title: Direct angiotensin II type 2 receptor stimulation ameliorates insulin resistance in type 2 diabetes mice with PPARγ activation.
abstract: OBJECTIVE
  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 PPARγ activation, mainly focusing on adipose tissue.
  
  
  METHODS
  T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPARγ 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.
  
  
  RESULTS
  Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPARγ pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-α concentration; however, these effects were attenuated by PPARγ blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPARγ 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 β cell damage in diabetic pancreatic tissue.
  
  
  CONCLUSIONS
  The present study demonstrated that direct AT(2) receptor stimulation by C21 accompanied with PPARγ activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic β cells.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan.
authors.forename: Kousei
authors.initials: K
authors.lastname: Ohshima
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ogimoto
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlöf
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Steckelings
authors.forename: Tomas
authors.initials: T
authors.lastname: Unger
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D052242:Adiponectin; D000813:Anilides; D001786:Blood Glucose; D007328:Insulin; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D047495:PPAR gamma; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha