Axonal potassium conductance and glycemic control in human diabetic nerves

doi:10.1016/j.clinph.2004.12.019

Clinical Neurophysiology

Volume 116, Issue 5, May 2005, Pages 1181-1187

https://doi.org/10.1016/j.clinph.2004.12.019 Get rights and content

Abstract

Objective

To investigate the effects of hyperglycemia on axonal excitability and potassium conductance in human diabetic nerves.

Methods

Threshold tracking was used to measure excitability indices, which depend on potassium channels (supernormality, late subnormality, threshold electrotonus, and a current/threshold relationship) in median motor axons of 96 diabetic patients. The effects of hyperglycemia on these indices were analyzed.

Results

Among diabetic patients, higher serum hemoglobin A1c (HbA1c) levels were significantly associated with greater supernormality (P=0.04) and smaller late subnormality (P=0.02), suggestive of reduced nodal/paranodal potassium currents under hyperglycemia. Threshold electrotonus and current/threshold relationships did not correlate with HbA1c levels, but partly related with nerve conduction slowing.

Conclusions

Hyperglycemia could reduce nodal potassium conductances, possibly due to reduced membranous potassium gradient or suppression of potassium channels. In contrast, internodal potassium conductances may be determined by both metabolic factors and structural changes such as exposure of internodal channels by demyelination.

Significance

Measurements of the excitability indices could provide new insights into nodal and internodal axonal membrane properties in human diabetic neuropathy, whereas multiple factors can affect especially internodal properties.

Introduction

The pathophysiology of diabetic neuropathy has not been well understood, and presumably includes a complex interplay between metabolic abnormalities directly related with hyperglycemia and structural nerve damage caused by microangiopathy (Dyck, 1996, Greene et al., 1987, Sima, 1996). For example, hyperglycemia results in a decrease in Na⁺–K⁺ pump activity that would lead to a reduced the trans-axonal Na⁺ or K⁺ gradient, and thereby reduced ionic currents (Sima and Brismar, 1985, Brismar et al., 1987, Brismar, 1993, Misawa et al., 2005, Misawa et al., 2004, Horn et al., 1996, Quasthoff, 1998, Shneider et al., 1993). In contrast, demyelination exposes the ion channels expressed on the internodal axonal membrane, probably resulting in an increase in ionic conductances. Thus, alternations in axonal ionic conductances can be one of the consequence of the complex functional and structural abnormalities in diabetes, but this has rarely been investigated in diabetic patients, presumably because of the lack of appropriate tools to non-invasively assess axonal ionic conductances in vivo.

In the 1990s, the threshold tracking technique was developed to measure a number of axonal excitability indices, such as supernormality, late subnormality, threshold electrotonus and a current/threshold relationship, non-invasively in human subjects. The indices depend on the biophysical properties of the axonal membrane and can provide indirect insights into function of Na⁺, K⁺ or inward rectifying channels (Bostock et al., 1998; Kiernan et al., 2000). Recent studies showed indirect evidence of reduced nodal Na⁺ currents in diabetic patients, possibly due to a decrease in membranous Na⁺ gradient under hyperglycemia; strength–duration time constant, which partly depends on persistent Na⁺ currents, is significantly shorter in diabetic patients with poor control than in those with good control (Misawa et al., 2005), and refractory periods, which is dependent on nodal transient Na⁺ channels, are significantly shorter in diabetic patients with poor control than normal, possibly due to less Na⁺ currents when generating an action potential, and thereby lower inactivation of the channels (Misawa et al., 2004).

A previous study using threshold electrotonus suggests that inward rectification may be impaired in human diabetic neuropathy (Horn et al., 1996), whereas there are no reports focusing on changes in K⁺ conductances in human diabetics. To investigate the effects of hyperglycemia on axonal excitability and K⁺ conductance in human diabetic nerves, we measured multiple excitability indices, which depend on K⁺ channels.

Section snippets

Patients

A total of 96 patients with diabetes mellitus, who were referred to the EMG clinic, Chiba University Hospital, between October, 2000 and February, 2004, were studied. Twelve patients had type 1 diabetes mellitus, and the remaining 84 had type 2 diabetes. They ranged in age from 19 to 82 years (mean 58 years) with disease duration of 1–32 years (mean 11 years). Eighty-five of the patients had mild-to-moderate symptomatic neuropathy, and the remaining 11 were asymptomatic with normal nerve

Conventional nerve conduction studies

In median motor nerve conduction studies, all parameters including distal latencies, motor nerve conduction velocities, CMAP amplitudes, and F-wave latencies were significantly different in the diabetic patients and normal controls (P<0.001); The mean (SEM) distal latency was 4.4 (0.1) ms in patients and 3.6 (0.1) ms in normals, the mean conduction velocity was 49.5 (0.5) m/s in patients and 54.1 (0.4) m/s in normals, and the mean CMAP amplitudes was 7.6 (0.3) mV in patients and 10.8 (1.3) mV in

Discussion

Our results showed a number of differences in excitability indices between diabetic patients and normal controls, and the effects of hyperglycemia on the axonal excitability properties in diabetics. First, as a group, diabetic patients had less late subnormality in the recovery cycle, smaller threshold changes to depolarizing currents in threshold electrotonus, and lesser threshold changes to depolarizing and hyperpolarizing currents in current/threshold relationships. These findings raise the

Acknowledgements

We thank Prof. Hugh Bostock (Institute of Neurology, London, UK) for helpful comments.

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Sensory and motor axonal excitability testing in early diabetic neuropathy
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Citation Excerpt :
However, these correlations are weak, and without correlation to other measures that were significantly different, it is hard to conclude anything from this finding. Previous studies showed weak correlations to recovery cycle measures (Krishnan and Kiernan, 2005, Misawa et al., 2005). We found no correlation to sensory excitability parameters, whereas another study also found correlation to recovery cycle parameters (Sung et al., 2017).
The aim of the present study was to gain insight into the pathophysiology of diabetic polyneuropathy (DPN) and examine the diagnostic value of sensory and motor axonal excitability testing.
One hundred and eleven type 2 diabetics with and without DPN (disease duration: 6.36 ± 0.25 years) and 60 controls were included. All participants received a thorough clinical examination including Michigan Neuropathy Screening Instrument (MNSI) score, nerve conduction studies (NCS), and sensory and motor excitability tests. Patients were compared by the likelihood of neuropathy presence, ranging from no DPN (17), possible/probable DPN (46) to NCS-confirmed DPN (48).
Motor excitability tests showed differences in rheobase and depolarizing threshold electrotonus measures between NCS-confirmed DPN group and controls but no changes in hyperpolarising threshold electrotonus or recovery cycle parameters. Sensory excitability showed even less changes despite pronounced sensory NCS abnormalities. There were only weak correlations between the above motor excitability parameters and clinical scores.
Changes in excitability in the examined patient group were subtle, perhaps because of the relatively short disease duration.
Less pronounced excitability changes than NCS suggest that axonal excitability testing is not of diagnostic value for early DPN and does not provide information on the mechanisms.
Measurement of axonal excitability: Consensus guidelines
2020, Clinical Neurophysiology
Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal excitability techniques have been utilised to investigate the pathophysiological mechanisms underlying neurological diseases. This document presents guidelines derived for such studies, based on a consensus of international experts, and highlights the potential difficulties when interpreting abnormalities in diseased axons. The present manuscript provides a state-of-the-art review of the findings of axonal excitability studies and their interpretation, in addition to suggesting guidelines for the optimal performance of excitability studies.
In vivo evidence of reduced nodal and paranodal conductances in type 1 diabetes
2016, Clinical Neurophysiology
Citation Excerpt :
The information gained from axonal excitability recordings cannot be obtained from standard nerve conduction studies, which focus on measures such as action potential amplitude and latency and which are insensitive to more subtle changes that may occur in impulse conduction. Previous studies of excitability in diabetic patients have focussed mainly on motor axons in type 2 diabetic patients and have demonstrated disparate changes in multiple conductances including Na+ conductances (Kitano et al., 2004), K+ conductances (Misawa et al., 2005) and energy-dependent Na+/K+ pump function (Kwai et al., 2013). DPN however is typically characterised by sensory symptoms.
Diabetic neuropathy is a debilitating complication of diabetes. Animal models of type 1 diabetes (T1DM) suggest that functional and structural changes, specifically axo-glial dysjunction, may contribute to neuropathy development. The present study sought to examine and characterise early sensory axonal function in T1DM patients in the absence of clinical neuropathy.
Thirty patients with T1DM (15M:15F) without neuropathy underwent median nerve sensory and motor axonal excitability studies to examine axonal function. A verified mathematical model of human motor and sensory axons was used to elucidate the underlying causes of observed alterations.
Compared to controls (NC), T1DM patients demonstrated significant axonal excitability abnormalities in sensory and motor axons. These included marked reductions in sensory and motor subexcitability during the recovery cycle (T1DM 7.9 ± 0.4:10.4 ± 0.6%, NC 10.4 ± 0.7:15.4 ± 1.2%, P < 0.01) and during hyperpolarizing threshold electrotonus at 10–20 ms (T1DM −75.5 ± 0.8:−69.7 ± 0.8%, NC −78.4 ± 1:−72.7 ± 0.9%, P < 0.01). Mathematical modelling demonstrated that these changes were due to reduced nodal Na⁺ currents, nodal/paranodal K⁺ conductances and Na⁺/K⁺ pump dysfunction, consistent with axo-glial dysjunction as outlined in animal models of T1DM.
The study provided support for the occurrence of early changes in nodal and paranodal conductances in patients with T1DM.
These data indicate that axonal excitability techniques may detect early changes in diabetic patients, providing a window of opportunity for prophylactic intervention in T1DM.
Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy
2015, Clinical Neurophysiology
Citation Excerpt :
The modeling of the diabetic patients showed reduced nodal fast and slow K+ currents, but not significantly in MGO-treated mice. The discrepancy could be explained by the presence of hyperglycemia in the patients and normoglycemia in the MGO-treated mice, because hyperglycemia could reduce nodal K+ conductance, either by reduced transmembrane K+ gradient or direct suppression of the channels (Misawa et al., 2005a). One of the hallmarks of diabetic neuropathy is abnormal axonal excitability.
To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy.
(1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1 week after serial administration of MGO (50 mg/kg).
(2) Excitability testing in patients with diabetic neuropathy (N = 17) and healthy controls (N = 12) were also conducted, and data were interpreted using mathematical modeling.
In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes.
Ih was upregulated after MGO administration in normal mice.
MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.
Evidence for a causal relationship between hyperkalaemia and axonal dysfunction in end-stage kidney disease
2014, Clinical Neurophysiology
Citation Excerpt :
However, studies undertaken during the K+ clamp phase of the protocol demonstrated that axonal depolarization remained unchanged for as long as serum K+ remained elevated, despite the significant removal of other dialyzable uraemic toxins. While other molecules such as glucose may influence nerve excitability (Misawa et al., 2005), glucose is a stable component of the dialysate which ensures that glucose concentrations remain stable across a dialysis session (Burmeister et al., 2007). These findings therefore provide evidence for a causal relationship between serum K+ and axonal depolarization in haemodialysis patients.
Potassium (K⁺) has been implicated as a factor in the development of uraemic neuropathy. This study was undertaken to investigate whether hyperkalaemia plays a causal role in axonal dysfunction in end-stage kidney disease (ESKD).
Median motor nerve excitability studies were undertaken in four haemodialysis patients during a modified dialysis session. The serum K⁺ level was “clamped” (fixed) for the first 3 h of dialysis, whilst allowing all other solutes to be removed, this was followed by dialysis against low dialysate K⁺ for a further 4 h. Blood chemistry and nerve excitability studies were undertaken prior to, during and following dialysis. Results were compared to results from the same patients during routine dialysis sessions.
All patients demonstrated significant nerve excitability abnormalities reflective of nerve membrane depolarization in pre-dialysis recordings (p < 0.01). After the 3 h clamp period, serum K⁺ remained elevated (5.0 mmol/L) and nerve excitability remained highly abnormal, despite the significant clearance of other uraemic toxins. In contrast, studies undertaken during routine dialysis sessions demonstrated significant improvement in both serum K⁺ and nerve function after 3 h.
The current study has established a causal relationship between serum K⁺ and axonal membrane depolarization in haemodialysis patients.
From a clinical perspective, strict K⁺ control may help improve nerve function in ESKD.
Mechanisms of axonal dysfunction in diabetic and uraemic neuropathies
2013, Clinical Neurophysiology
The global burden imposed by metabolic diseases and associated complications continue to escalate. Neurological complications, most commonly peripheral neuropathy, represent a significant cause of morbidity and disability in patients with diabetes and chronic kidney disease. Furthermore, health care costs are substantially increased by the presence of complications making investigation into treatment a matter of high priority. Over the last decade nerve excitability techniques have entered the clinical realm and enabled in vivo assessment of biophysical properties and function of peripheral nerves in health and disease. Studies of excitability in diabetic neuropathy have demonstrated alteration in biophysical properties, including changes in Na⁺ conductances and Na⁺/K⁺ pump function, which may contribute to the development of neuropathic symptoms. Interventional studies have demonstrated that these changes are responsive to pharmacological agents. Excitability studies in patients with chronic kidney disease have demonstrated prominent changes that may contribute to the development of uraemic neuropathy. In particular, these studies have demonstrated strong correlation between hyperkalaemia and the development of nerve dysfunction. These studies have provided a basis for future work assessing the benefits of potassium restriction as a therapeutic strategy in this condition.

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View full text

Axonal potassium conductance and glycemic control in human diabetic nerves

Abstract

Objective

Methods

Results

Conclusions

Significance

Introduction

Section snippets

Patients

Conventional nerve conduction studies

Discussion

Acknowledgements

Neuroscience

Clin Neurophysiol

Clin Neurophysiol

Function and distribution of three types of rectifying channel in rat spinal root myelinated axons

J Physiol (Lond)

Intracellular recording from vertebrate myelinated axons: mechanism of depolarizing afterpotential

J Physiol (Lond)

Threshold tracking techniques in the study of human peripheral nerve

Muscle Nerve

Abnormal Na-currents in diabetic rat nerve nodal membrane

Diabet Med

Reversible and irreversible nodal dysfunction in diabetic neuropathy

Ann Neurol

Membrane properties in chronic inflammatory demyelinating polyneuropathy

Brain

Pathologic alterations in the diabetic neuropathies of humans: a review

J Neuropathol Exp Neurol

Sorbitol, phosphoinositides, and sodium–potassium–ATPase in the pathogenesis of diabetic complications

N Engl J Med

Abnormal axonal inward rectification in diabetic neuropathy

Muscle Nerve

Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment

Brain

Effects of membrane polarization and ischaemia on the excitability properties of human axons

Brain