Metformin is the first choice drug for the treatment of patients with diabetes, 
but its use is debated in patients with advanced cardiorenal disease. 
Epidemiological data suggest that metformin may reduce cardiac events, in 
patients both with and without heart failure. Experimental evidence suggests 
that metformin reduces cardiac ischemia-reperfusion injury. It is unknown 
whether metformin improves cardiac function (remodeling) in a long-term post-MI 
remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats 
that were subjected to either myocardial infarction (MI) or sham operation. 
Animals were randomly allocated to treatment with normal water or 
metformin-containing water (250 mg·kg(-1)·day(-1)). At baseline, 6 wk, and 12 
wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT) 
were performed. Echocardiography and hemodynamic parameters were assessed 12 wk 
after MI. In the MI model, infarct size was significantly smaller after 12-wk 
metformin treatment (29.6 ± 3.2 vs. 38.0 ± 2.2%, P < 0.05). Moreover, metformin 
resulted in less left ventricular dilatation (6.0 ± 0.4 vs. 7.6 ± 0.6 mm, P < 
0.05) and preservation of left ventricular ejection fraction (65.8 ± 3.7% vs. 
48.6 ± 5.6%, P < 0.05) compared with MI control. The improved cardiac function 
was associated with decreased atrial natriuretic peptide mRNA levels in the 
metformin-treated group (50% reduction compared with MI, P < 0.05). Insulin 
resistance did not occur during cardiac remodeling (as indicated by normal OGTT) 
and fasting glucose levels and the pattern of the OGTT were not affected by 
metformin. Molecular analyses suggested that altered AMP kinase phosphorylation 
status and low insulin levels mediate the salutary effects of metformin. 
Altogether our results indicate that metformin may have potential to attenuate 
heart failure development after myocardial infarction, in the absence of 
diabetes and independent of systemic glucose levels.