Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle: ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-09-18

AUTHORS

Astrid J. Hjelholt, Evelina Charidemou, Julian L. Griffin, Steen B. Pedersen, Anders Gudiksen, Henriette Pilegaard, Niels Jessen, Niels Møller, Jens O. L. Jørgensen

ABSTRACT

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 2 × 2 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 (GIRAUC), 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 < 0.0001) and abrogated GH-induced insulin resistance (mean GIRAUC [95% CI] [mg min−1 kg−1] during the HEC: control, 595 [493, 718]; GH, 468 [382, 573]; GH+acipimox, 654 [539, 794]; acipimox, 754 [618, 921]; GH vs GH+acipimox: p = 0.004). GH did not significantly change either the accumulation of DAGs and ceramides or insulin signalling in skeletal muscle, but GH antagonised the insulin-stimulated increase in PDHa activity (mean ± SEM [% from the basal state to the HEC]: control, 47 ± 19; GH, −15 ± 21; GH+acipimox, 3 ± 21; acipimox, 57 ± 22; main effect: p = 0.02).Conclusions/interpretationGH-induced insulin resistance in skeletal muscle is: (1) causally linked to lipolysis; (2) not associated with either accumulation of DAGs and ceramides or impaired insulin signalling; (3) likely to involve substrate competition between glucose and lipid intermediates.Trial registrationClinicalTrials.gov NCT02782208FundingThe work was supported by the Grant for Growth Innovation (GGI), which was funded by Merck KGaA, Darmstadt, Germany.Graphical abstract More... »

PAGES

2641-2653

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00125-020-05262-w

DOI

http://dx.doi.org/10.1007/s00125-020-05262-w

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1130931684

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/32945898


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32 Abstract Insulin resistance
33 Aims/hypothesisGrowth hormone
34 Conclusions/interpretationGH
35 Darmstadt
36 GH
37 GH administration
38 GH-deficient male participants
39 Germany
40 Graphical abstract Insulin resistance
41 Growth Innovation
42 KGaA
43 Merck KGaA
44 MethodsNine GH-deficient male participants
45 NCT02782208FundingThe work
46 NEFA
47 PDHa activity
48 ResultsCo-administration
49 accumulation
50 accumulation of diacylglycerol
51 acid
52 acipimox
53 active form
54 activity
55 administration
56 administration of GH
57 analysis
58 basal state
59 biopsy
60 ceramide
61 clamp
62 competition
63 crossover study
64 data
65 dehydrogenase
66 dehydrogenase activity
67 design
68 diacylglycerol
69 elevation
70 factorial design
71 fatty acids
72 form
73 glucose
74 glucose infusion rate
75 grants
76 growth hormone
77 hormone
78 human individuals
79 hyperinsulinaemic euglycaemic clamp
80 hypothesisGrowth hormone
81 increase
82 individuals
83 infusion rate
84 innovation
85 insulin
86 insulin resistance
87 insulin sensitivity
88 insulin signaling
89 insulin-stimulated increase
90 intermediates
91 interpretationGH
92 levels
93 levels of diacylglycerol
94 lipid intermediates
95 lipolysis
96 male participants
97 mechanism
98 muscle
99 muscle biopsy
100 outcomes
101 participants
102 patients
103 primary outcome
104 pyruvate dehydrogenase
105 pyruvate dehydrogenase activity
106 rate
107 resistance
108 sensitivity
109 serum levels
110 signaling
111 skeletal muscle
112 skeletal muscle biopsies
113 state
114 study
115 substrate competition
116 underlying mechanism
117 visits
118 wherefore data
119 work
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