Commentary :
Diabetes has been one of the crucial diseases
worldwide, which has to be controlled adequately for long years. It has three
diabetic complications of micro-angiopathy such as neuropathy, retinopathy and
nephropathy. Among them, DiabeticPeripheral Neuropathies (DPNs) are most prevalent to manage in primary care
setting. In this article, recent topics concerning DPNs are introduced [1]. DPNs have a
variety of symptoms and signs, then DPNs are often described in plural forms
[2]. DPNs are classified into two categories, which are local and general. The
former includes mononeuropathy and multifocal neuropathy. The latter includes diabetic
polyneuropathy (DPN) and others. DPN has Distal Symmetric Polyneuropathy
(DSPN) and Diabetic Autonomic Neuropathy (DAN) [2]. For examples, DSPN shows
bilateral numbness of extremities and DAN shows Orthostatic Hypotension (OH). What are DSPN and DAN like in clinical settings? We
have been treating lots of diabetic patients for many years. Two conditions
would be shown which are easy to understand. One is the research for DSPN, in
which Sural Nerve Conduction Velocity (SNCV) and Sural Nerve Action Potential
(SNAP) were measured in patients with Diabetes
Mellitus (DM), Hemodialysis (HD) and control r [3]. In our study, there were
four groups, which are 1) Both DM/HD, 2) DM only, 3) HD only, 4) control. The
results of SNCV and SNAP showed from abnormal to normal in group 1,2,3,4,
respectively, in this order [3]. Another is the situation of DAN with severe status
of symptom. The case is 58 year-old man with neuropathy, retinopathy,
nephropathy and remarkable OH. When he was lying position, his Blood Pressure
(BP) was 164/98 mmHg. As he changed to sit on the bed, BP decreased to 140/82
mmHg. Just after standing up with 4-5 steps, his BP suddenly decreased to 98/56
mmHg associated with prompt dizziness and almost feint and unconsciousness due
to OH. These phenomenon would be from typical DAN. Author and colleagues have continued clinical
practice and research for patients with Type
1 and 2 Diabetes Mellitus (T1DM, T2DM). Especially, we reported the
clinical comparison of Low Carbohydrate Diet (LCD) and Calorie Restriction (CR)
in T2DM. Furthermore, investigation of Latent Autoimmune Diabetes in Adults
(LADA) was reported in T1DM [4-6]. In both of T1DM and
T2DM, clinically important management would be Glycemic Control (GC) in the
case of various situations. There was a study between the degree of GC and diabetic
neuropathy [7]. It showed rather equivocal effect of DPNs for intensive GC
in T2DM, which was from non-optimized HbA1c values [7]. The optimum GC values
have not been shown for improving neuropathy results in T2DM by randomized
trials [8]. On contrast, almost normal range of GC for more than
20 years prevented DPN in T1DM [9]. In the case of poorly controlled T2DM,
Insulin-Providing Agents (IPAs) cannot bring normalization of HbA1c for long
years because of potential severe hypoglycemia
[8]. Consequently, the beneficial effect for normal range of HbA1c without
hypoglycemia to Neuropathy Outcome Measures (NOMs) have not been studied in
T2DM. In addition to mean value of GC, Glycemic
Variability (GV) [10] and metabolic various memories would influence DPN and
also diabetic microangiopathies. Further, Impaired Glucose
Tolerance (IGT) may exacerbate the pathophysiological changes of neuropathy as
an indicator of small-fiber influence [11-13]. In the STENO-2 study, long-term
rigorous glycemic control (A1c <6.5%) and multifactor intervention
significantly reduced the risk of developing cardiovascular
disease, nephropathy, retinopathy, and autonomic neuropathy. However, the
risk of developing DSPN was not significant. In order to prevent onset and progression of DSPN,
it is important to maintain adequate GC and also GV. It is speculated from the
pathology of IGT neuropathy [14,15]. There is a recently significant report that both
neuropathy of small-diameter and large-diameter were significant related to
strict GC around average HbA1c 6.1%. It could avoid not only hypoglycemia, but
also GV, which were associated with stable management of body weight, blood
pressure and lipid [16]. In the case of T2DM with relatively short
duration, DPN could be improved by total care of GC and GV [16]. Regarding the evaluation of neuropathy, there has
been a standard classification for the severity of neuropathy, which is the
Toronto Consensus on Diabetic Neuropathies [17]. It considers a confirmed DPN
as a combination of the presence of abnormal Nerve
Conduction Velocity (NCV) and a symptom, or a sign. As a result, patients
with NDS>2 and Sensory NCV of Sural Nerve (SNCV) <42 m/s were usually
estimated as the presence of the neuropathy. This criteria have been applied
for lots of reports about neuropathy [3]. In T2DM, intensive GC has been said to reduce
diabetic micro vascular complications. Then, continuation of strict GC may
prevent and ameliorate DPN. The intensive GC in T2DM is associated with a
reduction in micro vascular complications. The strict GC may prevent and/or
ameliorate the progress of DPN. However, Kumamoto Study showed that strict GC
level as HbA1c 7.1% prevented NCV in T2DM [18]. In the UK Prospective Diabetes
Study (UKPDS), the intensive and conventional GC as HbA1c 7.0% vs. 7.9% showed
a similar effect on DPN [19]. Action to Control Cardiovascular
Risk in Diabetes (ACCORD) trial showed that intensive care as HbA1c 6.3%
prevented loss of ankle reflex and light-touch sensation but increased
CVD-related mortality and severe hypoglycemia [8]. Consequently, these studies
could not establish the optimum GC value for preventing the neuropathy
deterioration in T2DM. In order to obtain the beneficial effect in the
light of diabetic complication, it would be necessary to maintain tight GC more
than 3-5 years. In T2DM, chronic hyperglycemia has played a crucial role in
progress of DPN. Furthermore, metabolic syndrome components would probably
cause pathophysiological neuropathy. Glucose intolerance and obesity may have a
role in progress of neuropathy. However, hyperlipidemia and hypertension
showed equivocal results for neuropathy. In addition to GC, GV has been crucial
factor to glucose variability. GV may show risk for progress of DPN apart from
HbA1c values. From the cross-sectional investigation of T2M, GV showed a
relationship with DPN value, which was studied by Continuous Glucose Monitoring
(CGM). In these studies, GV data from CGM had been evaluated in the
cross-sectional study associated with DPN data [20-25]. There is a recent significant report [26]. It was
the neurophysiological comparison between two groups of subnormal level of
HbA1c 6.5% and conventional treatment of HbA1c 7.2%. The former group showed
formerly uncontrolled situation, but maintaining the HbA1c level for 4 years
could bring the improvement of neurophysiological and some corneal nervefiber measures. In contrast, the latter group showed the deteriorated data
at the level of 7.2% [26]. Consequently, the standard level of diabetes care as
HbA1c 7.0% does not seem to be enough for DPN. Regarding diabetic neuropathy, recent research shows
the several related genes, such as Aldose Reductase Gene (AKR1B1), Vascular
Endothelial Growth Factor (VEGF), 5, 10-Methylene-Tetrahydrofolilate Reductase
(MTFR), Apolipoprotein E (APOE) and Angiotensin Converting Enzyme (ACE) genes.
They would contribute significantly in the pathogenesis of DN, and may serve as
biomarkers to predict future progress of neuropathy development and/or
treatment response [27]. In summary, recent topics concerning diabetic
neuropathy were described. Diabetic practice and various researches have been
in progress for long, and this article would be expected to become useful
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*Corresponding
author: Hiroshi
Bando, Tokushima University/Medical Research, Nakashowa 1-61, Tokushima
770-0943, Japan, Tel: +81-90-3187-2485, Email: pianomed@bronze.ocn.ne.jp Citation Diabetic peripheral neuropathies, Distal
symmetric polyneuropathy, Diabetic autonomic neuropathy, Orthostatic
hypotension, Nerve conduction velocity.Diabetic Peripheral Neuropathies (DPNs) from Basic and Clinical Aspects
Hiroshi Bando
Abstract
Full-Text
References
Bando
H. Diabetic Peripheral Neuropathies (DPNs) from basic and clinical aspects (2019)
J Obesity and Diabetes 3: 36-38. Keywords
