Diabetic neuropathy is associated with activation of the TNF‐α system in subjects with type 1 diabetes mellitus

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Abstract
Summary: Objective  The development of diabetic neuropathy (DN) is predicted by cardiovascular risk factors associated with insulin resistance. As inflammation seems to be implicated in the pathogenesis of insulin resistance, we investigated whether subjects with type 1 diabetes mellitus (T1DM) and DN have an increase in plasma concentrations of inflammatory proteins involved in insulin resistance.Design  Cross‐sectional.Patients  One hundred twenty subjects, all diagnosed with T1DM 14 years before.Measurements  (1) Sex, age, body mass index, waist‐to‐hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) DN (peripheral and cardiac autonomic), retinopathy and nephropathy; (3) plasma concentrations of soluble fractions of tumour necrosis factor α receptors 1 and 2 (sTNFR1 and sTNFR2), interleukin‐6, high‐sensitive C‐reactive protein, adiponectin and leptin; and (4) insulin resistance (by way of a mathematical estimation of the glucose disposal rate – eGDR‐).Results  Thirty‐six subjects had DN and 84 did not. Subjects with DN received higher insulin doses (57·6 ± 16·7 vs. 49·2 ± 15·0 IU/day; P = 0·008) and had higher WHR (0·85 ± 0·07 vs. 0·81 ± 0·10; P = 0·007) and HbA1c values (8·5 (7·6–9·6) vs. 7·7 (7·3–8·9)%; P = 0·049) than subjects without DN. They also had higher values of sTNFR1 (2·42 ± 0·60 vs. 1·96 ± 0·66 µg/l; P = 0·001) and sTNFR2 (4·73 ± 1·33 vs. 4·14 ± 1·09 µg/l; P = 0·015), and were more insulin resistant (eGDR values: 7·28 (5·83–8·03) vs. 8·30 (7·17–9·03) mg kg−1 min−1; P = 0·003). The relationship between DN and either sTNFR1 or sTNFR2 remained essentially unchanged after adjusting for several confounders, including glycaemic control, WHR, lipid profile, blood pressure and other microvascular complications (OR for sTNFR1: 2·592 (1·222–5·498), P = 0·013; OR for sTNFR2: 2·124 (1·258–3·587), P = 0·005).Conclusions  The activity of the TNF‐α system is increased in subjects with type 1 diabetes mellitus and diabetic neuropathy, regardless of their glycaemic control and cardiovascular risk factors associated with insulin resistance. These results suggest that TNF‐α may play a pathogenic role in the development of diabetic neuropathy.