TY - JOUR
T1 - Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity
AU - Nellemann, B.
AU - Vendelbo, M.H.
AU - Nielsen, Thomas Svava
AU - Bak, A.M.
AU - Høgild, M.
AU - Pedersen, S.B.
AU - Biensø, Rasmus Sjørup
AU - Pilegaard, Henriette
AU - Møller, N.
AU - Jessen, N.
AU - Jørgensen, Jens Otto Lunde
N1 - This article is protected by copyright. All rights reserved.
PY - 2014/2
Y1 - 2014/2
N2 - Aim: Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting. Methods: Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Control, GH, Fasting (36 h) and GH + Fasting. GH (30 ng × kg-1 × min-1) or saline was infused throughout the metabolic study day. Substrate metabolism and insulin sensitivity were assessed by indirect calorimetry and isotopically determined rates of glucose turnover before and after a hyperinsulinemic euglycemic clamp. PDHa activity, PDH-E1α phosphorylation, PDK4 expression and activation of insulin signalling proteins were assessed in skeletal muscle. Results: Both fasting and GH promoted lipolysis, which was associated with ≈50% reduction in insulin sensitivity compared with the control day. PDHa activity was significantly reduced by GH as well as fasting. This was associated with increased inhibitory PDH-E1α phosphorylation on site 1 (Ser293) and 2 (Ser300) and up-regulation of PDK4 mRNA, while canonical insulin signalling to glucose transport was unaffected. Conclusion: Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects.
AB - Aim: Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting. Methods: Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Control, GH, Fasting (36 h) and GH + Fasting. GH (30 ng × kg-1 × min-1) or saline was infused throughout the metabolic study day. Substrate metabolism and insulin sensitivity were assessed by indirect calorimetry and isotopically determined rates of glucose turnover before and after a hyperinsulinemic euglycemic clamp. PDHa activity, PDH-E1α phosphorylation, PDK4 expression and activation of insulin signalling proteins were assessed in skeletal muscle. Results: Both fasting and GH promoted lipolysis, which was associated with ≈50% reduction in insulin sensitivity compared with the control day. PDHa activity was significantly reduced by GH as well as fasting. This was associated with increased inhibitory PDH-E1α phosphorylation on site 1 (Ser293) and 2 (Ser300) and up-regulation of PDK4 mRNA, while canonical insulin signalling to glucose transport was unaffected. Conclusion: Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects.
U2 - 10.1111/apha.12183
DO - 10.1111/apha.12183
M3 - Journal article
C2 - 24148194
SN - 1748-1708
VL - 210
SP - 392
EP - 402
JO - Acta Physiologica
JF - Acta Physiologica
IS - 2
ER -
