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Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota 58203
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 · day1 ip)
treatment. Mechanical properties were assessed in ventricular myocytes
including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocities of
shortening/relengthening (±dL/dt). Intracellular
Ca2+ transients were evaluated as Ca2+-induced
Ca2+ release and Ca2+ clearing constant. Levels
of sarco(endo)plasmic reticulum Ca2+-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, TR90, and intracellular Ca2+ clearing compared with control.
IGF-I treatment prevented the diabetes-induced abnormalities in PS,
±dL/dt, TR90, and Ca2+ 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.
diabetic cardiomyopathy; insulin-like growth factor I; ventricular myocytes; sarco(endo)plasmic reticulum Ca2+-ATPase; glucose transporter 4
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