It has been estimated that 5 million people will suffer from diabetes in the UK by 20251. Cardiovascular complications are common in type I diabetes mellitus (T1DM). There is increased risk of bradyarrhythmias, atrioventricular block and bundle branch block as a result of dysfunction of the cardiac conduction system (CCS) 2,3. The CCS is responsible for the generation and transmission of electrical activity in the heart and consists of the sinoatrial and atrioventricular nodes (SAN; AVN), bundle of His (HIS), right and left bundle branches (RBB; LBB) and right and left Purkinje fibres (RPFs; LPFs). In the rat streptozotocin (STZ)-induced model of T1DM, in vivo ECG recordings have shown a significant (P<0.05) decrease in heart rate (HR) and prolongation of the QRS complex, evidence of dysfunction of the CCS4. The aim of this study was to investigate the cellular basis of the effect of T1DM on the CCS using the rat model. A possible direct action of STZ on the heart was investigated using the Langendorff-perfused rat heart. Protein expression was investigated immunohistochemistry. Antibodies were used to label the cardiomyocyte outer membrane (Caveolin3, Cav3), the funny channel (HCN4), Ca2+-handing proteins (RyR2 and SERCA2a), sympathetic neurones (NF165) and gap junction proteins (Cx40 and Cx43). The research was conducted in accordance with the Guide for the Care and Use for Laboratory Animals in UAE and UK. We showed that STZ had no direct effect on the functioning of the CCS – there were nochanges in RR, PR and QRS parameters after perfusion of hearts with STZ (60 mg/kg for 90 min; n=5, P>0.05). T1DM rats showed decrease in body weight and heart weight but increase in heart to body weight ratio and blood glucose (n=16, P<0.05). Based on Cav3 labelling, significant cellular hypotrophy was observed in HIS, RBB, RPFs and LPFs (n=5, P<0.05). Surprisingly, HCN4 expression was significantly increased in the SAN, AVN and HIS. However, RyR2 labelling was significantly decreased in the AVN, HIS, RBB, LBB, RPFs and LPFs and SERCA2a labelling was significantly decreased in the AVN, HIS, RPFs and LPFs; downregulation of these Ca2+-handling proteins (involved in the Ca2+ clock pacemaker mechanism) could account for the lower HR. NF165 labelling was significantly decreased in the SAN, HIS, RPFs and LPFs; the assumed downregulation of sympathetic innervation could also help explain the reduced HR in diabetic hearts. The upregulation of HCN4 (involved in the membrane clock pacemaker mechanism) could be a compensatory mechanism. Cx40 expression was significantly decreased in HIS, LBB, RPFs and LPFs and Cx43 labelling was significantly decreased in the RPFs and LPFs. The downregulation (and redistribution) of the connexins in His-Purkinje system could account for the prolongation of QRS complex.