By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
SYNOPSIS: The hallmark of neuropathy associated with type 2 diabetes is reduction of sensory nerve action potential amplitude and not a reduction in conduction velocity, supporting the hypothesis that hyperglycemia causes axonal dysfunction and injury.
SOURCE: Peterson M, et al. Association between HbA1c and peripheral neuropathy in a 10-year follow-up study of people with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes. Diabet Med 2017; Sept. 20. doi: 10.1111/dme.13514.
What is the relationship between HbA1c and peripheral neuropathy in patients with normal glucose tolerance (NGT), prediabetes or impaired glucose tolerance (IGT), and type 2 diabetes? To answer this question, Peterson et al performed a 10-year follow-up study on 87 of an original 119 patients recruited between 2004-2007 and enrolled in the population-based Västerbotten (Sweden) Intervention Programme. Of the original 119 patients, six died and 26 declined participation. Clinical definitions followed 1999 WHO criteria for glucose intolerance and diabetes: NGT as a fasting and two-hour plasma glucose concentration of < 6.1 mmol/L (110 mg/dL) and < 7.8 mmol/L (140 mg/dL), respectively; IGT as < 7.0 mmol/L (125 mg/dL) and > 7.8 mmol/L (140 mg/dL), respectively; and type 2 diabetes as > 7.0 mmol/L (125 mg/dL) and > 11.1 mmol/L (200 mg/dL), respectively. Evaluations included a social and medical history questionnaire, assessment of exposure to nicotine or other toxins, serum measurements of HbA1c, complete blood counts, C-reactive protein, lipid profile, creatinine, and homocysteine and thyroid-stimulating hormone levels to exclude B12 deficiency and hypothyroidism. All patients underwent standard nerve conduction studies of the right peroneal motor and sural sensory nerves, the latter deemed most appropriate to evaluate sensory nerve function. Statistical analysis was performed using ANOVA for continuous variables, the chi-square test for categorical variables, paired t-tests, Kendall’s tau and Pearson’s correlation coefficient and regression analyses, with P < 0.5 considered significant.
On average, the mean sural sensory amplitude decreased from 10.9 uV to 7.0 uV (P < 0.001) among 74 participants who underwent sural nerve study on both occasions, but no statistically significant decrease of conduction velocity was found between the two periods. Sural sensory nerve action potential amplitude decreased by approximately 1% for every 1% increase in HbA1c, whereas no statistically significant association between nerve conduction velocity slowing and HbA1c level increase was appreciated. Sural sensory amplitude decrease, but not nerve conduction velocity slowing, is associated with increasing HbA1c levels, supporting the notion that axonal degeneration, rather than demyelination, is the central feature of type 2 diabetic neuropathy.
COMMENTARY
More than 8% of the general population, and 15% in the over 40-year-old age group, has polyneuropathy, with prediabetes and type 2 diabetes being the most common causes in the United States and Europe. At least 50% of all diabetics develop some form of neuropathy during their lifetime, the most common being a distal, stocking-glove, sensory neuropathy. Etiology remains uncertain, with multiple pathways implicated, most notably the polyol pathway, whereby excess glucose is converted to sorbitol, resulting in osmotic imbalance and stress, with compensatory loss of myoinositol, essential for sodium/potassium ATPase function. Hyperglycemia, with its resultant increased glycolysis, promotes neuronal injury by forming uridine 5-diphosphate-N-acetylglucosamine, which binds serine/threonine onto transcription factors, promoting inflammation and nerve injury. Additionally, increased glycolysis results in the accumulation of diacylglycerol, which activates protein kinase C, leading to insulin resistance, vasoconstriction, hypoxia, and nerve damage. Amadori products form when glucose reacts with protein-bound amino groups, producing advanced glycation end products, which cross link essential proteins, resulting in nerve injury. Excess glucose metabolism overproduces electron donors, resulting in a high proton gradient across the inner mitochondrial membrane, overwhelming the antioxidant response with consequent nerve dysfunction. Emerging evidence also suggests that Schwann cells provide needed energy for axonal function, and disruption of the normal bioenergetic cross talk between Schwann cells and axons may underlie diabetic neuropathy.1
REFERENCE
- Feldman EL, et al. New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain. Neuron 2017;93:1296-1313.
The hallmark of neuropathy associated with type 2 diabetes is reduction of sensory nerve action potential amplitude and not a reduction in conduction velocity, supporting the hypothesis that hyperglycemia causes axonal dysfunction and injury.
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