Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy

Abstract

This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05), shortened strength-duration time constant (P<0.01), increased superexcitability (P<0.01), decreased subexcitability (P<0.05), decreased accommodation to depolarizing current (P<0.01), and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1-8) and G2+3 (TNSr 9-24) groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01) in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches.

Fig 1. This flowchart depicts the recruitment and the subjects involved in the final data analysis.

Patients were divided into group G0, G1, and G2+3 based on total neuropathy score-reduced (TNSr).

Fig 2

(A and B) Comparison of the stimulus response curve, (C and D) strength-duration time constant, (E and F) recovery cycle, and (G and H) threshold electrotonus in diabetic patients (G0: empty circle, G1: filled circle, and G2: triangle) and healthy controls (line). Sensory profiles are shown in the left column, while motor profiles are shown in the right.

Fig 3. The difference between healthy control (HC, white bar) and type 2 diabetic patients who have no clinical neuropathy (no clinical neuropathy, black bar) in sensory nerve excitability parameters.

(A) No clinical neuropathy group shows greater threshold stimulus for 50% SNAP, (B) shorter strength-duration time constant (SDTC), (C) increased superexcitability, (D) decreased subexcitability, (E) greater peak of TEd, and (F) the TEh in a 90–100 ms time window. *P<0.05; ** P<0.01; *** P<0.001

Fig 4. Correlation analysis in patients without clinically relevant neuropathy (n = 78).

(A) Correlation between sensory superexcitability and HbA1c level. (B) Correlation between motor subexcitability and HbA1c level. (C) Correlation between sensory and motor superexcitability parameters. (D) Correlation between sensory and motor subexcitability parameters.

Fig 5. Progression of diabetic neuropathy from pathophysiologic, symptomatologic, and nerve excitability viewpoints.

(A) Pathogenesis of diabetic neuropathy typically progresses from metabolic alteration, to ion current defect, and then the development of further structural and functional defects. (B) Both positive and negative clinical signs/symptoms would also progress in extent and severity as diabetic neuropathy worsens. (C) Sensory excitability changes, reflecting sensory axonal dysfunction, could be detected even in asymptomatic patients. Superexcitability, subexcitability, SDTC, and TEd parameter changes progress over the course of diabetic neuropathy, and eventually the peak response decreases, reflecting axonal loss. (D) Motor excitability changes in superexcitability, SDTC, TEh, and TEd parameters could be detected in later stages of diabetic neuropathy compared to sensory axons.