Metformin is a commonly used drug in the treatment of type 2 diabetes. metformin suppresses endogenous glucose output and increases peripheral insulin sensitivity (stumvoll et al., 1995; fery et al., 1997). diabetes is often associated with heart disease and worsens the prognosis of patients with heart conditions. until recently it was unclear whether metformin was a suitable therapeutic in heart patients because unstable or acute congestive heart failure was reported to be associated with an increased risk of lactic acidosis with metformin (khurana and malik, 2010). a recent study, however, suggested that metformin is not contraindicated in conditions of heart failure. results from a recent meta-study show that it might in fact be the most suitable drug to reduce mortality in diabetic patients with heart conditions (eurich et al., 2007). for example, one study showed that diabetic patients with heart failure have a lower risk of readmission for heart failure if they are treated with metformin than do patients treated without or with other insulin sensitizers (masoudi et al., 2005). the mechanisms of this metformin effect are unknown, and the question arises: does this cardioprotective effect directly manifest in the cardiomyocyte? the er is the major hub for protein sorting and folding in the cell. protein overload of the er can lead to activation of the unfolded protein response (upr). upr pathways are crucial in the pathogenesis of many human disorders, including neurophysiological diseases, metabolic disorders such as insulin resistance and type 2 diabetes, and cardiovascular diseases such as cardiac hypertrophy, heart failure, atherosclerosis and ischemic heart disease (araki et al., 2003; kim et al., 2008; minamino and kitakaze, 2010; thoms et al., 2009). three signaling branches have been described whereby unfolded proteins can be sensed and upr activated (ron and walter, 2007; rutkowski and hegde, 2010). protein kinase rna (pkr)-like er kinase (perk) initiates one of these signaling pathways. perk is an er-resident transmembrane protein that couples er stress signals to translation inhibition. perk phosphorylates the eukaryotic initiation factor 2  (eif2 ) and itself at its cytoplasmic kinase domain, which leads to reduction of global protein biosynthesis, one of the feedback loops to reduce protein stress in the er. eif2 phosphorylation promotes the expression of activating transcription factors (atfs) such as atf4 and atf5. inositol-requiring enzyme 1 (ire1) is the er-bound sensor of another upr signaling pathway. ire1 is a conserved transmembrane protein with an er-luminal sensor for misfolded proteins. activation of ire1 initiates the non-conventional splicing of the transcription factor x-box-binding protein 1 (xbp1), which is responsible for the activation of a larger number of er-stress responsive genes, including chaperones of the er. the third er sensor in upr pathways is the membrane-bound transcription factor atf6. upon activation, atf6 is cleaved and releases its cytoplasmic domain, which enters the nucleus and activates er stress response element (erse)-dependent gene products, including the er-luminal chaperone binding immunoglobulin protein [bip; also referred to as 78-kda glucose-regulated protein (grp78)]. unfolded proteins in the er are not the only trigger for upr signaling. energy deprivation, hypoxia, disturbed er ca levels, pathogens, drugs and secondary metabolites can also induce upr signaling. accordingly, the upr response can be termed endoplasmic reticulum stress signaling (erss). er stress that is prolonged or severe can lead to apoptosis. apoptotic cell death of cardiomyocytes is involved in several cardiac disorders. all three erss branches have been associated