gms | German Medical Science

28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga

24. bis 27.11.2004, Hannover

The PPARgamma-Activating ARB Irbesartan Stimulates Expression of the Insulin-Signaling Protein CAP and Enhances Insulin-Induced Glucose-Uptake

Der PPARgamma-Aktivierende ARB Irbesartan stimuliert die Expression des Insulinsignalproteins CAP

Meeting Abstract (Hypertonie 2004)

  • M. Clemenz - Center for Cardiovascular Research, (Berlin, D)
  • M. Schupp - Center for Cardiovascular Research, (Berlin, D)
  • J. Frank - Center for Cardiovascular Research, (Berlin, D)
  • M. Goebel - Center for Cardiovascular Research, (Berlin, D)
  • T. Unger - Center for Cardiovascular Research, (Berlin, D)
  • U. Kintscher - Center for Cardiovascular Research, (Berlin, D)

Hypertonie 2004. 28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga. Hannover, 24.-27.11.2004. Düsseldorf, Köln: German Medical Science; 2005. Doc04hochP27

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Veröffentlicht: 10. August 2005

© 2005 Clemenz et al.
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Angiotensin type 1 receptor (AT1R) blockers (ARBs) have been recently shown to decrease the incidence of new onset diabetes in clinical studies. However, the underlying mechanism of the anti-diabetic actions of ARBs are widely unknown. We could recently demonstrate that certain ARBs are partial agonists of the insulin-sensitizing nuclear hormone receptor Peroxisome Proliferator-Activated Receptor gamma(PPARg). To identify further anti-diabetic mechanisms of ARBs, we studied the regulation of insulin-induced glucose-uptake and insulin signaling, by the PPARg-activating ARB irbesartan in murine 3T3-L1 adipocytes.

To exclude AT1R-dependent effects of irbesartan all experiments were performed in the absence of angiotensin II. Glucose uptake was measured by determining the rate of [3H]2-deoxy-D-glucose uptake in the presence and absence of irbesartan (10µmol/L). Irbesartan induced insulin-stimulated glucose-uptake by 26.2+/-2.6% (p<0.05 vs.insulin-alone). To identify new molecular targets for irbesartan-induced glucose-uptake we examined the regulation of various insulin-signaling molecules carrying a PPAR response element by quantitative real-time PCR. We identified CAP, an adapter protein required for insulin-induced Glut-4 translocation, as a target of irbesartan. Irbesartan induced CAP mRNA expression by 1.8+/-0.2-fold (p<0.05 vs.vehicle-treated cells) after 24h stimulation independently of AT1R-blockade (absence of angiotensinII). The full PPARg agonist pioglitazone led to 2.26+/-0.3-fold induction of CAP mRNA (p<0.05 vs.vehicle-treated cells).

In the present study we demonstrate that the PPARg-activating ARB irbesartan induces expression of the insulin-signaling protein CAP independently of AT1R-blockade, which was associated by a stimulation of insulin-induced glucose-uptake in adipocytes. PPARg-dependent CAP regulation by irbesartan may provide a new mechanism for the anti-diabetogenic effects of certain ARBs.