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Fritzen, A.M.* ; Domingo-Espín, J.* ; Lundsgaard, A.M.* ; Kleinert, M. ; Israelsen, I.* ; Carl, C.S.* ; Nicolaisen, T.S.* ; Kjøbsted, R.* ; Jeppesen, J.F.* ; Wojtaszewski, J.F.P.* ; Lagerstedt, J.O.* ; Kiens, B.*

ApoA-1 improves glucose tolerance by increasing glucose uptake into heart and skeletal muscle independently of AMPKα2.

Mol. Metab. 35:100949 (2020)
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Objective: Acute administration of the main protein component of high-density lipoprotein, apolipoprotein A-I (ApoA-1), improves glucose uptake in skeletal muscle. The molecular mechanisms mediating this are not known, but in muscle cell cultures, ApoA-1 failed to increase glucose uptake when infected with a dominant-negative AMP-activated protein kinase (AMPK) virus. We therefore investigated whether AMPK is necessary for ApoA-1-stimulated glucose uptake in intact heart and skeletal muscle in vivo.Methods: The effect of injection with recombinant human ApoA-1 (rApoA-1) on glucose tolerance, glucose-stimulated insulin secretion, and glucose uptake into skeletal and heart muscle with and without block of insulin secretion by injection of epinephrine (0.1 mg/kg) and propranolol (5 mg/kg), were investigated in 8 weeks high-fat diet-fed (60E%) wild-type and AMPK alpha(2) kinase-dead mice in the overnight-fasted state. In addition, the effect of rApoA-1 on glucose uptake in isolated skeletal muscle ex vivo was studied.Results: rApoA-1 lowered plasma glucose concentration by 1.7 mmol/l within 3 h (6.1 vs 4.4 mmol/l; p < 0.001). Three hours after rApoA-1 injection, glucose tolerance during a 40-min glucose tolerance test (GTT) was improved compared to control (area under the curve (AUC) reduced by 45%, p < 0.001). This was accompanied by an increased glucose clearance into skeletal (+110%; p < 0.001) and heart muscle (+100%; p < 0.001) and an increase in glucose-stimulated insulin secretion 20 min after glucose injection (+180%; p < 0.001). When insulin secretion was blocked during a GTT, rApoA-1 still enhanced glucose tolerance (AUC lowered by 20% compared to control; p < 0.001) and increased glucose clearance into skeletal (+50%; p < 0.05) and heart muscle (+270%; p < 0.001). These improvements occurred to a similar extent in both wild-type and AMPK alpha(2) kinase-dead mice and thus independently of AMPK alpha(2) activity in skeletal- and heart muscle. Interestingly, rApoA-1 failed to increase glucose uptake in isolated skeletal muscles ex vivo.Conclusions: In conclusion, ApoA-1 stimulates in vivo glucose disposal into skeletal and heart muscle independently of AMPK alpha(2). The observation that ApoA-1 fails to increase glucose uptake in isolated muscle ex vivo suggests that additional systemic effects are required. (C) 2020 The Author(s). Published by Elsevier GmbH.
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Publication type Article: Journal article
Document type Scientific Article
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Keywords Apolipoprotein A-1 (apoa-1) ; Amp-activated Protein Kinase (ampk) ; Glucose Uptake ; Skeletal Muscle ; Insulin ; Metabolism; Apolipoprotein-a-i; High-density-lipoprotein; Activated Protein-kinase; Insulin Sensitivity; Phosphorylation Sites; Ampk; Hdl; Secretion; Reveals; Network
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Quellenangaben Volume: 35, Issue: , Pages: , Article Number: 100949 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)