Reduced contractile response to insulin and IGF-I in ventricular myocytes from genetically obese Zucker rats.
Obesity plays a pivotal role in the pathophysiology of metabolic and cardiovascular diseases. Resistance to insulin is commonly seen in metabolic disorders such as obesity and diabetes. Insulin-like growth factor-I (IGF-I) mimics insulin in many tissues and has been shown to enhance cardiac contractile function and growth. Because IGF-I resistance often accompanies resistance to insulin, we sought to determine whether IGF-I-induced myocardial contractile was elevated and whether heart and kidney size were enlarged in obese compared with lean rats. The myocyte contraction profile in the obese rats showed a decreased peak shortening associated with prolonged relengthening and normal shortening duration, a pattern similar to that observed in diabetes. IGF-I (1-500 ng/ml) caused a dose-dependent increase in peak shortening in lean but not obese animals, but it did not alter the duration of shortening and relengthening. Consistent with contractile data, IGF-I induced a dose-dependent increase in Ca(2+) transients only in myocytes of lean rats. IGF-I receptor mRNA levels were significantly reduced in obese rat hearts. These results suggest that the IGF-I-induced cardiac contractile responses are attenuated in the Zucker model of obesity. The mechanisms underlying this alteration may be related to the decreased receptor number and/or changes in intracellular Ca(2+) handling in these animals.
Ren
J
J
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota 58203, USA. jren@medicine.nodak.edu
Sowers
J R
JR
Walsh
M F
MF
Brown
R A
RA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D017526:Receptor, IGF Type 1 / Q000235:genetics; D012016:Reference Values; D016276:Ventricular Function / Q000187:drug effects*
D007328:Insulin; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D002118:Calcium