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Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the

Anne-Marie Madec1, Roméo Cassel, Séverine Dubois

  • 12INSERM U1060/University Lyon 1/Inra 1235, Lyon-Sud Medicine, Faculty, 165 Chemin du Grand Revoyet-BP 12, 69921 Oullins Cedex, France. anne-marie.coquelet-madec@univ-lyon1.fr.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 7, 2013
PubMed

Insights

Renin-angiotensin system (RAS) blockade protects pancreatic beta cells from high glucose damage. Losartan, an AT1R blocker, prevents endoplasmic reticulum stress and improves insulin secretion by inhibiting the PLC-IP3-calcium pathway.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Inhibition of the renin-angiotensin system (RAS) delays type 2 diabetes onset in high-risk individuals.
  • High glucose (HG) conditions can impair pancreatic beta-cell function, a key factor in diabetes pathogenesis.

Purpose of the Study:

  • To investigate the protective effects of RAS inhibition on human islet beta-cell function under glucotoxic conditions.
  • To elucidate the molecular mechanisms, specifically the role of the AT1R-PLC-IP3-calcium pathway, in mediating these protective effects.

Main Methods:

  • Human islets were cultured under normal or high glucose conditions.
  • Islets were treated with losartan (AT1R blocker) and/or U73122 (PLC inhibitor).
  • Assessed RAS activation, endoplasmic reticulum (ER) stress markers, calcium levels, and protein expressions related to the PLC-IP3-calcium pathway.

Main Results:

  • High glucose induced RAS activation, ER stress, and altered ER calcium handling in human islets.
  • Losartan treatment prevented these detrimental effects and improved insulin secretion.
  • Losartan's protective effects were linked to the inhibition of the AT1R-PLC-IP3-calcium pathway, as U73122 mimicked losartan's actions.

Conclusions:

  • AT1R blockade protects human islets from high glucose-induced damage.
  • The protective mechanism involves the inhibition of the PLC-IP3-calcium signaling pathway.
  • RAS inhibition represents a potential therapeutic strategy to preserve beta-cell function in diabetes.
Keywords:
AT1R inhibitorER stressPLC-IP3-calcium pathwayRAScalcium homeostasisdiabeteshuman pancreatic β-cells

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