Prediabetic insulin resistance is not permissive to the development of cardiac resistance to insulin-like growth factor I in ventricular myocytes

Resistance to insulin-like growth factor I (IGF-1)-induccd cardiac contractile response has been reported in diabetes. To evaluate the role of prediabetic insulin resistance to cardiac IGF-1 resistance, whole body insulin resistance was generated with dietary sucrose and contractile function was evaluated in ventricular rnyocytes. Mechanical properties were evaluated using an lonOptix(TM) system and intracellular Ca2+ transients were measured as changes in fura-2 fluorescence intensity (DeltaFFI). After 8 weeks of feeding, sucrose rats displayed euglycemia, hepatomeglay and normal heart size, and glucose intolerance, confirming the presence of insulin resistance. Myocytes from sucrose-fed rats displayed decreased peak shortening (PS), reduced resting FFI, increased intracellular Ca2+ clearing, associated with normal duration of shortening and relengthening compared to myocytes from starch-fed rats. IGF-1 (10(-10) 10(-6) M) caused a similar concentration-dependent decrease in PS in both groups. Only the highest concentration of IGF-1 elicited an inhibition on DeltaFFI in Sucrose myocytes. In addition, the IGF-1-induced response was abolished by the IGF-1 receptor antagonist H-1356 in both groups, and by the nitric oxide synthase inhibitor L-NAME in starch but not sucrose myocytes. These results indicated prediabetic insulin resistance alters cardiac contractile function at the myocytes level, but may not be permissive to cardiac contractile resistance to IGF-1. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.