Background Type 2 diabetes mellitus (T2DM) is a major comorbidity worsening the outcome after acute myocardial infarction (MI). 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.

Methods Mice 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, metabolic profiling was carried out by expression analysis for both the area at risk and the remote area. Collagen deposition in the myocardium was analyzed histologically before and after MI.

Results HFHSD 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. Expression analysis of metabolic markers revealed an impaired glucose utilization in HFHSD animals after MI especially in the remote area which tended to be improved by IGF1 treatment. Further collagen III staining demonstrated that collagen deposition in the heard was 10% higher in HFHSD mice compared to the control group. MI leads to30 % higher collagen III deposition in the remote area of HFHSD mice, which could be prevented by an IGF1 treatment. The same could be seen in the area risk, where HFHSD mice showed 20% higher collagen deposition after MI compared to the control group and an IGF treatment prevented this.

Conclusion Despite a similar signal transduction mediated by IGF1 and insulin, IGF1 was able to preserve cardiac function after MI in a prediabetic mouse model. This effect could be due to an improved glucose utilization and reduced collagen storage after myocardial infarction followed by IGF1 treatment. 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.