Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPAR gamma Activation

Kousei Ohshima*, Masaki Mogi, Fei Jing, Jun Iwanami, Kana Tsukuda, Li-Juan Min, Akiyoshi Ogimoto, Bjorn Dahlof, Ulrike Muscha Steckelings, Tomas Unger, Jitsuo Higaki, Masatsugu Horiuchi

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPAR? activation, mainly focusing on adipose tissue.T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPAR? antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[(3)H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined.Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPAR? pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-? concentration; however, these effects were attenuated by PPAR? blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPAR? DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored ? cell damage in diabetic pancreatic tissue.The present study demonstrated that direct AT(2) receptor stimulation by C21 accompanied with PPAR? activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic ? cells.
Original languageEnglish
Article numbere48387
Issue number11
Publication statusPublished - 14 Nov 2012

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