Improving insulin sensitivity via activation of PPAR-gamma increases telomerase activity in the heart of OLETF rats.
This study was conducted to examine telomere biology in terms of improving insulin sensitivity in a type 2 diabetic animal model: Otsuka Long-Evans Tokushima fatty (OLETF) rats. To improve insulin sensitivity, pioglitazone (PG; 10 mg.kg(-1).day(-1)) was administrated to OLETF rats from 20 to 40 wk of age, and the effects of treatment were compared with those in untreated OLETF or control Long-Evans Tokushima Otsuka fatty rats. At the end of the study, the homeostasis model assessment of insulin resistance significantly increased in OLETF rats but decreased in OLETF rats treated with PG. No shortening of telomere length was observed in the heart tissue of OLETF rats, whereas telomerase activity was decreased in OLETF heart tissue. The mRNA expression of both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. The protein expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase was reduced in OLETF rats. On the other hand, myocardial matrix metalloproteinase-9 expression was elevated in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. However, protein and mRNA expression of Sirt1, a lifespan modulator, were attenuated in OLETF rat hearts, although they were enhanced in OLETF rats with PG treatment. Myocardial fibrosis was less extensive and diastolic dysfunction more greatly ameliorated in PG-treated OLETF rats than in OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisom proliferator-activated receptor-gamma may exert regulatory effects on cardiac telomere biology and may have desirable morphological and functional effects on the diabetic heart.
Makino
Naoki
N
Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, Japan. makinon@beppu.kyushu-u.ac.jp
Maeda
Toyoki
T
Oyama
Jun-ichi
J
Higuchi
Yosihiro
Y
Mimori
Koji
K
D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D056564:Sirtuin 1 / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D013002:Somatomedins; D035341:Telomeric Repeat Binding Protein 2; D045162:Thiazolidinediones; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; D020780:Matrix Metalloproteinase 9; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077205:Pioglitazone