Painful diabetic neuropathy is associated with increased nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control

Abstract

Aims/Introduction

Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control.

Materials and Methods

This exploratory substudy of an open‐label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal–bolus insulin at baseline and 1‐year follow up, and 18 controls at baseline only.

Results

Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain.

Conclusions

This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy.

There has been a resurgence of interest in identifying new drug targets or, predictive biomarkers of disease‐modifying therapies in diabetic neuropathy. We show that the presence of painful diabetic neuropathy was associated with greater corneal nerve regeneration and an improvement in painful neuropathic symptoms in patients with type 2 diabetes undergoing intensive glycemic control.

INTRODUCTION

In patients with type 1 diabetes, 6.5 years of intensive glycemic control reduced the incidence of diabetic peripheral neuropathy (DPN) by 60%, prevented peroneal nerve conduction velocity slowing¹ and continued to benefit patients 8 years after completion of the DCCT². However, in patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS)³ and Veterans Affairs Co‐operative Study in Type 2 Diabetes Mellitus (VA‐CSDM) trial⁴ reported no impact on the incidence of DPN, and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed no effect on vibration perception over a period of 6 years⁵. Furthermore, multiple phase III clinical trials failed to show an improvement in diabetic neuropathy, and there are currently no US Food and Drug Administration approved therapies for DPN⁶. It is unclear whether this failure is a consequence of inadequate translation of experimental therapies, inadequate end‐points or the enrolment of patients with a widely varying severity of DPN⁷.

The prevalence of painful diabetic peripheral neuropathy (pDPN) and DPN increases with age and duration of diabetes⁸. Hyperglycemia, hyperlipidemia and hypertension are associated with DPN⁹; whereas obesity, physical inactivity and smoking cigarettes are associated with pDPN⁸, ¹⁰. Neuropathic pain might be present at any stage of DPN¹¹, and has been linked to a complex interplay between ongoing small nerve fiber degeneration and regeneration¹², ¹³. Indeed, skin biopsy studies have shown comparable intra‐epidermal nerve fiber density in patients with and without painful neuropathy¹⁴ and painful diabetic neuropathy¹⁵, ¹⁶. However, more detailed immunohistological studies have shown an increase in regenerating intra‐epidermal¹⁷, ¹⁸ and dermal nerve fibers containing substance P and calcitonin gene‐related peptide in patients with painful compared with painless diabetic neuropathy¹⁹. Recently, Bönhof et al.²⁰ showed comparable intra‐epidermal nerve fiber density, but increased growth‐associated protein‐43 staining indicative of regenerating dermal nerves in patients with painful diabetic neuropathy. We also utilized corneal confocal microscopy (CCM) to show significantly greater corneal sub‐basal nerve plexus degeneration in patients with painful compared with painless DPN¹⁵, ²¹, ²². These studies suggest that patients with painful diabetic neuropathy might have greater small fiber degeneration, but also an increased capacity for nerve regeneration.

CCM has been used to identify early small fiber regeneration in several clinical trials²³. Indeed, early corneal nerve regeneration occurred 6 months²⁴ after pancreas and kidney transplantation, and was followed by an improvement in nerve conduction and neuropathic symptoms after 24 months²⁴, ²⁵. We also recently reported that exenatide and pioglitazone or basal–bolus insulin effectively reduce glycated hemoglobin (HbA1c)²⁶ and induce corneal nerve regeneration²⁷.

The present substudy of the Qatar study²⁶ assessed whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control with exenatide and pioglitazone or insulin.

MATERIALS AND METHODS

This was an exploratory substudy of an open‐label, randomized controlled trial (clinicaltrials.gov ID: NCT02887625)²⁶, that examined the efficacy of exenatide and pioglitazone versus basal–bolus insulin in patients with poorly controlled type 2 diabetes. This substudy has not been registered in a public clinical trial database. Participants with type 2 diabetes were enrolled from the National Diabetes Center in Hamad General Hospital, Doha, Qatar, and studied at baseline and 1‐year follow up, and control participants without diabetes were enrolled from Rumailah Hospital, Doha, Qatar, and studied at baseline only from October 2016 to November 2018.

The present study received ethical approval from the Hamad Medical Corporation IRB (IRB# 13‐00076), and all participants consented to participate in the study. The study followed the tenets of the declaration of Helsinki.

Study cohort

Individuals aged 18–75 years with HbA1c >7.5% (>58 mmol/mol) on near maximum dose of metformin (>1,500 mg/day) and sulfonylurea (>4 mg glimepiride or >60 mg gliclazide); with normal liver and kidney function, and electrocardiogram; and stable bodyweight (±1 kg) in the past year were recruited. The exclusion criteria are described in detail in our previous report²⁷, but included any cause of neuropathy apart from diabetes, corneal dystrophies, corneal surgery or trauma in the past year, antidiabetic treatment other than metformin and sulfonylureas, diabetic proliferative retinopathy, and abnormally high albumin excretion.

Interventions

Participants were randomized to receive exenatide and pioglitazone or glargine and aspart insulin treatment to achieve and maintain an HbA1c <7.0% (<53 mmol/mol)²⁷.

Demographic and metabolic measures

Age, sex, diabetes duration, bodyweight, body mass index (BMI), blood pressure, HbA1c, total cholesterol, triglyceride, high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) were recorded from the electronic health record.

DPN assessment

pDPN was defined on a Douleur Neuropathique en 4 (DN4) questionnaire score ≥4, as previously described²⁸. The DN4 questionnaire has been validated for distinguishing neuropathic pain from non‐neuropathic pain²⁹ in Arabic³⁰ and for pDPN²⁸. It consists of 10 questions relating to symptoms and signs, and each question is equally weighted. A score ≥4 has 80% sensitivity and 92% specificity for pDPN²⁸. The questionnaire was administered by the investigator in English or Arabic. Medications for pDPN were recorded.

CCM was carried out using the HRT‐3‐RCM device (Heidelberg Engineering GmbH, Heidelberg, Germany), as described in our previously published protocol³¹. Corneal nerve fiber density (CNFD; fibers/mm²), length (CNFL) (mm/mm²) and branch density (CNBD) (branches/mm²) were quantified manually using CCMetrics³².

Sudomotor function was measured by electrochemical skin conductance (ESC) using Sudoscan (Impeto Medical SAS, Paris, France), as described previously³³. Sudoscan evaluates sympathetic innervation based on sweat chloride concentrations generated by the sweat gland in response to the voltage applied³³, and is reported as ESC in microSiemens (µS).

Vibration perception threshold (VPT) was measured using a Neurothesiometer (Horwell Scientific Laboratory Supplies, London, UK) on the pulp of the large toe on both feet, and the average value of three measurements was recorded as a VPT in Volts (V) ranging from 0 to 50 V.

Statistical analysis

Continuous variables between controls, participants with type 2 diabetes, with and without pDPN were compared using one‐way anova. Continuous variables were compared between the two study groups (with and without pDPN) using the unpaired t‐test, whereas categorical variables were compared using the χ²‐test. Within each group, changes between baseline and 1‐year follow up were compared for the continuous variables using the paired t‐test. Linear regression was used to analyze the association between the change in CCM measures with type of treatment, change in DN4 score, bodyweight, diastolic blood pressure, HbA1c, cholesterol, triglyceride and LDL. No adjustment for multiple testing was carried out, as the study was exploratory in nature. All analyses were carried out using IBM SPSS (version 23; Armonk, NY, USA). A two‐tailed P value of ≤0.05 was considered significant.

RESULTS

Difference between participants with and without pDPN and healthy controls

A total of 41 participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN, and 18 control participants were studied (Table 1). The proportion of those treated with basal–bolus insulin (P = 0.84) or a combination of exenatide and pioglitazone (P = 0.84) were comparable between the two groups. Three out of 13 participants with pDPN (23%) were taking medication to relieve pain. Participants with type 2 diabetes were age‐matched with control participants. Participants with pDPN were older (P < 0.01), had a higher DN4 score (P < 0.0001) and a lower percentage undertook physical activity (P < 0.05) compared with participants without pDPN. Sex (P = 0.94), duration of diabetes (P = 0.27), HbA1c (P = 0.66), total cholesterol (P = 1.00), triglyceride (P = 0.72), HDL (P = 0.28), LDL (P = 0.45), systolic blood pressure (P = 0.83), diastolic blood pressure (P = 0.91), bodyweight (P = 0.51) and BMI (P = 0.12) were comparable between participants with and without pDPN.

Table 1.

Comparison of baseline characteristics between patients with type 2 diabetes with and without painful diabetic peripheral neuropathy and healthy controls

	Controls (n = 18)	Patients without painful diabetic neuropathy (n = 28)	Patients with painful diabetic neuropathy (n = 13)	P‐value
Age (years)	53.0 ± 11.0	50.7 ± 9.4	57.6 ± 5.1	<0.01
Diabetes duration (years)		12.0 ± 8.0	9.3 ± 6.3	0.27
Male, n (%)		16/28 (69.6)	7/12 (30.4)	0.94
Basal‐bolus insulin, n (%)		12/28(42.9)	6/13(46.2)	0.84
Exenatide plus pioglitazone, n (%)		16/28(57.1)	7/13(53.8)
Physical activity		11/27 (49.7)	1/12(8.3)	<0.05
HbA1c (mmol/mol)		90.1 ± 21.1	87.0 ± 20.7	0.66
HbA1c (%)		10.4 ± 1.9	10.1 ± 1.9
Total cholesterol (mmol/L)		4.9 ± 0.9	4.9 ± 1.2	1.00
Triglyceride (mmol/L)		1.9 ± 1.2	2.1 ± 1.1	0.72
HDL (mmol/L)		1.2 ± 0.5	1.1 ± 0.3	0.28
LDL (mmol/L)		2.9 ± 0.9	2.6 ± 0.7	0.45
Systolic BP (mmHg)		129.1 ± 15.9	127.5 ± 25.4	0.83
Diastolic BP (mmHg)		78.1 ± 11.4	77.6 ± 14.2	0.91
Bodyweight (kg)		85.0 ± 13.4	89.5 ± 22.2	0.51
BMI (kg/m2)		29.9 ± 4.7	33.7 ± 7.6	0.12
DN4 score	0 ± 0	1.1 ± 1.0††	5.5 ± 1.4†††	<0.0001
CNFD (fibers/mm2)	33.7 ± 5.7	27.4 ± 8.0‡	26.0 ± 8.7‡	0.64
CNBD (branches/mm2)	110.4 ± 45.0	67.3 ± 32.1††	54.0 ± 27.6†††	0.20
CNFL (mm/mm2)	25.1 ± 4.3	18.8 ± 4.8†††	17.4 ± 5.6†††	0.46
VPT (V)	7.2 ± 4.1	7.8 ± 4.4†	14.1 ± 8.0†	0.07
ESC feet (µS)	66.9 ± 18.4	66.6 ± 17.4	64.2 ± 24.1	0.79

Numeric variables and frequency distribution for categorical variables are summarized as the mean ± standard deviation or n (%), and were compared between patients with and without painful diabetic peripheral neuropathy using the unpaired t‐test and χ²‐test, respectively. Variables between controls and patients with type 2 diabetes with and without painful diabetic peripheral neuropathy were compared using one‐way anova, and significant differences between them are denoted as ^‡ P ≤ 0.05, ^† P ≤ 0.01, ^†† P ≤ 0.001, ^††† P ≤ 0.0001. BMI, body mass index; BP, blood pressure; DN4, Douleur Neuropathique en 4; CNBD corneal nerve branch density; CNFD, corneal nerve fiber density; CNFL, corneal nerve fiber length; ESC, electrochemical skin conductance; HbA1c, glycated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; VPT, vibration perception threshold. Bold values are indicates statistically significant.

Participants with type 2 diabetes had a significantly higher DN4 score (P ≤ 0.001) and VPT (P ≤ 0.01), and lower corneal nerve fiber measures (P ≤ 0.05), but comparable ESC compared with healthy controls. Corneal nerve fiber measures, ESC and VPT were comparable between participants with and without pDPN.

Difference in clinical characteristics and neuropathy measures between baseline and 1‐year follow up

Between baseline and 1‐year follow up, participants with pDPN showed a significant decrease in HbA1c (P < 0.0001), increase in bodyweight (P < 0.01), but no change in total cholesterol (P = 0.06), triglyceride (P = 0.26), HDL (P = 0.72), LDL (P = 0.19), systolic blood pressure (P = 0.16), diastolic blood pressure (P = 0.39) and BMI (P = 0.18; Table 2; Figures 1 and 2). There was a significant decrease in the DN4 score (P < 0.01), and an increase in CNFD (P < 0.05), CNBD (P < 0.01) and CNFL (P < 0.0001), but no change in ESC (P = 0.96) and VPT (P = 0.32).

Table 2.

Baseline and 1‐year follow‐up clinical and neuropathy measures of patients with type 2 diabetes with and without painful diabetic neuropathy

	Patients without painful diabetic neuropathy (n = 28)		P‐value	Patients with painful diabetic neuropathy (n = 13)		P‐value
	Baseline	1‐year follow up		Baseline	1‐year follow up
HbA1c (mmol/mol)	90.1 ± 21.1	53.5 ± 11.7↓	<0.0001	87.0 ± 20.7	60.1 ± 20.2↓	<0.0001
HbA1c (%)	10.4 ± 1.9	7.0 ± 1.1↓	<0.0001	10.1 ± 1.9	7.7 ± 1.8↓	<0.0001
Total cholesterol (mmol/L)	4.9 ± 0.9	4.3 ± 0.9↓	<0.01	4.9 ± 1.2	4.2 ± 0.7	0.06
Triglyceride (mmol/L)	1.9 ± 1.2	1.5 ± 1.1↓	<0.01	2.1 ± 1.1	1.8 ± 1.0	0.26
HDL (mmol/L)	1.2 ± 0.5	1.2 ± 0.3	0.30	1.1 ± 0.3	1.1 ± 0.2	0.72
LDL (mmol/L)	2.8 ± 0.9	2.5 ± 1.0↓	<0.05	2.6 ± 0.7	2.3 ± 0.5	0.19
Systolic BP (mmHg)	129.1 ± 15.9	124.2 ± 16.4	0.12	127.5 ± 25.4	135.2 ± 15.3	0.16
Diastolic BP (mmHg)	78.1 ± 11.4	70.6 ± 9.8↓	<0.0001	77.6 ± 14.2	74.4 ± 11.6	0.39
Bodyweight (kg)	85.0 ± 13.4	88.9 ± 15.4↑	<0.0001	89.5 ± 22.2	95.6 ± 24.8↑	<0.01
BMI (kg/m2)	29.9 ± 4.7	30.2 ± 4.7	0.19	33.7 ± 7.6	34.4 ± 8.5	0.18
DN4 score	1.1 ± 1.0	1.0 ± 1.1	0.66	5.5 ± 1.4	4.23 ± 1.9↓	<0.01
CNFD (fibers/mm2)	27.4 ± 8.0	27.6 ± 6.5	0.91	26.0 ± 8.7	31.5 ± 8.2↑	<0.05
CNBD (branches/mm2)	67.3 ± 32.1	81.8 ± 37.8↑	<0.01	54.0 ± 27.6	102.2 ± 58.9↑	<0.01
CNFL (mm/mm2)	18.8 ± 4.8	20.0 ± 4.7	0.13	17.4 ± 5.6	23.5 ± 5.8↑	<0.0001
VPT (V)	7.8 ± 4.4	7.6 ± 3.9	0.77	14.1 ± 8.0	13.0 ± 7.1	0.32
ESC feet (µS)	66.6 ± 17.4	64.7 ± 16.4	0.54	64.2 ± 24.1	64.0 ± 23.3	0.96

Numeric variables are summarized as the mean ± standard deviation. Variables were compared using the paired t‐test. BMI, body mass index; BP, blood pressure; DN4, Douleur Neuropathique en 4; CNBD corneal nerve branch density; CNFD, corneal nerve fiber density; CNFL, corneal nerve fiber length; ESC, electrochemical skin conductance; HbA1c, glycated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; VPT, vibration perception threshold. Bold values are indicates statistically significant.

Figure 1.

Comparison of percentage change in clinical and neuropathy measures over a 1‐year period between patients with and without painful diabetic neuropathy. Chol, total cholesterol; DBP, diastolic blood pressure; DN4, Douleur Neuropathique en 4; ESC, electrochemical skin conductance; HbA1c, glycated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; SBP, systolic blood pressure; Trig, triglyceride; VPT, vibration perception threshold.

Figure 2.

Corneal confocal microscopy images of the sub‐basal nerve plexus showing corneal nerve morphology in a patient with type 2 diabetes without painful diabetic peripheral neuropathy at (a) baseline and (c) 1‐year follow up with (b,d) the nerves traced, and a patient with type 2 diabetes and painful diabetic peripheral neuropathy (e) at baseline and (g) 1‐year follow up with (f,h) the nerves traced. The main nerve fibers are highlighted in red and the branches in blue. The origin of the branches is shown as green dots.

Participants without pDPN had a significant decrease in HbA1c (P < 0.0001), increase in bodyweight (P < 0.0001), decrease in total cholesterol (P < 0.01), triglyceride (P < 0.01), LDL (P < 0.05) and diastolic blood pressure (P < 0.0001), but no change in HDL (P = 0.30), systolic blood pressure (P = 0.12) and BMI (P = 0.19). There was a significant increase in CNBD (P < 0.01), but no change in CNFD (P = 0.91), CNFL (P = 0.13), DN4 score (P = 0.66), ESC (P = 0.54) and VPT (P = 0.77).

Difference in change in clinical and neuropathy measures between those with and without pDPN

Participants with pDPN showed a comparable change in HbA1c (P = 0.14), total cholesterol (P = 0.79), triglyceride (P = 0.72), HDL (P = 0.59), LDL (P = 0.87), diastolic blood pressure (P = 0.30), body weight (P = 0.28) and BMI (P = 0.24) compared with those without pDPN (Table 3; Figure 1). Systolic blood pressure increased in participants with pDPN, whereas it decreased in participants without pDPN (P < 0.05). Participants with pDPN had a significantly greater increase in CNBD (P < 0.05) and CNFL (P = 0.001) compared with those without pDPN. Both groups showed a comparable change in the DN4 score (P = 0.40), ESC (P = 0.77) and VPT (P = 0.53).

Table 3.

Comparison of changes in clinical and neuropathy measures over a 1‐year period between patients with and without painful diabetic neuropathy

	Patients without painful diabetic neuropathy (n = 28)	Patients with painful diabetic neuropathy (n = 13)	P‐value
ΔHbA1c (mmol/mol)	−36.6 ± 16.2	−26.8 ± 20.2	0.14
ΔHbA1c (%)	−3.4 ± 1.5	−2.5 ± 1.9	0.14
ΔTotal cholesterol (mmol/L)	−0.6 ± 0.9	−0.7 ± 1.2	0.79
ΔTriglyceride (mmol/L)	−0.4 ± 0.8	−0.3 ± 0.9	0.72
ΔHDL (mmol/L)	−0.1 ± 0.4	0 ± 0.3	0.59
ΔLDL (mmol/L)	−0.4 ± 0.8	−0.3 ± 0.8	0.87
ΔSystolic BP (mmHg)	−4.9 ± 16.1	7.7 ± 18.7	<0.05
ΔDiastolic BP (mmHg)	−7.6 ± 9.6	−3.2 ± 13.0	0.30
ΔBodyweight (kg)	4.0 ± 4.7	6.1 ± 6.3	0.28
ΔBMI (kg/m2)	0 ± 1.7	0.8 ± 1.9	0.24
ΔDN4 score	0.1 ± 1.1	−0.6 ± 2.7	0.40
ΔCNFD (fibers/mm2)	0.2 ± 8.0	5.5 ± 7.4	0.06
ΔCNBD (branches/mm2)	14.5 ± 25.4	48.2 ± 46.0	<0.05
ΔCNFL (mm/mm2)	1.2 ± 3.9	6.1 ± 3.8	0.001
ΔVPT (V)	−0.2 ± 3.8	−1.1 ± 2.8	0.53
ΔESC feet (µS)	−2.0 ± 14.1	−0.2 ± 14.4	0.77

Numeric variables are summarized as the mean ± standard deviation. Variables were compared using unpaired t‐test. BMI, body mass index; BP, blood pressure; DN4, Douleur Neuropathique en 4; CNBD corneal nerve branch density; CNFD, corneal nerve fiber density; CNFL, corneal nerve fiber length; ESC, electrochemical skin conductance; HbA1c, glycated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; VPT, vibration perception threshold. Bold values are indicates statistically significant.

Association of change in CCM measures and painful symptoms with clinical characteristics

The change in CCM measures was not associated with the type of treatment (P = 0.47) and decrease in HbA1c (P = 0.61). However, it was negatively associated with bodyweight gain, with every 2‐kg increase in bodyweight, CNFD decreased by 1 fiber/mm (95% confidence interval −1.0–0.0), but this association just missed statistical significance (P = 0.0501).

The change in DN4 score had no association with medications for neuropathic pain at baseline (P = 0.21), decrease in HbA1c (P = 0.81) or gain in bodyweight (P = 0.67).

There was no association between the change in DN4 score and change in CNFD (P = 0.93), CNBD (P = 0.25) or CNFL (P = 0.28).

DISCUSSION

The present study shows that treatment of patients with type 2 diabetes and poor glycemic control with exenatide and pioglitazone or basal–bolus insulin markedly improves glycemic control, and is associated with an improvement in painful diabetic neuropathy and corneal nerve regeneration.

Painful symptoms in DPN have been associated with active nerve degeneration and regeneration¹². Indeed, although there are no differences in intra‐epidermal nerve fiber density between those with and without pDPN³⁴, ³⁵, there was a significantly lower CNFL in patients with pDPN compared with those with painless DPN¹⁵, ²¹; and in another study, CNFD was significantly lower in patients with pDPN²². Quantitative sensory testing has also shown increased thermal thresholds in patients with pDPN compared with those with painless DPN³⁶, ³⁷. More recently, we showed lower intra‐epidermal nerve fiber density and corneal nerve fibers in a large group of patients with painful compared with painless diabetic neuropathy³⁸. In this study, CCM measures, sudomotor function and vibration perception threshold were comparable between patients with and without pDPN, although the number of patients with painful diabetic neuropathy was much smaller than in previous studies¹⁵, ²¹, ²², ³⁸.

A large improvement in HbA1c (>2–3%) has been reported to be associated with treatment‐induced neuropathic pain and autonomic neuropathy³⁹. However, the present study showed that despite a mean reduction in HbA1c of 3.4% among those without pDPN, and 2.5% among those with pDPN, there was no increase in the DN4 score, consistent with our previous findings²⁷. Furthermore, of the 27 patients without pDPN, only one developed pDPN after 1 year of intensive glycemic control.

There is a need for better neuropathy phenotyping to enable trial enrichment of participants who are more likely to respond to therapies, whether to reduce the severity of pain with therapies targeting pain or nerve regeneration in clinical trials of disease‐modifying therapies for DPN. Thus, there has been a resurgence of interest in identifying biomarkers of specific pain mechanisms that might allow more effective targeted use of existing therapies³⁵. Quantitative sensory testing has been used in a phenotype‐stratified randomized, double‐blind, placebo‐controlled study to show that oxcarbazepine had a significantly greater effect in patients with an irritable nociceptor phenotype⁴⁰. Similarly, the conditioned pain modulation test has been used to identify altered descending spinal pathways to predict greater efficacy of duloxetine⁴¹. We also showed altered rate‐dependent depression of the H‐reflex, indicative of abnormal descending inhibitory pathways in patients with pDPN²². However, a deep phenotyping approach to identify outcomes of disease‐modifying therapies has not been undertaken to date. Indeed, despite multiple trials of disease‐modifying therapies, there are currently no US Food and Drug Administration‐approved therapies for DPN⁶. Several studies showed that subclinical small nerve fiber injury precedes large fiber damage in DPN⁴², ⁴³. Furthermore, early small fiber repair has been shown in several small clinical intervention trials²³, ⁴⁴, and after pancreas and kidney transplantation, normalization of glycemia was associated with corneal nerve regeneration after 6 months, followed by an improvement in neuropathic symptoms and nerve conduction after 24 months²⁴, ²⁵. More recently, we showed that both exenatide and pioglitazone or basal–bolus insulin effectively reduce HbA1c and induce corneal nerve regeneration, independent of changes in HbA1c, bodyweight and lipids²⁷. Preclinical studies have reported that glucagon‐like peptide‐1 receptor agonists have a neuroprotective effect⁴⁵ and suppresses pain hypersensitivity in diabetes⁴⁶, and although earlier clinical trials showed no benefit⁴⁷, ⁴⁸, we recently showed corneal nerve regeneration with exenatide²⁷. Thiazolidinediones have been reported to alleviate neuropathic pain by attenuating proinflammatory cytokine expression⁴⁹, and preclinical studies show a prevention of nerve conduction slowing⁵⁰, ⁵¹. Indeed, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial reported that rosiglitazone significantly reduced the 4‐year cumulative incidence of clinical DPN compared with insulin⁵². Insulin treatment has also been shown to have a neurotrophic effect and reduce tactile allodynia⁵³, and intensive insulin treatment might prevent nerve conduction slowing⁵⁴ and loss of ankle reflexes⁵⁵.

We acknowledge this is a small exploratory study with potential confounders in relation to the small cohort size and effect of different treatments. Nevertheless, we showed that patients with pDPN have optimal nerve regeneration in response to improved glycemic control. We also showed that nerve regeneration might be limited due to weight gain, and, of course, recently we showed that weight loss with bariatric surgery is associated with corneal nerve regeneration⁵⁶. Disease‐modifying treatments are also more likely to be of benefit in early or mild neuropathy where there is predominantly small fiber damage⁵⁷, ⁵⁸. These findings highlight the complex pathogenesis and risk factors determining outcomes in clinical trials of diabetic neuropathy and argues strongly for pre‐trial enrichment of participants.

We conclude that pDPN is associated with greater corneal nerve regeneration and improvement in painful neuropathic symptoms in patients with type 2 diabetes after intensive glycemic control. The underlying mechanism is not clear and merits further study.

DISCLOSURE

The authors declare no conflict of interest.

J Diabetes Investig. 2021; 12: 1642–1650