Progressive Axonal Dysfunction Precedes Development of Neuropathy in Type 2 Diabetes

Abstract

To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA1c levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0–1 [n = 35]), grade 1 (TNS 2–8 [n = 42]), and grade 2/3 (TNS 9–24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA1c level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction.

Symptomatic and Electrodiagnostic Features of Peripheral Neuropathy in Scleroderma

“…A TNS score of ≥2 was considered to be abnormal in any of the 3 components (sensory symptoms, vibration sensibility, and pin sensibility). A score of greater than or equal 2 on the TNS has been shown to be indicative of at least mild neuropathy (15). …”

Assessing Decreased Sensation and Increased Sensory Phenomena in Diabetic Polyneuropathies

“…More recently, NES have been used as a biomarker for presymptomatic diabetic neuropathy. Although needing critical confirmation, some initial studies (76,77) demonstrate subtle changes in nerve excitability prior to the onset of diabetic neuropathy, as determined by either NCS or symptoms. The utility of NES as a biomarker for presymptomatic diabetic neuropathy is provocative and will need to be tested further in larger prospective studies.…”

Diabetic neuropathies

“…A near majority of patients with IGT or diabetes have small fiber neuropathy, the prototype of painful neuropathy, with burning feet, accompanied by thermal-evoked pain and/or allodynia. Ectopic discharges related to pain perception arise from DRG neurons and axons and accompany changes in sensory neuron sodium channels [17,18]. The NaV1.7 sodium channel accumulates at nerve fiber endings and amplifies small sub-threshold depolarizations, regulating excitability.…”

“…The NaV1.7 sodium channel accumulates at nerve fiber endings and amplifies small sub-threshold depolarizations, regulating excitability. In large studies of type 2 diabetics, SCN9A mutations resulted in a gain of function in the sodium channel Nav1.7 in 28% of patients with biopsyconfirmed small fiber neuropathy [17,18]. Loss-of function mutations in SCN9A are associated with congenital insensitivity to pain and gain-of-function mutations have been linked to spontaneous pain in several rare disorders.…”