title: Dysregulated pyruvate dehydrogenase complex in Zucker diabetic fatty rats.
abstract: The mitochondrial pyruvate dehydrogenase complex (PDC) is inactivated in many tissues during starvation and diabetes. We investigated carbohydrate oxidation (CHO) and the regulation of the PDC in lean and obese Zucker diabetic fatty (ZDF) rats during fed and starved conditions as well as during an oral glucose load without and with pharmacologically reduced levels of free fatty acids (FFA) to estimate the relative contribution of FFA on glucose tolerance, CHO, and PDC activity. The increase in total PDC activity (20-45%) was paralleled by increased protein levels ( approximately 2-fold) of PDC subunits in liver and muscle of obese ZDF rats. Pyruvate dehydrogenase kinase-4 (PDK4) protein levels were higher in obese rats, and consequently PDC activity was reduced. Although PDK4 protein levels were rapidly downregulated (57-62%) in both lean and obese animals within 2 h after glucose challenge, CHO over 3 h as well as the peak of PDC activity (1 h after glucose load) in liver and muscle were significantly lower in obese rats compared with lean rats. Similar differences were obtained with pharmacologically suppressed FFA by nicotinic acid, but with significantly improved glucose tolerance in obese rats, as well as increased CHO and delta increases in PDC activity (0-60 min) both in muscle and liver. These results demonstrated the suppressive role of FFA acids on the measured parameters. Furthermore, the results clearly demonstrate a rapid reactivation of PDC in liver and muscle of lean and obese rats after a glucose load and show that PDC activity is significantly lower in obese ZDF rats.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schummer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Werner
authors.forename: Norbert
authors.initials: N
authors.lastname: Tennagels
authors.forename: Dieter
authors.initials: D
authors.lastname: Schmoll
authors.forename: Guido
authors.initials: G
authors.lastname: Haschke
authors.forename: Hans-Paul
authors.initials: HP
authors.lastname: Juretschke
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
authors.forename: Martin
authors.initials: M
authors.lastname: Gerl
authors.forename: Werner
authors.initials: W
authors.lastname: Kramer
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Herling
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D013217:Starvation / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D017346:Protein Serine-Threonine Kinases