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      The association of elevated serum lipocalin 2 levels with diabetic peripheral neuropathy in type 2 diabetes

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          Abstract

          A variety of studies have demonstrated the role of lipocalin 2 (LCN2) in both diabetes and neurological disorders. Nevertheless, the relationship between LCN2 and diabetic peripheral neuropathy (DPN) needs to be elucidated in humans. Therefore, this study aimed to investigate the association of LCN2 with DPN in type 2 diabetes (T2D). A total of 207 participants with T2D and 40 participants with normal glucose tolerance (NGT) were included in this study. All participants were classified into DPN group and non-DPN (NDPN) group based on the Toronto Clinical Neuropathy Scoring (TCNS). Demographic and biochemical parameters were measured. Serum LCN2 levels were determined using an ELISA technique. Serum LCN2 levels in NGT group were lower than those in either DPN group ( P = 0.000) or NDPN group ( P = 0.043), while serum LCN2 levels in DPN group were higher than NDPN group ( P = 0.001). Moreover, serum LCN2 levels positively correlated to TCNS scores, which reflects neuropathy severity ( r = 0.438, P = 0.000). Multivariate stepwise regression analysis showed that BMI, triglycerides, and diastolic pressure were independently associated with serum LCN2 in DPN. Additionally, logistic regression analysis demonstrated that LCN2 (odds ratio (OR) = 1.009) and diabetes duration (OR = 1.058) were independently associated with the occurrence of DPN in T2D. Our report reveals the association of serum LCN2 with DPN in T2D. LCN2 might be used to evaluate DPN severity and serve a role in the pathogenesis of DPN.

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          Most cited references31

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          Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes

          Purpose of Review: Diabetic peripheral neuropathy eventually affects nearly 50% of adults with diabetes during their lifetime, and is associated with substantial morbidity including pain, foot ulcers, and lower limb amputation. This review summarizes the epidemiology, risk factors, and management of diabetic peripheral neuropathy and related lower extremity complications. Recent Findings: The prevalence of peripheral neuropathy is estimated to be between 6% and 51% among adults with diabetes depending on age, duration of diabetes, glucose control, and type 1 versus type 2 diabetes. The clinical manifestations are variable, ranging from asymptomatic to painful neuropathic symptoms. Because of the risk of foot ulcer (25%) and amputation associated with diabetic peripheral neuropathy, aggressive screening and treatment in the form of glycemic control, regular foot exams, and pain management are important. There is an emerging focus on lifestyle interventions including weight loss and physical activity as well. Summary: The American Diabetes Association has issued multiple recommendation statements pertaining to diabetic neuropathies and the care of the diabetic foot. Given that approximately 50% of adults with diabetes will be affected by peripheral neuropathy in their lifetime, more diligent screening and management are important to reduce the complications and health care burden associated with the disease.
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            Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans.

            Lipocalin-2, a 25-kDa secreted glycoprotein, is a useful biomarker for early detection of various renal injuries. Because lipocalin-2 is abundantly expressed in adipose tissue and liver, we investigated its relevance to obesity-related pathologies. We used real-time PCR and in-house immunoassays to quantify the mRNA and serum concentrations of lipocalin-2 in C57BL/KsJ db/db obese mice and their age- and sex-matched lean littermates. We analyzed the association between serum lipocalin-2 concentrations and various metabolic and inflammatory variables in 229 persons (121 men and 108 women) recruited from a previous cross-sectional study, and we evaluated the effect of the insulin-sensitizing drug rosiglitazone on serum lipocalin-2 concentrations in 32 diabetic patients (21 men and 11 women). Compared with the lean littermates, lipocalin-2 mRNA expression in adipose tissue and liver and its circulating concentrations were significantly increased in db/db diabetic/obese mice (P <0.001). These changes were normalized after rosiglitazone treatment. In humans, circulating lipocalin-2 concentrations were positively correlated (P <0.005) with adiposity, hypertriglyceridemia, hyperglycemia, and the insulin resistance index, but negatively correlated (P = 0.002) with HDL cholesterol. There was also a strong positive association between lipocalin-2 concentrations and high sensitivity C-reactive protein (hs-CRP), independent of age, sex, and adiposity (P = 0.007). Furthermore, rosiglitazone-mediated decreases in lipocalin-2 concentrations correlated significantly with increases in insulin sensitivity (r = 0.527; P = 0.002) and decreases in hs-CRP concentrations (r = 0.509; P = 0.003). Lipocalin-2 is an inflammatory marker closely related to obesity and its metabolic complications. Measurement of serum lipocalin-2 might be useful for evaluating the outcomes of various clinical interventions for obesity-related metabolic and cardiovascular diseases.
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              Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity

              OBJECTIVE The proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms. METHODS AND RESULTS Under conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-α (TNF-α), a critical insulin resistance–inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-α production in fat tissues. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice. CONCLUSIONS Lipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                12 October 2021
                01 November 2021
                : 10
                : 11
                : 1403-1409
                Affiliations
                [1 ]Department of Endocrinology and Laboratory for Diabetes , The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
                [2 ]Graduate School , Wannan Medical College, Wuhu, Anhui, People’s Republic of China
                [3 ]Institute of Endocrine and Metabolic Diseases , University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
                [4 ]Hefei National Laboratory for Physical Sciences at the Microscale , Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
                Author notes
                Correspondence should be addressed to W Wang: hfww2001@ 123456ustc.edu.cn

                *(X Zhang, X Shen and W Zhou contributed equally to this work)

                Author information
                http://orcid.org/0000-0003-1410-6714
                http://orcid.org/0000-0002-4123-8280
                Article
                EC-21-0290
                10.1530/EC-21-0290
                8630760
                34636748
                cbb36fbe-03e9-4f1b-b890-c422ddb4469b
                © The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 29 September 2021
                : 12 October 2021
                Categories
                Research

                diabetic peripheral neuropathy,diabetic complication,lipocalin 2,type 2 diabetes

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