Publication Date:
2013-12-03
Description:
As shown in a large clinical prospective trial, inhibition of the renin-angiotensin system (RAS) can delay the onset of type 2 diabetes in high-risk individuals. We evaluated the beneficial effects of RAS inhibition on β-cell function under glucotoxic conditions. Human islets from 13 donors were cultured in 5.5 mM (controls) or 16.7 mM glucose [high glucose (HG)] for 4 d with or without losartan (5 μM), a selective AT1R blocker, and/or U73122 (2 μM), a selective PLC inhibitor, during the last 2 d. HG induced RAS activation with overexpression of AT1R ( P 〈0.05) and angiotensinogen ( P 〈0.001) mRNAs. HG increased endoplasmic reticulum (ER) stress markers ( P 〈0.001) such as GRP78, sXBP1, and ATF4 mRNAs and Grp78 protein levels ( P 〈0.01). HG also decreased reticular calcium concentration ( P 〈0.0001) and modified protein expressions of ER calcium pumps with reduction of SERCA2b ( P 〈0.01) and increase of IP3R2 ( P 〈0.05). Losartan prevented these deleterious effects and was associated with improved insulin secretion despite HG exposure. AT1R activation triggers the PLC-IP3-calcium pathway. Losartan prevented the increase of PLC β1 and 1 protein levels induced by HG ( P 〈0.05). U73122 reproduced all the protective effects of losartan. AT1R blockade protects human islets from the deleterious effects of glucose through inhibition of the PLC-IP3-calcium pathway.—Madec, A.-M., Cassel, R., Dubois, S., Ducreux, S., Vial, G., Chauvin, M.-A., Mesnier, A., Chikh, K., Bosco, D., Rieusset, J., Van Coppenolle, F., Thivolet, C. Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway.
Print ISSN:
0892-6638
Electronic ISSN:
1530-6860
Topics:
Biology
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