Aims/hypothesis We investigated the significance of microangiopathy in the development of foot ulcer, which is still disputed. Methods We assessed microangiopathy by histological analysis of the capillary ultrastructure using transmission electron microscopy and capillary density and arteriolar morphology in paraffin-embedded sections from the skin of type 2 diabetic patients: 30 neuroischaemic patients (Isc) revascularised with peripheral angioplasty and 30 neuropathic patients (Neu) with foot ulcer, compared with ten non-diabetic volunteers. Results In the diabetic patients, capillaries in the dermal papillary layer were fewer (−22.2%, 159 ± 43 vs 205 ± 52 mm 2 in non-diabetic volunteers, p < 0.01). They also showed detrimental remodelling, with a 2.2-fold increase in capillary basement membrane thickness (3.44 ± 1.19 vs 1.53 ± 0.34 μm in non-diabetic volunteers, p < 0.001) and a 57.7% decrease in lumen area (14.6 ± 11.1 vs 34.7 ± 27.5 μm 2 , p < 0.001). No differences were observed between the diabetic Isc or Neu patients. Isc were more prone to develop arteriolar occlusion than Neu (16.8 ± 6.9% vs 6.7 ± 3.7%, respectively, p < 0.001).No patient had been amputated at 30 days and healing time was significantly longer in Isc (180 ± 120 vs 64 ± 50 days in Neu, p < 0.001). Conclusions/interpretation Capillary microangiopathy is present in equal measure in neuroischaemic and neuropathic diabetic foot skin. The predominance of arteriolar occlusions with neuroischaemia indicated the existence of an additional 'small vessel disease' that did not affect an effective revascularisation and did not worsen the prognosis of major amputations but slowed the healing process of the neuroischaemic foot ulcer. Trial registration: ClinicalTrials.gov NCT02610036.

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Diabetes mellitus is associated with cardiac arrhythmias, ventricular fibrillation and sudden death. These cardiac effects may result directly from the absence of insulin signaling in the heart or as in indirect consequence of diabetic sequelae (e.g., hyperlipidemia, hypertension or coronary artery disease). To study the electrical consequences of absent insulin signaling in the heart, we used a cardiac-specific insulin receptor knockout (CIRKO) mouse model. We recorded action potentials and Kþ currents in myocytes isolated from CIRKO mice and their control littermates. Action potential duration at 90% (APD90) was significantly prolonged in left ventricle, apex and septum from CIRKO mice compared to WT. Conversely, no differences in APD90 were observed in right ventricular myocytes. Outward potassium currents recorded using whole-cell voltage clamp method showed a reduction in both peak and sustained current in CIRKO mice. Neither the voltage dependence of steady-state inactivation nor recovery from inactivation of the rapidly inactivating outward Kþ current (Ito,f) were affected. In addition, the inward rectifier Kþ current (IK1) was not different between both groups. Consistent with the APD prolongation, CIRKO mice showed QT interval prolongation, compared to WT littermates. Western blot and real time q-PCR analyses revealed that the protein levels and mRNA expression of Kv4.2 were significantly reduced in CIRKO hearts. We conclude that the absence of insulin signaling in the heart causes a reduction in Kv4.2 message and protein that in turn, reduces Ito,f, prolongs APD in left ventricle and prolongs the QT interval.