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

K. Chokkalingam, K. Jewell, Luke Norton, J. Littlewood, L. J C Van Loon, P. Mansell, I. A. Macdonald, K. Tsintzas

Research output: Contribution to journalArticle

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Abstract

Aim: 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: R d was similar under basal conditions but slightly elevated (∼10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by ∼40%, P < 0.05) and clamp conditions (by ∼20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by ∼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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)284-292
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

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Carbohydrate-Restricted Diet
Nutrition
Muscle
Skeletal Muscle
Fats
Carbohydrates
Insulin
High Fat Diet
Glucose
Muscles
Oxidation
Clamping devices
Pyruvate Dehydrogenase Complex
Glycogen
Indirect Calorimetry
Metabolism
Glucose Clamp Technique
Insulin Resistance
Blood Glucose
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Chokkalingam, K.; Jewell, K.; Norton, Luke; Littlewood, J.; Van Loon, L. J C; Mansell, P.; Macdonald, I. A.; Tsintzas, K.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 1, 01.2007, p. 284-292.

Research output: Contribution to journalArticle

Chokkalingam, K. ; Jewell, K. ; Norton, Luke ; Littlewood, J. ; Van Loon, L. J C ; Mansell, P. ; Macdonald, I. A. ; Tsintzas, K. / 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. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 1. pp. 284-292.
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abstract = "Aim: 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: R d was similar under basal conditions but slightly elevated (∼10{\%}, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by ∼40{\%}, P < 0.05) and clamp conditions (by ∼20{\%}, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30{\%}, P < 0.05) and muscle glycogen storage (by ∼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. Conclusion: 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.",
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T1 - High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans

T2 - An important role for skeletal muscle pyruvate dehydrogenase kinase 4

AU - Chokkalingam, K.

AU - Jewell, K.

AU - Norton, Luke

AU - Littlewood, J.

AU - Van Loon, L. J C

AU - Mansell, P.

AU - Macdonald, I. A.

AU - Tsintzas, K.

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N2 - Aim: 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: R d was similar under basal conditions but slightly elevated (∼10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by ∼40%, P < 0.05) and clamp conditions (by ∼20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by ∼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. Conclusion: 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.

AB - Aim: 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: R d was similar under basal conditions but slightly elevated (∼10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by ∼40%, P < 0.05) and clamp conditions (by ∼20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by ∼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. Conclusion: 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.

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