Rosemary extract activates AMPK, inhibits mTOR and attenuates the high glucose and high insulin-induced muscle cell insulin resistance

Appl Physiol Nutr Metab. 2021 Jul;46(7):819-827. doi: 10.1139/apnm-2020-0592. Epub 2021 Jan 20.

Abstract

Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus. In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mmol/L glucose and 100 nmol/L insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reducing the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: RE phosphorylated muscle cell AMPK and ACC under both normal and HG+HI conditions. The HG+HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. RE restored the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.

Keywords: AMPK; GLUT4; IRS-1; extrait de romarin; hyperglycemia; hyperglycémie; hyperinsulinemia; hyperinsulinémie; insulin resistance; insulinorésistance; mTOR; muscle squelettique; rosemary extract; skeletal muscle.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Cells, Cultured
  • Deoxyglucose / metabolism
  • Disease Models, Animal
  • Enzyme Activation / drug effects*
  • Glucose Transporter Type 4 / metabolism
  • Hyperglycemia / metabolism*
  • Hyperinsulinism / metabolism*
  • Insulin / blood
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / physiology*
  • Muscle Fibers, Skeletal / metabolism*
  • Phosphorylation
  • Plant Extracts / pharmacology*
  • Rats
  • Rosmarinus*
  • Serine / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Tyrosine / metabolism

Substances

  • Blood Glucose
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Plant Extracts
  • Tyrosine
  • Serine
  • Deoxyglucose
  • mTOR protein, rat
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases