TY - JOUR

T1 - Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle

T2 - a 2x2 factorial, randomised, crossover study in human individuals

AU - Hjelholt, Astrid J.

AU - Charidemou, Evelina

AU - Griffin, Julian L.

AU - Pedersen, Steen B.

AU - Gudiksen, Anders

AU - Pilegaard, Henriette

AU - Jessen, Niels

AU - Møller, Niels

AU - Jørgensen, Jens O. L.

PY - 2020

Y1 - 2020

N2 - Aims/hypothesisGrowth hormone (GH) causes insulin resistance that is linked to lipolysis, but the underlying mechanisms are unclear. We investigated if GH-induced insulin resistance in skeletal muscle involves accumulation of diacylglycerol (DAG) and ceramide as well as impaired insulin signalling, or substrate competition between fatty acids and glucose.MethodsNine GH-deficient male participants were randomised and examined in a 2x2 factorial design with and without administration of GH and acipimox (an anti-lipolytic compound). As-treated analyses were performed, wherefore data from three visits from two patients were excluded due to incorrect GH administration. The primary outcome was insulin sensitivity, expressed as the AUC of the glucose infusion rate (GIR(AUC)), and furthermore, the levels of DAGs and ceramides, insulin signalling and the activity of the active form of pyruvate dehydrogenase (PDHa) were assessed in skeletal muscle biopsies obtained in the basal state and during a hyperinsulinaemic-euglycaemic clamp (HEC).ResultsCo-administration of acipimox completely suppressed the GH-induced elevation in serum levels of NEFA (GH versus GH+acipimox, p

AB - Aims/hypothesisGrowth hormone (GH) causes insulin resistance that is linked to lipolysis, but the underlying mechanisms are unclear. We investigated if GH-induced insulin resistance in skeletal muscle involves accumulation of diacylglycerol (DAG) and ceramide as well as impaired insulin signalling, or substrate competition between fatty acids and glucose.MethodsNine GH-deficient male participants were randomised and examined in a 2x2 factorial design with and without administration of GH and acipimox (an anti-lipolytic compound). As-treated analyses were performed, wherefore data from three visits from two patients were excluded due to incorrect GH administration. The primary outcome was insulin sensitivity, expressed as the AUC of the glucose infusion rate (GIR(AUC)), and furthermore, the levels of DAGs and ceramides, insulin signalling and the activity of the active form of pyruvate dehydrogenase (PDHa) were assessed in skeletal muscle biopsies obtained in the basal state and during a hyperinsulinaemic-euglycaemic clamp (HEC).ResultsCo-administration of acipimox completely suppressed the GH-induced elevation in serum levels of NEFA (GH versus GH+acipimox, p

KW - Acipimox

KW - Ceramides

KW - Diacylglycerols

KW - Fatty acids

KW - Growth hormone

KW - Insulin resistance

KW - Insulin signalling

KW - Pyruvate dehydrogenase activity

KW - FREE FATTY-ACIDS

KW - ADIPOSE-TISSUE

KW - GLUCOSE DISPOSAL

KW - METABOLISM

KW - SENSITIVITY

KW - ACTIVATION

KW - MECHANISMS

KW - EXPRESSION

KW - 3-KINASE

KW - FOREARM

U2 - 10.1007/s00125-020-05262-w

DO - 10.1007/s00125-020-05262-w

M3 - Journal article

C2 - 32945898

VL - 63

SP - 2641

EP - 2653

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 12

ER -