Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes.

Diabetic cardiomyopathy is characterized by cardiac dysfunction and altered level/function of insulin-like growth factor I (IGF-I). Both endogenous and exogenous IGF-I have been shown to effectively alleviate diabetes-induced cardiac dysfunction and oxidative stress. This study was designed to examine the effect of cardiac overexpression of IGF-I on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse myocytes. Both IGF-I heterozygous transgenic mice and their wild-type FVB littermates were made diabetic with a single injection of STZ (200 mg/kg, i.p.) and maintained for 2 weeks. The following mechanical indices were evaluated in ventricular myocytes: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/- dL/dt). Intracellular Ca2+ was evaluated as resting and peak intracellular Ca2+ levels, Ca2+-induced Ca2+ release and intracellular Ca2+ decay rate (tau). STZ led to hyperglycemia in FVB and IGF-I mice. STZ treatment prolonged TPS and TR90, reduced Ca2+-induced Ca2+ release, increased resting intracellular Ca2+ levels and slowed tau associated with normal PS and +/- dL/dt. All of which, except the elevated resting intracellular Ca2+, were prevented by the IGF-I transgene. In addition, myocytes from STZ-treated FVB mice displayed an attenuated contractile response to the beta-adrenergic agonist isoproterenol, which was restored by the IGF-I transgene. Contractile response to the alpha-adrenergic agonist phenylephrine and angiotensin II was not affected by either STZ treatment or IGF-I. These results validate the beneficial role of IGF-I in diabetic cardiomyopathy, possibly due to an improved beta-adrenergic response.

Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes.

Insulin resistance is a metabolic syndrome commonly seen in obesity. Leptin, the obese gene product, plays a role in the regulation of cardiac function. Elevated leptin levels have been demonstrated under insulin-resistant states such as obesity and hypertension, although their role in cardiac dysfunction is unknown. This study was designed to determine the impact of prediabetic insulin resistance on leptin levels and leptin-induced cardiac contractile response. Whole-body insulin resistance was generated with a 10-week dietary sucrose feeding. Contractile and intracellular Ca(2+) properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt), fura-fluorescence intensity change (deltaFFI) and decay rate (tau). Sucrose-fed rats displayed significantly elevated body weight and plasma leptin levels, depressed PS, +/-dL/dt, shortened TPS, prolonged TR(90) and tau, as well as reduced deltaFFI compared to the starch-fed control group. Leptin (1-1000 nM) elicited a concentration-dependent depression of PS and deltaFFI in myocytes from both starch and sucrose groups. Leptin-induced contractile depression was abolished by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyle ester, elevation of the extracellular Ca(2+) concentration, the Janus activated kinase 2 inhibitor AG-490 or the mitogen activated protein kinase inhibitor SB203580 in myocytes from both sucrose and starch groups. Moreover, AG-490 and SB203580 unmasked a positive response of PS in myocytes from both groups. These data indicate that insulin resistance directly induces hyperleptinemia and cardiac contractile dysfunction, without affecting leptin-mediated cardiac contractile function at the myocyte level.