Prediabetes/early diabetes‐associated neuropathy predominantly involves sensory small fibres

Abstract

The aim of this study was to investigate the characteristics of prediabetes (preDM) and early (<3 years) diabetes mellitus type 2 (eDM2)-associated neuropathy and the value of recently proposed diagnostic criteria for diabetic sensorimotor polyneuropathy (DSPN). A prospective case-control study in a group of 48 consecutive patients with eDM2, 16 preDM patients and 40 age- and sex-matched normoglycaemic controls was performed. Clinical and laboratory diagnostic tests were used to detect neuropathic abnormalities; these were further classified in terms of recent diagnostic criteria. Criteria for confirmed DSPN based on abnormal nerve conduction (NC) studies were met in 7 (14.6%) eDM2 patients compared to no control (p < 0.05), and the proportion significantly increased to 37.5% compared to 2.5% controls (p < 0.001), if intraepidermal nerve fibre density (IENFD) was used as an alternative criterion in addition to NC. The subclinical DSPN criteria based on NC abnormalities were met in 4.2% eDM2 patients, while the proportion of preDM and eDM2 cases with subclinical sensory small-fibre involvement documented by IENFD reached 12.5% and 22.9% compared with 2.5% controls (p = 0.005 for eDM2). The absolute IENFD values from distal leg were significantly lower in both eDM2 (p < 0.0001) and preDM patients (p = 0.005) compared to controls. Neuropathy associated with preDM/eDM2 predominantly involves sensory small fibres.

Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients?

“…Recent publications support the prevailing hypothesis that alterations of small-caliber nerve fibers represent the earliest effects of diabetes on the peripheral nervous system (6)(7)(8)10,11,24). This has been based on a number of observations, including: 1) findings of altered thermal thresholds in patients with normal NCSs (7,8); 2) reduced intraepithelial nerve fiber density (IENFD) at the ankle and IENFD ratios in diabetic patients without symptoms or signs of peripheral neuropathy and normal NCSs (8,11); and 3) reduced IENFD in patients with impaired glucose tolerance (6,10,24).…”

“…This has been based on a number of observations, including: 1) findings of altered thermal thresholds in patients with normal NCSs (7,8); 2) reduced intraepithelial nerve fiber density (IENFD) at the ankle and IENFD ratios in diabetic patients without symptoms or signs of peripheral neuropathy and normal NCSs (8,11); and 3) reduced IENFD in patients with impaired glucose tolerance (6,10,24). Based on these findings, some authors have recommended that small-fiber testing be used as a surrogate measure in future clinical trials (25), and, in particular, skin-punch biopsy measuring IENFD has been singled out for its high sensitivity in identifying SFN (26,27).…”

“…While earlier reports seemed to indicate simultaneous loss of small-and large-diameter nerve fibers, with preserved small/large ratios (5), more recent studies have suggested the presence of early involvement of small-diameter Ad and C fibers (6)(7)(8)(9)(10)(11). Some suggest a temporal relationship of small-fiber impairment preceding that of large fibers.…”

Does dysfunction of the autonomic nervous system affect success of renal denervation in reducing blood pressure?

“…However, peripheral autonomic neuropathy can also develop in individuals with merely impaired glucose tolerance, well before diabetes becomes manifest clinically and as a consequence of obesity, in the presence of normal glucose metabolism. 10,32 …”

Diabetic neuropathies

“…Distal sensory unmyelinated axon loss in skin biopsies may occur in the absence of more proximal sural axon loss in diabetic sensory neuropathy. The absolute IENFD values from distal leg are lower in early type 2 diabetes and prediabetic patients compared to controls and may improve with appropriate intervention [15]. Small thinly myelinated Aδ (A-delta) axons, innervating cutaneous mechanoreceptors and thermal receptors, can also be demonstrated using skin biopsies.…”