Cardiomyopathic Changes in Offspring of Diabetic Rats.

Abstract

Background: Infants born to mothers with gestational diabetes are known to have organomegally and asymmetric septal hypertrophy. The purpose of this study is to evaluate the myocardial response in the offspring of severely diabetic rats and characterize the mitogen-activated protein kinase (MAPK) signaling pathways that may mediate these responses. Hypothesis: In a rat model of infant of diabetic mothers (IDM), cardiomyopathic changes develop in the offspring and that the MAPKs will regulate the cardiac responses. Methods: Pregnant rats were given either 50mg/ kg of streptozotocin or normal saline intravenously on day 7 of gestation (term=23 d). Maternal blood glucose levels were monitored. Animals were studied on days 18 (E18) and 21 (E21) of gestation, and postnatal days 1 (NB1), 5 (NB5) and 21 (NB21). Hearts were harvested and the ventricles weighed and then frozen in liquid nitrogen. MAPKs measured by Western blot included total and activated (phosphorylated) levels of c-jun-n terminal kinase 1 (JNK1 and pJNK1) and 2 (JNK2 and pJNK2) and extracellular signal-regulated kinase 1/2 (ERK1/2 and pERK1/2). NB1 and NB21 pups underwent echocardiographic study to evaluate left ventricular dimensions and function. Results: The mean heart to body weight ratio (HW/BW) was significantly elevated in the offspring of diabetic mothers when compared to controls due to a significant decline in BW (see Table 1). No differences were observed between controls and IDM offspring in the levels of ERK1/2, pERK1/2, JNK1, pJNK1 and pJNK2. Total JNK2 differed by age and treatment when analyzed by two-way ANOVA (p<.05). Echocardiographic analysis revealed a greater than two-fold increase in end-systolic LV volume and reduced LV ejection fraction in the NB1 IDM pups compared to controls although cardiac output was unchanged. LV dimensions and function were not different between IDM and control pups at NB21. Conclusions: With severe diabetes, IDM had diminished somatic growth that exceeds the decline in heart growth. A cardiomyopathy was present in the immediate newborn period that did not result in activation of the MAPK pathways and resolved by 21d postnatally.