The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN’s sensitivity and performance.

Aims/IntroductionTo measure the elasticity of the tibial nerve using sonoelastography, and to associate it with diabetic neuropathy severity, the cross‐sectional area of the tibial nerve and neurophysiological findings in type 2 diabetic patients.Materials and MethodsThe elasticity of the tibial nerve was measured as the tibial nerve:acoustic coupler strain ratio using high‐resolution ultrasonography in 198 type 2 diabetic patients stratified into subgroups by neuropathy severity, and 29 control participants whose age and sex did not differ from the diabetic subgroups.ResultsThe elasticity of the tibial nerve in patients without neuropathy (P < 0.001) was reduced compared with controls (0.76 ± 0.023), further decreasing (0.655 ± 0.014 to 0.414 ± 0.018) after developing neuropathy. The cut‐off value of elasticity of the tibial nerve that suggested the presence of neuropathy was 0.558. The area under the curve (0.829) was greater than that for the cross‐sectional area (0.612). The cross‐sectional area of the tibial nerve in diabetic patients without neuropathy (6.11 ± 0.13 mm2) was larger than that in controls (4.84 ± 0.16 mm2), and increased relative to neuropathy severity (P < 0.0001). The elasticity of the tibial nerve was negatively associated with neuropathy severity (P < 0.0001), cross‐sectional area (P = 0.002) and 2000 Hz current perception threshold (P = 0.011), and positively associated with nerve conduction velocities (P < 0.0001).ConclusionsDetermining the elasticity of the tibial nerve in type 2 diabetic patients could reveal early biomechanical changes that were likely caused by thickened fibrous sheaths of peripheral nerves, and might be a novel tool for characterizing diabetic neuropathy.

Aims/Introduction:  Morphological changes to corneal C‐fibers in Japanese type 1 diabetic patients were visualized by corneal confocal microscopy (CCM). The effects of prior glycemic control and blood pressure on morphological parameters were clarified.Materials and Methods:  Corneal nerve fibers were visualized by CCM in 38 Japanese type 1 diabetic patients (14 with and 24 without neuropathy) and 38 controls. Morphological parameters were compared and related to annual mean HbA1c, blood pressure, and serum lipid levels of previous years prior to CCM examination.Results:  Compared with controls, diabetic patients had reduced corneal nerve fiber length (CNFL; 9.80 ± 0.38 vs 13.65 ± 0.88 mm/mm2; P < 0.001), reduced density (CNFD; 25.32 ± 1.04 vs 36.62 ± 2.37/mm2; P < 0.0005), lower frequency of beading (22.38 ± 0.73 vs 30.44 ± 1.03/0.1 mm; P < 0.0001), and increased tortuosity (3.13 ± 0.09 vs 1.74 ± 0.06; P < 0.0001). These changes were found in patients without neuropathy. There was no difference in nerve branches between controls and diabetic patients. The mean annual HbA1c level for the 7–10 years prior to CCM examination was an independent predictor of reduced CNFL and CNFD; HbA1c levels obtained 1–3 months and 1 year prior to CCM, as well as blood pressure 3, 5, and 6 years prior to CCM, were independent predictors of reduced beading frequency.Conclusions:  Corneal confocal microscopy is a novel, noninvasive technique to evaluate morphological changes of corneal C‐fibers in type 1 diabetes. Antecedent hyperglycemia and blood pressure have different time‐dependent effects on CNFL and CNFD and the frequency of beading. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00157.x, 2011)

This study aims to establish the corneal nerve fiber (CNF) morphological alterations in a large cohort of type 2 diabetic patients and to investigate the association between the bead size, a novel parameter representing composite of accumulated mitochondria, glycogen particles, and vesicles in CNF, and the neurophysiological dysfunctions of the peripheral nerves. 162 type 2 diabetic patients and 45 healthy control subjects were studied in detail with a battery of clinical and neurological examinations and corneal confocal microscopy. Compared with controls, patients had abnormal CNF parameters. In particular the patients had reduced density and length of CNF and beading frequency and increased bead size. Alterations in CNF parameters were significant even in patients without neuropathy. The HbA1c levels were tightly associated with the bead size, which was inversely related to the motor and sensory nerve conduction velocity (NCV) and to the distal latency period of the median nerve positively. The CNF density and length positively correlated with the NCV and amplitude. The hyperglycemia-induced expansion of beads in CNF might be a predictor of slow NCV in peripheral nerves in type 2 diabetic patients.

OBJECTIVETo investigate the impact of normalizing HbA 1c by extensive HbA 1c control (EHC) on neuropathy outcome measures (NOMs), nephropathy, and retinopathy in type 2 diabetes. RESEARCH DESIGN AND METHODSDetailed clinical and neurological examinations were performed in two cohorts of 38 patients with uncontrolled type 2 diabetes (HbA 1c 9.6% [81.4 mmol/mol]) at baseline and after glycemic control (GC) with or without EHC by diet restriction and hypoglycemic agents over 4 years along with 48 control subjects with normal glucose tolerance (NGT) and 34 subjects with impaired glucose tolerance (IGT) only at baseline. EHC patients, control subjects, and subjects with IGT underwent oral glucose tolerance tests. Glycemic variability (GV) was evaluated by SD and coefficient of variation of monthly measured HbA 1c levels and casual plasma glucose. RESULTSIn the EHC cohort, HbA 1c levels over 4.3 years and the last 2 years improved to 6.1% (43.2 mmol/mol) and 5.8% (39.9 mmol/mol) with 7.3 kg body wt reduction, and 50% and 28.9% of patients returned to IGT and NGT, respectively, at end point. Baseline neurophysiological and corneal nerve fiber (CNF) measures were impaired in patients. Normalized HbA 1c with EHC improved neurophysiological and CNF measures to be similar for those for IGT, while GC without EHC (mean HbA 1c level 7.0% [53.5 mmol/mol]) improved only vibration perception. The mean normalized HbA 1c levels by EHC determined NOM improvements. The high GV and baseline HbA 1c levels compromised NOMs. Albumin excretion rate significantly decreased, while retinopathy severity and frequency insignificantly worsened on EHC. CONCLUSIONSNormalizing HbA 1c in type 2 diabetes of short duration improves microvascular complications including neuropathy and nephropathy more effectively than standard GC but not retinopathy.Intensive glycemic control (GC) has shown an equivocal efficacy regarding diabetic peripheral neuropathy (DPN) in type 2 diabetes (1), mainly due to nonoptimized HbA 1c levels. Randomized trials (2,3) have not been able to establish the optimum GC level for improving neuropathy outcomes in type 2 diabetes. In type 1