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Using sural nerve biopsies to assess changes in sural nerve myelinated fiber density (MFD) over a 52-week period in 427 type 1 and type 2 diabetic patients with neuropathy, Wiggin et al. defined 2 groups of patients with:
To identify predictors of diabetic neuropathy, baseline participant’s characteristics were compared between the two groups (clinical signs and symptoms, electrophysiological measurements, HbA1c, triglycerides, cholesterol, albumin, and hematocrit). Two analyzes were conducted:
These analyses were performed on samples and data from participants in two identical, randomized placebo-controlled clinical diabetic neuropathy trials testing acetyl-L-carnitine (ALC).1 Eligibility criteria included HbA1c >5.9%, age between 18 and 70 years, diabetes duration of >1 year, and diabetic neuropathy as defined by the San Antonio Conference.2 Because ALC treatment did not affect sural nerve MFD loss in these trials (p=0.87), data from patients receiving the active treatment were pooled with those of patients on placebo.
In the primary analysis, five baseline variables were significantly correlated with loss of sural nerve MFD over 52 weeks: dominant peroneal motor nerve conduction velocities (NCV; p = 0.005), non-dominant median motor NCV (p = 0.02), sural sensory NCV (p = 0.05), HbA1C (p = 0.02), and triglycerides level (p = 0.02).In the secondary analysis, baseline triglycerides were significantly higher (p=0.04) and peroneal motor NCV significantly lower (p=0.008) in the progressing group. No correlations were found with the other variables.
A comprehensive knowledge of the causes and mechanisms of diabetic neuropathy is still lacking. Major studies such as the Diabetes Control and Complications Trial (DCCT) have reported a positive correlation with the most commonly-used non-invasive biomarker of chronic hyperglycemia, namely HbA1c.3 There is also a growing body of evidence attracting attention on a possible etiological role of dyslipidemia in diabetic microangiopathies. For example, in the EURODIAB study, cholesterol and fasting triglycerides were significantly associated with the development of diabetic neuropathy.4 In the FIELD study, lipid-modifying therapy with fenofibrate reduced the incidence of macrovascular events and microvascular complications of type 2 diabetes, the latter including retinopathy, nephropathy, and autonomic neuropathy.5
The study by Wiggin et al. was designed to evaluate the mechanisms underlying diabetic neuropathy progression in a study population with both type 1 and type 2 diabetes. The primary outcome measure they used, MFD, is a quantitative and highly-reproducible measure of nerve health. The most relevant results of the study are those of the secondary analysis, in which the two groups of progressors and non-progressors were well-balanced in terms of initial diabetic neuropathy status, diabetes type, and use of insulin therapy – all factors known to have a significant impact on neuropathy development and/or progression.
This analysis identified high fasting triglycerides levels as the only independent variable associated with progression of diabetic neuropathy. The other correlate, peroneal motor nerve conduction velocities, is obviously linked to the neuropathy itself.
As stressed by the authors, these findings support the emerging idea that atherogenic dyslipidemia contributes to the development of diabetic neuropathy. This, they continue, may explain the earlier incidence of diabetic neuropathy in individuals with type 2 compared with type 1 diabetes, since the latter often have normal to supranormal triglycerides levels, as a combined result of (i) lack of endogenous portal insulin secretion, (ii) decreased incidence of metabolic syndrome and obesity, (iii) normal mean insulin sensitivity, and (iv) systemic hyperinsulinemia. Dyslipidemia develops thus later (if at all) in the course of type 1 diabetes despite lesser use of lipid-lowering therapies, and the delayed development of an abnormal lipid profile coincides with the delayed onset and progression of diabetic neuropathy.6,7
Figure 2. Fasting triglycerides levels in patients with non-progressing
and progressing diabetic neuropathy followed up to 52 weeks. *p=0.