Journal
MOLECULAR METABOLISM
Volume 35, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.molmet.2020.01.013
Keywords
Apolipoprotein A-1 (ApoA-1); AMP-Activated protein kinase (AMPK); Glucose uptake; Skeletal muscle; Insulin; Metabolism
Categories
Funding
- Danish Diabetes Academy - Novo Nordisk Foundation [NNF17SA0031406]
- Benzon Foundation
- Danish Council for Independent Research/Medicine [4004-00233, 4183-00249]
- University of Copenhagen
- Swedish Research Council [K2014-54X-22426-01-3, 2016-02124, 2009-1039]
- Swedish Diabetes Foundation
- Albert Pahlsson Foundation
- Novo Nordisk Foundation
- NovoNordisk A/S
- Krapperup Foundation
- Swedish Foundation for Strategic Research [IRC15-0067]
- Diabetes Research and Wellness Foundation Sweden
- Swedish Research Council [2016-02124] Funding Source: Swedish Research Council
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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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