Starvation amidst plenty: PDKs and diabetes mellitus

Abstract

The pyruvate dehydrogenase complex (PDC) catalyzes the formation of acetylCoA from pyruvate. The PDC acts to proportion fuel use and synthesis in most eukaryotic cells. The liver complex is active in the well-fed state, promoting the synthesis of fatty acids (FA), whereas in starvation, its activity is significantly reduced to conserve 3-C compounds for gluconeogenesis. The activity of PDC is controlled by the pyruvate dehydrogenase kinases (PDKs), which inactivate PDC by phosphorylating specific serine residues. The PDKs tailor PDC activity to the needs of a given tissue by differential expression of isoforms, primarily PDK2 and PDK4. The recently identified crystal structure of PDK2 showed a novel serine protein kinase, which has a C-terminal kinase domain that is structurally similar to the prokaryotic histidine kinases, whereas the catalytic mechanism is similar to the eukaryotic serine kinases. The lipoyl region of PDC is sensitive to the NAD+/NADH and CoA/acetylCoA, which respectively alter the redox and acetylation states of the lipoyl group. The N-terminal domain of PDK2 binds to the lipoyl group and monitors these changes, adjusting the kinase activity accordingly.Huang, et al. [1xRegulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-γ ligands, glucocorticoids and insulin. Huang, B. et al. Diabetes. 2002; 51: 276–283Crossref | PubMedSee all References][1] set out to determine which factors positively regulate the expression of PDK2 and PDK4. In Morris hepatoma 7800 C1 cells, they found that glucocorticoids (dexamethasone) and the peroxisome proliferator-activated receptor γ (PPARγ) ligand WY-14,643 upregulated the expression of PDK4 by independent signaling mechanisms. These compounds had no effect on the expression of PDK2. Insulin was able to prevent and reverse the stimulation of PDK4 expression by dexamethasone, but was less effective at blunting the effects of WY-14,643; a mimic of FA. Insulin also reduced the expression of PDK2.These data correlate with the physiological situation during starvation, in which serum levels of both glucocorticoids and FA are relatively high. Further, they suggest that the diminished effects of insulin that are characteristic of diabetes mellitus (DM) (hypoinsulinemia in type 1 and hepatic insulin resistance in type 2) are responsible, at least in part, for the failure of the liver to reduce gluconeogenesis, thus leading to hyperglycemia. This is particularly relevant to diabetes because elevated serum FA are symptomatic of the disease.These data demonstrate, at the molecular level, that diabetes could be considered ‘starvation amidst plenty’, as hepatic PDK expression remains in the starvation mode, even though the insulin should be signaling plentiful nutrients. At the same time, these observations show that the consequences of insulin resistance in type 2 DM are multifaceted and extend beyond the classical picture, which focused on diminished insulin-stimulated uptake of glucose by the muscle as the source of hyperglycemia.