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Jens Lagerstedt

Associate professor

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

Author

  • Andreas Mæchel Fritzen
  • Joan Domingo-Espín
  • Anne Marie Lundsgaard
  • Maximilian Kleinert
  • Ida Israelsen
  • Christian S. Carl
  • Trine S. Nicolaisen
  • Rasmus Kjøbsted
  • Jacob F. Jeppesen
  • Jørgen F.P. Wojtaszewski
  • Jens O. Lagerstedt
  • Bente Kiens

Summary, in English

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 AMPKα2 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 AMPKα2 kinase-dead mice and thus independently of AMPKα2 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 AMPKα2. The observation that ApoA-1 fails to increase glucose uptake in isolated muscle ex vivo suggests that additional systemic effects are required.

Department/s

  • Medical Protein Science
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • LINXS - Lund Institute of advanced Neutron and X-ray Science

Publishing year

2020-05

Language

English

Publication/Series

Molecular Metabolism

Volume

35

Document type

Journal article

Publisher

Elsevier GmbH

Topic

  • Physiology
  • Endocrinology and Diabetes

Keywords

  • AMP-Activated protein kinase (AMPK)
  • Apolipoprotein A-1 (ApoA-1)
  • Glucose uptake
  • Insulin
  • Metabolism
  • Skeletal muscle

Status

Published

Research group

  • Medical Protein Science

ISBN/ISSN/Other

  • ISSN: 2212-8778