High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: An important role for skeletal muscle pyruvate dehydrogenase kinase 4.
OBJECTIVE
The aim of this report was to study the effect of high-fat (HF)/low-carbohydrate (CHO) diet on regulation of substrate metabolism in humans.


METHODS
Ten healthy men consumed either a HF (75% energy as fat) or control (35%) diet for 6 d in random order. On d 7, blood glucose disappearance rate (Rd) was determined before and during a hyperinsulinemic euglycemic clamp. Substrate oxidation was determined by indirect calorimetry. Muscle biopsies were obtained prediet, postdiet, and postclamps.


RESULTS
Rd was similar under basal conditions but slightly elevated (approximately 10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by approximately 40%, P < 0.05) and clamp conditions (by approximately 20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by approximately 25%, P < 0.05). Muscle pyruvate dehydrogenase complex activity was blunted under basal and clamp conditions after HF compared with control (P < 0.05) and was accompanied by an approximately 2-fold increase (P < 0.05) in pyruvate dehydrogenase kinase 4 (PDK4) mRNA and protein expression.


CONCLUSIONS
Short-term HF/low-CHO dietary intake did not induce whole-body insulin resistance, but caused a shift in im glucose metabolism from oxidation to glycogen storage. Insulin-stimulated CHO oxidation and muscle pyruvate dehydrogenase complex activity were blunted after the HF diet. Up-regulation of muscle PDK4 expression was an early molecular adaptation to these changes, and we showed for the first time in healthy humans, unlike insulin-resistant individuals, that insulin can suppress PDK4 but not PDK2 gene expression in skeletal muscle.
Chokkalingam
K
K
Center for Integrated Systems Biology and Medicine, Institute of Clinical Research, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
Jewell
K
K
Norton
L
L
Littlewood
J
J
van Loon
L J C
LJ
Mansell
P
P
Macdonald
I A
IA
Tsintzas
K
K
D000328:Adult; D050260:Carbohydrate Metabolism; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004041:Dietary Fats / Q000008:administration & dosage*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis
D004040:Dietary Carbohydrates; D004041:Dietary Fats; D007328:Insulin; D012333:RNA, Messenger; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D005947:Glucose