In an ongoing investigation of the effects of age on G protein-coupled receptor signaling in human atrial tissue, we have found that the density of atrial muscarinic acetylcholine receptor (mAChR) increases with age but reaches statistical significance only in patients with diabetes. Moreover, we find that in elderly subjects of similar ages, those with diabetes have 1.7-fold higher levels of Galpha(i2) and twofold higher levels of Gbeta(1). Diabetes does not affect other atrial G proteins, including Galpha(i3,) Galpha(s), Galpha(o), and Gbeta(2). These data represent the first demonstration of an increase in a G(i)-coupled receptor, Galpha(i2), and Gbeta(1), in atrium of patients with diabetes. These findings suggest a molecular explanation for the increased risk of cardiac disease in patients with diabetes, because increased signaling through G(i) has been shown to lead to the development of dilated cardiomyopathy.