Serum Levels of Inflammatory Proteins Are Associated With Peripheral Neuropathy in a Cross-Sectional Type-1 Diabetes Cohort.

Sharad Purohit,Bruce Bode,Risa Bernard,Jennifer Bryant,Lynn Kim Hoang Tran,Mingfang He,Jin-Xiong She,Shan Bai,Diane Hopkins,John Chip Reed,Chandramohan Wakade,Paul Minh Huy Tran,Wenbo Zhi,Melissa Gardiner,John Morgan,Khaled Bin Satter

doi:10.3389/fimmu.2021.654233

Abstract

Chronic low-grade inflammation is involved in the pathogenesis of type-1 diabetes (T1D) and its complications. In this cross-section study design, we investigated association between serum levels of soluble cytokine receptors with presence of peripheral neuropathy in 694 type-1 diabetes patients. Sex, age, blood pressure, smoking, alcohol intake, HbA1c and lipid profile, presence of DPN (peripheral and autonomic), retinopathy and nephropathy was obtained from patient’s chart. Measurement of soluble cytokine receptors, markers of systemic and vascular inflammation was done using multiplex immunoassays. Serum levels were elevated in in DPN patients, independent of gender, age and duration of diabetes. Crude odds ratios were significantly associated with presence of DPN for 15/22 proteins. The Odds ratio (OR) remained unchanged for sTNFRI (1.72, p=0.00001), sTNFRII (1.45, p=0.0027), sIL2Rα (1.40, p=0.0023), IGFBP6 (1.51, p=0.0032) and CRP (1.47, p=0.0046) after adjusting for confounding variables, HbA1C, hypertension and dyslipidemia. Further we showed risk of DPN is associated with increase in serum levels of sTNFRI (OR=11.2, p<10), sIL2Rα (8.69, p<10-15), sNTFRII (4.8, p<10-8) and MMP2 (4.5, p<10-5). We combined the serum concentration using ridge regression, into a composite score, which can stratify the DPN patients into low, medium and high-risk groups. Our results here show activation of inflammatory pathway in DPN patients, and could be a potential clinical tool to identify T1D patients for therapeutic intervention of anti-inflammatory therapies.

Highlights

The morbidity and mortality associated with type-1 diabetes (T1D) is mainly related to the development of long-term microand macro-vascular complications [1]
We have shown that serum levels of insulin like growth factor binding proteins (IGFBP), TNF-a and IL-6 pathways were able to stratify T1D patients into risk categories for a number of complications [28], including nephropathy [24] and retinopathy [25]
We report increased serum levels of five out of twenty-two proteins assessed in T1D patients with diabetic peripheral neuropathy (DPN)

Summary

Introduction

The morbidity and mortality associated with type-1 diabetes (T1D) is mainly related to the development of long-term microand macro-vascular complications [1]. The microvascular damage due to hyperglycemia can lead to neuropathy, retinopathy, and nephropathy [2,3,4]. The macro-vascular damage can lead to thrombosis [5]. The major characteristic of diabetic peripheral neuropathy (DPN) is the progressive loss of nerve fibers from both the autonomic and peripheral nervous system. This loss of sensory function has major detrimental effects, including risk of foot ulcerations, amputations, and increased mortality rates [6]

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Results

Conclusion