title: Antidiabetic treatment restores adiponectin serum levels and APPL1 expression, but does not improve adiponectin-induced vasodilation and endothelial dysfunction in Zucker diabetic fatty rats.
abstract: BACKGROUND
  Adiponectin is able to induce NO-dependent vasodilation in Zucker lean (ZL) rats, but this effect is clearly alleviated in their diabetic littermates, the Zucker diabetic fatty (ZDF) rats. ZDF rats also exhibit hypoadiponectinemia and a suppressed expression of APPL1, an adaptor protein of the adiponectin receptors, in mesenteric resistance arteries. Whether an antidiabetic treatment can restore the vasodilatory effect of adiponectin and improve endothelial function in diabetes mellitus type 2 is not known.
  
  
  METHODS
  During our animal experiment from week 11 to 22 in each case seven ZDF rats received an antidiabetic treatment with either insulin (ZDF+I) or metformin (ZDF+M). Six normoglycemic ZL and six untreated ZDF rats served as controls. Blood glucose was measured at least weekly and serum adiponectin levels were quantified via ELISA in week 11 and 22. The direct vasodilatory response of their isolated mesenteric resistance arteries to adiponectin as well as the endothelium-dependent and -independent function was evaluated in a small vessel myograph. Additionally, the expression of different components of the adiponectin signaling pathway in the resistance arteries was quantified by real-time RT-PCR.
  
  
  RESULTS
  In ZDF rats a sufficient blood glucose control could only be reached by treatment with insulin, but both treatments restored the serum levels of adiponectin and the expression of APPL1 in small resistance arteries. Nevertheless, both therapies were not able to improve the vasodilatory response to adiponectin as well as endothelial function in ZDF rats. Concurrently, a downregulation of the adiponectin receptors 1 and 2 as well as endothelial NO-synthase expression was detected in insulin-treated ZDF rats. Metformin-treated ZDF rats showed a reduced expression of adiponectin receptor 2.
  
  
  CONCLUSIONS
  An antidiabetic treatment with either insulin or metformin in ZDF rats inhibits the development of hypoadiponectinemia and downregulation of APPL1 in mesenteric resistance arteries, but is not able to improve adiponectin induced vasodilation and endothelial dysfunction. This is possibly due to alterations in the expression of adiponectin receptors and eNOS.
authors.affiliation: Klinik und Poliklinik für Innere Medizin 2, Franz-Josef-Strauss Allee 11, University of Regensburg, Regensburg, 93042, Germany. peterm.schmid@ukr.de
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schmid
authors.forename: Markus
authors.initials: M
authors.lastname: Resch
authors.forename: Christian
authors.initials: C
authors.lastname: Schach
authors.forename: Christoph
authors.initials: C
authors.lastname: Birner
authors.forename: Guenter A
authors.initials: GA
authors.lastname: Riegger
authors.forename: Andreas
authors.initials: A
authors.lastname: Luchner
authors.forename: Dierk H
authors.initials: DH
authors.lastname: Endemann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D052242:Adiponectin / Q000097:blood*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D051381:Rats; D011924:Rats, Zucker; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C515694:Appl1 protein, rat; D015415:Biomarkers; D007004:Hypoglycemic Agents; D009419:Nerve Tissue Proteins