Peripheral polyneuropathy in type 2 diabetes mellitus and impaired glucose tolerance. Correlations between morphology, neurophysiology, and clinical findings

Abstract: Diabetic peripheral polyneuropathy (PN) is a common and serious complication of diabetes. The prevalence of PN is rising with the global burden of type 2 diabetes. The causal mechanisms of PN are not fully understood, but both vascular and metabolic factors play a role. New methods of investigating PN need to be correlated with standard methods in well-defined, population-based cohorts.
Objectives: The overall aim was to investigate endoneurial microvascular abnormalities of the sural nerve and intraepidermal nerve fiber loss in type 2 diabetes and impaired glucose tolerance (IGT), in relation to glucose dysmetabolism, and clinical and neurophysiological measures of PN.
Methods: Subjects were recruited from a prospective, population-based study of males from Malmö, Sweden (6956 responders). From this cohort, 182 individuals in three groups were identified, [69 with type 2 diabetes, 51 IGT, and 62 normal glucose tolerance (NGT)], matched for age, height, and body mass index (BMI). Endoneurial microangiopathy and myelinated nerve fiber density (MNFD) were assessed in 30 sural nerve biopsies (from 10 men with type 2 diabetes, 10 IGT, and 10 NGT). Intraepidermal nerve fibers (IENF) were assessed in skin biopsies from the distal leg in 86 subjects (50 men with type 2 diabetes, 15 IGT, and 21 NGT) and graded as absent IENF, low (1–3 IENF/section), or high (> 4 IENF/section) counts of IENF. The subjects underwent oral glucose tolerance test, clinical examination (Total Neuropathy Score; combined Neuropathy Symptom Score and Neuropathy Disability Score), and neurophysiological tests (nerve conduction and quantitative sensory testing) at baseline and at follow-up (6–10 years later). Vibrotactile sense of the index (median nerve) and little fingers (ulnar nerve) was assessed in 58 subjects (23 type 2 diabetes, 7 IGT, 28 NGT) with persistent glucose tolerance for 15 years.
Results: Increased endoneurial capillary density was linked to current diabetes and future progression from IGT to diabetes. Decreased capillary luminal area was associated with deterioration of glucose tolerance. Increased basement membrane area was related to clinical PN. A low baseline sural nerve MNFD (< 4700 fibers/mm2) was associated with future progression of neurophysiological dysfunction in the peroneal and median nerves. MNFD correlated negatively with BMI. Absence of IENF was related to low sural nerve amplitude and conduction velocity, and high cold perception threshold. Vibrotactile sense was impaired in the index and particularly the little finger of diabetic subjects, mainly at high frequencies (250–500 Hz). IGT did not affect vibrotactile sense.
Conclusions: Sural nerve endoneurial microangiopathy is related to glucose dysmetabolism and clinical PN. MNFD may predict future nerve dysfunction. Obesity may be a risk factor for PN. IENF count correlates with neurophysiological measures of PN. Vibrotactile sense is impaired in the fingers, particularly innervated by the ulnar nerve at high frequencies, in patients with type 2 diabetes but not those with IGT.