title: IGF-I attenuates diabetes-induced cardiac contractile dysfunction in ventricular myocytes.
abstract: Diabetic cardiomyopathy is characterized by impaired ventricular contraction and altered function of insulin-like growth factor I (IGF-I), a key factor for cardiac growth and function. Endogenous IGF-I has been shown to alleviate diabetic cardiomyopathy. This study was designed to evaluate exogenous IGF-I treatment on the development of diabetic cardiomyopathy. Adult rats were divided into four groups: control, control + IGF-I, diabetic, and diabetic + IGF-I. Streptozotocin (STZ; 55 mg/kg) was used to induce experimental diabetes immediately followed by a 7-wk IGF-I (3 mg. kg(-1). day(-1) ip) treatment. Mechanical properties were assessed in ventricular myocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca(2+) transients were evaluated as Ca(2+)-induced Ca(2+) release and Ca(2+) clearing constant. Levels of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and glucose transporter (GLUT4) were assessed by Western blot. STZ caused significant weight loss and elevated blood glucose, demonstrating the diabetic status. The diabetic state is associated with reduced serum IGF-I levels, which were restored by IGF-I treatment. Diabetic myocytes showed reduced PS and +/-dL/dt as well as prolonged TPS, TR(90), and intracellular Ca(2+) clearing compared with control. IGF-I treatment prevented the diabetes-induced abnormalities in PS, +/-dL/dt, TR(90), and Ca(2+) clearing but not TPS. The levels of SERCA and GLUT4, but not PLB, were significantly reduced in diabetic hearts compared with controls. IGF-I treatment restored the diabetes-induced decline in SERCA, whereas it had no effect on GLUT4 and PLB levels. These results suggest that exogenous IGF-I treatment may ameliorate contractile disturbances in cardiomyocytes from diabetic animals and could provide therapeutic potential in the treatment of diabetic cardiomyopathy.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota 58203, USA.
authors.forename: Faye L
authors.initials: FL
authors.lastname: Norby
authors.forename: Loren E
authors.initials: LE
authors.lastname: Wold
authors.forename: Jinhong
authors.initials: J
authors.lastname: Duan
authors.forename: Kadon K
authors.initials: KK
authors.lastname: Hintz
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000378:metabolism; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D051275:Glucose Transporter Type 4; D006352:Heart Ventricles / Q000166:cytology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D009124:Muscle Proteins; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D051275:Glucose Transporter Type 4; D007334:Insulin-Like Growth Factor I; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C495694:Slc2a4 protein, rat