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OBJECTIVEImpaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management.RESEARCH DESIGN AND METHODSThirty subjects with IGT and 17 age-matched control subjects underwent an oral glucose tolerance test, assessment of neuropathic symptoms and deficits, quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) at baseline and annually for 3 years.RESULTSTen subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years.CONCLUSIONSCCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status.

We have previously shown in rabbit that the pacemaker of the heart (the sinus node) is widespread and matches the wide distribution of the leading pacemaker site within the right atrium. There is, however, uncertainty about the precise location of the pacemaker in human heart, and its spatial relationships with the surrounding right atrial muscle. Therefore, the aim of the current study was to investigate the distribution of the sinus node tissue in a series of healthy human hearts and, for one of the hearts to construct a computer three-dimensional anatomical model of the sinus node, including the likely orientation of myocytes. A combination of experimental techniques-diffusion tensor magnetic resonance imaging (DT-MRI), histology, immunohistochemistry, image processing and computer modelling-was used. Our data show that the sinus node was larger than in previous studies and, most importantly, we identified a previously unknown area running alongside the sinus node (the ''paranodal area"), which is even more extensive than the sinus node. This area possesses properties of both nodal and atrial tissues and may have a role in pacemaking. For example, it could explain the wide spread distribution of the leading pacemaker site in human right atrium, a phenomenon known as the wandering pacemaker observed in clinics. In summary, a Additional Supporting Information may be found in the online version of this article.Abbreviations used: AM ¼ Atrial muscle; ANP ¼ Atrial natriuretic peptide; Ao ¼ Aorta; Cx40, Cx43 ¼ Connexin 40 and 43; 3D ¼ Three-dimensional; DT-MRI ¼ Diffusion tensor magnetic resonance imaging; HCN4 ¼ Ion channel responsible for hyperpolarization-activated or 'funny' current, I f ; IVC ¼ Inferior vena cava; Kir2.1 ¼ Ion channel responsible for background inward rectifier K þ current, I K1 ; Kir6.2 ¼ Ion channel responsible for ATP-sensitive K þ current, I KATP ; Kv1.4 ¼ Ion channel responsible for transient outward K þ current, I to ; LAA ¼ Left atrial appendage; MiRP2 ¼ Accessory protein for K þ channels; N av1.5, Nav 1 ¼ Na þ channel responsible for inward Na þ current, I Na ; PA ¼ Pulmonary artery; PV ¼ Pulmonary vein; RA ¼ Right atrium; RAA ¼ Right atrial appendage; RV ¼ Right ventricle; SCV ¼ Superior caval vein; SK2 ¼ Ion channel responsible for Ca 2þ -activated K þ current, I KCa ; TASK1 Twin-pore domain K þ channel; Tbx3 ¼ Transcription factor; TC ¼ Terminal crest.