Insulin‐like Growth Factor 1 Improves Cardiac Function after Acute Myocardial Infarction in a Prediabetic Mouse Model

Abstract

BackgroundType 2 diabetes mellitus (T2DM) is a major comorbidity worsening the outcome after acute myocardial infarction (MI). Reduced cardiac glucose uptake may be the underlying mechanism compromising cardiac function even under prediabetic conditions. Insulin‐like growth factor 1 (IGF1) is an anabolic hormone similar to insulin in molecular structure and signaling. IGF1 controls proliferation, differentiation and metabolism of cells. In previous studies we have shown that short‐term IGF1 treatment after MI improved cardiac function and reduced scar size in mouse hearts. Here we investigate whether IGF1 can maintain cardiac function also after MI under conditions of prediabetes.MethodsMice were fed standard chow or high fat/high sucrose diet (HFHSD) for 10 weeks to induce obesity and prediabetes. Phenotyping was performed by measurements of blood glucose, insulin levels, glucose (GTT) and insulin tolerance tests (ITT). Mice were subjected to 45 min left anterior descending coronary artery occlusion and 1‐week reperfusion. IGF1 or vehicle were given over 3 days using osmotic mini pumps. Heart function was analyzed echocardiographically before and one week after MI including strain analysis. In addition, a transcriptome analysis was carried out for both the area at risk and the remote area by next‐generation sequencing.ResultsHFHSD led to increased fasting blood glucose levels with up to 200 mg/dl and glucose intolerance. In line with this results, plasma insulin levels were elevated in HFHSD mice with 1.3 ng/L in comparison to 0.4 ng/l in standard chow mice. However, exogenous insulin was able to lower blood glucose in the ITT, indicating prediabetes but no T2DM. Functional analysis by EC indicated a slight improvement of ejection fraction (EF) in HFHSD mice with 71.1% in comparison to 64.0% in the control group. However, cardiac function after MI under prediabetic conditions (EF= 35.3%) worsened to the same extent as in the control group (EF= 34.4%). Treatment of IGF1 after MI preserved cardiac function not only in the control group but also in the prediabetes group, with higher EF (control: 45.5%; IGF1: 48.2%), higher stroke volume and lower end‐systolic volume. Strain analysis revealed that this improvement is rather by an improvement of the remote area than by the area at risk.ConclusionDespite a similar signal transduction mediated by IGF1 and insulin, IGF1 was able to preserve cardiac function after MI in a prediabetic mouse model. Thus, an IGF1‐based therapeutic intervention could be a promising approach to improve the worsened cardiac outcome after myocardial infarction even under prediabetic conditions and may also be protective under T2DM.Support or Funding InformationThis work was funded by the German Research Foundation (CRC 1116 “Master Switches in Cardiac Ischemia”, TP A06).