation. These findings confirm the importance of upregulation of PDK4 for glucose homeostasis and support PDK4 as a therapeutic target for diabetes.