Intraepidermal nerve-fibre density as a biomarker of the course of neuropathy in patients with Type 2 diabetes mellitus.

AIMS: This paper aims to investigate whether intraepidermal nerve-fibre density (IENFD) may be used as a marker of the course of neuropathy in patients with Type 2 diabetes mellitus. METHODS: Skin biopsies from the distal leg were serially evaluated in a group of 30 patients with Type 2 diabetes mellitus (median age 60 years, 17 men) with a short duration of diabetes (< 3 years) and good glucose control, and in 23 age- and sex-matched controls. The time intervals between biopsies were > 2 years (median 33.8 months). Eighteen patients with Type 2 diabetes mellitus had symptoms or signs of distal symmetrical diabetic polyneuropathy, 12 had no neuropathy. RESULTS: At first skin biopsy, IENFD was normal in all controls and in patients without neuropathy (mean 9.5 and 7.9 fibres/mm, respectively) compared with abnormal IENFD in 77.8% in patients with polyneuropathy (mean 3.4 fibres/mm). The annual rate of intraepidermal nerve-fibre (IENF) loss expressed as a percentage of the first IENFD value in patients with diabetic polyneuropathy was significantly higher [mean (se), 11.95 (3.82)%] compared with controls [1.92 (1.81)%, P < 0.001] and similar to patients without polyneuropathy [12.16 (4.38)%]. The rate of IENF loss did not correlate with degree of glucose control. CONCLUSIONS: The annual rate of IENF loss in patients with Type 2 diabetes mellitus was several times higher than that of healthy participants, irrespective of the presence of signs or symptoms of diabetic polyneuropathy at initial evaluation. The change in IENFD is not linear and should be expressed as a proportion of initial IENFD to serve as a marker of the course of diabetic neuropathy.

3,4-Diaminopyridine induced stimulus-bound repetitive firing in frog sympathetic ganglion: no changes in postsynaptic membrane excitability.

It has been shown previously that 3,4-diaminopyridine (3,4-DAP) facilitates synaptic transmission in the frog sympathetic ganglion inducing so-called stimulus-bound repetition (SBR), i.e. a brief burst of repetitive postganglionic discharges after a single orthodromic stimulus. In the present study we analyzed one of the possible mechanisms of the 3,4-DAP-induced SBR, namely changes in postsynaptic membrane excitability. We found that 3,4-DAP in concentration optimal for inducing SBR (2 X 10(-4) mol.l-1) had no direct effect on the excitability of the postsynaptic membrane of frog sympathetic neurones. The excitability was expressed as the threshold for action potentials elicited orthodromically, antidromically and directly, as well as the spike activity evoked by constant depolarizing current pulses. We also indirectly excluded the involvement of two other possible mechanisms of neuronal membrane excitability modulation in the 3,4-DAP-induced SBR, i.e. the M-current suppression by analyzing the participation of muscarinic receptor activation in the SBR, and inhibition of the Ca(2+)-activated K+ currents by measuring the duration of afterhyperpolarization of antidromic action potential. Our findings indicate that no remarkable changes in the properties of the postsynaptic membrane contribute to the generation of 3,4-DAP-induced SBR in the frog sympathetic ganglion. This strongly supports the hypothesis that the mechanism underlying SBR evoked by this drug is presynaptic.

Facilitatory effect of some drugs on transmission in the frog sympathetic ganglion.

Effects of 3,4-diaminopyridine and dimethylsulfoxide on transmission in frog sympathetic ganglion were analyzed. In the presence of either drug repetitive waves appeared in the compound action potential. Intracellular recording revealed a repetitive firing of certain populations of ganglionic neurons following each orthodromic stimulus. Antidromic stimulation did not evoke any repetitive response. Dependence of the repetitive response on drug concentration and stimulation rate is described. An enhancement and prolongation of fast EPSP was observed in the presence of both drugs. It is assumed that by interference with changes in membrane potassium permeability the drugs prolong the action potential in presynaptic terminals with a resulting increase in synaptic output of transmitter. The repetitive firing of the postsynaptic membrane subsequent to activation of the synapse is a consequence of its prolonged and more profound depolarization. Presumably, this is one of several mechanisms of drug-induced increase in efficacy of synaptic transmission in frog sympathetic ganglion known as stimulus-bound repetition.