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Chronic administration of the angiotensin type 2 receptor agonist C21 improves insulin sensitivity in C57BL/6 mice

Diego Tomás Quiroga1, Marina C Muñoz1, Carolina Gil1

  • 1Departamento de Química Biológica-Instituto de Química y Fisicoquímica Biológicas (CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.

Physiological Reports
|August 30, 2018
PubMed

Insights

Activating the angiotensin type 2 receptor (AT2R) with C21 enhances insulin sensitivity and glucose homeostasis in mice. This suggests the AT2R plays a protective role against insulin resistance and type 2 diabetes.

Area of Science:

  • Endocrinology
  • Metabolic Research
  • Pharmacology

Background:

  • The renin-angiotensin system influences insulin action, with angiotensin type 1 receptor (AT1R) having detrimental effects and angiotensin type 2 receptor (AT2R) showing protective potential against insulin resistance and type 2 diabetes.
  • Understanding the specific role of AT2R in modulating insulin sensitivity and glucose metabolism is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the effects of chronic pharmacological activation of the AT2R using the synthetic agonist C21 on insulin action and glucose homeostasis in C57Bl/6 mice.
  • To assess metabolic parameters, glucose and insulin tolerance, insulin signaling pathways, and key adipokine expressions in response to C21 treatment.

Main Methods:

  • C57Bl/6 mice were treated with C21 (1 mg/kg/day, ip) or vehicle for 12 weeks.
  • Evaluated metabolic parameters, performed glucose and insulin tolerance tests.
  • Assessed in vivo insulin signaling (Akt, ERK1/2 phosphorylation) in liver, adipose, and skeletal muscle tissues.
  • Measured adipose tissue adiponectin and TNF-α levels, adipocyte size, and UCP-1 expression.

Main Results:

  • C21 treatment led to decreased glycemia with unchanged insulinemia, improved insulin sensitivity, and enhanced glucose tolerance.
  • Observed reduced adipocyte size and increased adiponectin and UCP-1 expression in epididymal adipose tissue.
  • Increased basal Akt and ERK1/2 phosphorylation in the liver and enhanced insulin-stimulated Akt activation in adipose tissue.
  • Adipose tissue and skeletal muscle showed reduced ERK1/2 phosphorylation responsiveness to insulin.

Conclusions:

  • Chronic activation of AT2R with C21 significantly improves insulin sensitivity and glucose homeostasis in mice.
  • The AT2R appears to have a physiological role in maintaining insulin action, potentially through modulation of signaling pathways independent of the insulin receptor.
  • These findings highlight the therapeutic potential of targeting AT2R for managing insulin resistance and type 2 diabetes.
Keywords:
Adiponectinangiotensin type 2 receptorcompound 21insulin sensitivityrenin-angiotensin system

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