Cardiomyocyte dysfunction in insulin-resistant rats: A female advantage

Aims/hypothesis: The goal of this investigation was to determine whether there are sex-related differences in the development of cardiomyocyte dysfunction in prediabetic, insulin-resistant animals. Materials and methods: Male and female rats were maintained on a high-sucrose diet for 5-11 weeks, and mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection. Several in vitro interventions were used to manipulate intracellular Ca²⁺ in order to determine whether altered Ca²⁺ availability contributes to the cardiomyocyte dysfunction. Results: Myocyte shortening and relengthening were significantly slower in sucrose-fed (insulin-resistant) males than in starch-fed (normal) male rats, whereas only relengthening was slower in sucrose-fed females when compared with normal females. Areas under the contraction and relaxation phases for sucrose-fed males were also significantly larger than in diet-matched females, and the slowed cardiomyocyte mechanics appeared earlier in males (7 vs 10 weeks). Prolonged relaxation was ameliorated in myocytes from sucrose-fed female rats by all interventions (i.e. 10^-8 mol/l isoprenaline, elevated extracellular Ca²⁺, and higher rates of stimulation). Twice as much extracellular Ca²⁺ (4 mmol/l) was required to restore normal time courses of contraction and relaxation in sucrose-fed males than in females, and mechanical responses to higher frequency stimulation remained impaired (slower) in some myocytes from sucrose-fed male rats. Conclusions/ interpretation: These data suggest that in myocytes from insulin-resistant rats altered Ca ²⁺ handling occurs, contributing to abnormal excitation-contraction coupling; female rats seem to have some cardioprotection during early stages in the progression towards type 2 diabetes. Females show delayed onset and milder abnormalities in metabolic status and cardiomyocyte function, but with a much tighter temporal coupling of these dysfunctions.