{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T23:41:52Z","timestamp":1785800512543,"version":"3.56.0"},"reference-count":40,"publisher":"American Diabetes Association","issue":"11","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":2878,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,11,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Inflammatory processes have been implicated in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), but their possible relationship has not been assessed at the population level.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>We determined serum concentrations of mediators of subclinical inflammation among 1,047 participants 61\u201382 years of age from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany). Logistic and linear regression models were fitted to assess associations between immune mediators (log-transformed) and the presence of clinical DSPN (dichotomous variable) or Michigan Neuropathy Screening Instrument (MNSI) examination score (continuous variable), respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Serum concentrations of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1RA) were positively associated with the presence of DSPN and higher MNSI scores in age-adjusted and sex-adjusted analyses, whereas IL-6, IL-18, and soluble intercellular adhesion molecule-1 were positively associated with only MNSI scores. No associations were observed for adiponectin, C-reactive protein, or tumor necrosis factor-\u03b1. Associations for IL-1RA and IL-6 with the MNSI score remained statistically significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction or stroke, presence of neurological conditions, and use of nonsteroidal anti-inflammatory drugs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>We conclude that DSPN is linked to proinflammatory and anti-inflammatory, possibly compensatory, processes in the older general population. Future studies should clarify the temporal sequence and causality of these associations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/dc13-0382","type":"journal-article","created":{"date-parts":[[2013,9,6]],"date-time":"2013-09-06T03:56:03Z","timestamp":1378439763000},"page":"3663-3670","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":83,"title":["Association of Subclinical Inflammation With Polyneuropathy in the Older Population"],"prefix":"10.2337","volume":"36","author":[{"given":"Christian","family":"Herder","sequence":"first","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda W.C.","family":"Bongaerts","sequence":"additional","affiliation":[{"name":"Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Rathmann","sequence":"additional","affiliation":[{"name":"Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margit","family":"Heier","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology II, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Kowall","sequence":"additional","affiliation":[{"name":"Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Koenig","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\u2013Cardiology, University of Ulm Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Thorand","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology II, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Roden","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"},{"name":"Department of Endocrinology and Diabetology, University Hospital D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa","family":"Meisinger","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology II, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"},{"name":"Department of Endocrinology and Diabetology, University Hospital D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2013,10,15]]},"reference":[{"key":"2022031302212569000_B1","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B2","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.2337\/diacare.28.6.1480","article-title":"Underdiagnosis of peripheral neuropathy in type 2 diabetes","volume":"28","author":"Herman","year":"2005","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B3","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2337\/dc12-0744","article-title":"Older subjects with diabetes and prediabetes are frequently unaware of having distal sensorimotor polyneuropathy: The KORA F4 study","volume":"36","author":"Bongaerts","year":"2013","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B4","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nrendo.2011.113","article-title":"Neuropathy in prediabetes: does the clock start ticking early?","volume":"7","author":"Papanas","year":"2011","journal-title":"Nat Rev Endocrinol"},{"key":"2022031302212569000_B5","doi-asserted-by":"crossref","first-page":"584","DOI":"10.2337\/dc11-1421","article-title":"Impaired glycemia and diabetic polyneuropathy: the OC IG Survey","volume":"35","author":"Dyck","year":"2012","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B6","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrn2294","article-title":"Glucose neurotoxicity","volume":"9","author":"Tomlinson","year":"2008","journal-title":"Nat Rev Neurosci"},{"key":"2022031302212569000_B7","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrneurol.2011.137","article-title":"Diabetic neuropathy: cellular mechanisms as therapeutic targets","volume":"7","author":"Vincent","year":"2011","journal-title":"Nat Rev Neurol"},{"key":"2022031302212569000_B8"},{"key":"2022031302212569000_B9","doi-asserted-by":"crossref","first-page":"680","DOI":"10.2337\/dc08-2011","article-title":"Subclinical inflammation and diabetic polyneuropathy: MONICA\/KORA Survey F3 (Augsburg, Germany)","volume":"32","author":"Herder","year":"2009","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B10","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1210\/jc.2008-2385","article-title":"Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy","volume":"94","author":"Doupis","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031302212569000_B11","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1111\/j.1464-5491.2009.02863.x","article-title":"Incidence of Type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4\/F4 cohort study","volume":"26","author":"Rathmann","year":"2009","journal-title":"Diabet Med"},{"key":"2022031302212569000_B12","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s00125-002-1025-0","article-title":"High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. The KORA survey 2000","volume":"46","author":"Rathmann","year":"2003","journal-title":"Diabetologia"},{"key":"2022031302212569000_B13","volume-title":"Report of a WHO Consultation: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications","author":"World Health Organisation","year":"1999"},{"key":"2022031302212569000_B14","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.2337\/dc11-2028","article-title":"Postchallenge hyperglycemia is positively associated with diabetic polyneuropathy: the KORA F4 study","volume":"35","author":"Bongaerts","year":"2012","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B15","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1136\/jnnp.65.5.743","article-title":"Measuring vibration threshold with a graduated tuning fork in normal aging and in patients with polyneuropathy. European Inflammatory Neuropathy Cause and Treatment (INCAT) group","volume":"65","author":"Martina","year":"1998","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2022031302212569000_B16","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1046\/j.1464-5491.2002.00706.x","article-title":"A comparison of the Neuropen against standard quantitative sensory-threshold measures for assessing peripheral nerve function","volume":"19","author":"Paisley","year":"2002","journal-title":"Diabet Med"},{"key":"2022031302212569000_B17","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.2337\/dc11-S011","article-title":"Standards of medical care in diabetes\u20142011","volume":"34","author":"American Diabetes Association","year":"2011","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B18","doi-asserted-by":"crossref","first-page":"S181","DOI":"10.1002\/dmrr.848","article-title":"Practical guidelines on the management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot","volume":"24","author":"Apelqvist","year":"2008","journal-title":"Diabetes Metab Res Rev"},{"key":"2022031302212569000_B19","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1046\/j.1464-5491.2002.00698.x","article-title":"The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort","volume":"19","author":"Abbott","year":"2002","journal-title":"Diabet Med"},{"key":"2022031302212569000_B20","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.2337\/diacare.17.11.1281","article-title":"A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy","volume":"17","author":"Feldman","year":"1994","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0168-8227(98)00005-9","article-title":"A simplified diagnostic test for ambulatory screening of peripheral diabetic neuropathy","volume":"39","author":"Lunetta","year":"1998","journal-title":"Diabetes Res Clin Pract"},{"key":"2022031302212569000_B22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.immunol.021908.132612","article-title":"Immunological and inflammatory functions of the interleukin-1 family","volume":"27","author":"Dinarello","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"2022031302212569000_B23","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.2337\/db09-1199","article-title":"Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study","volume":"59","author":"Carstensen","year":"2010","journal-title":"Diabetes"},{"key":"2022031302212569000_B24","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1007\/s00125-006-0335-z","article-title":"Long-term treatment with interleukin-1\u03b2 induces insulin resistance in murine and human adipocytes","volume":"49","author":"Lagathu","year":"2006","journal-title":"Diabetologia"},{"key":"2022031302212569000_B25","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1210\/en.2006-0692","article-title":"Interleukin-1\u03b2-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression","volume":"148","author":"Jager","year":"2007","journal-title":"Endocrinology"},{"key":"2022031302212569000_B26","doi-asserted-by":"crossref","first-page":"4247","DOI":"10.1210\/en.2010-0340","article-title":"Interleukin-1\u03b2 may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation","volume":"151","author":"Nov","year":"2010","journal-title":"Endocrinology"},{"key":"2022031302212569000_B27","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1172\/JCI200215318","article-title":"Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets","volume":"110","author":"Maedler","year":"2002","journal-title":"J Clin Invest"},{"key":"2022031302212569000_B28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.tem.2009.12.010","article-title":"Cytokine production by islets in health and diabetes: cellular origin, regulation and function","volume":"21","author":"Donath","year":"2010","journal-title":"Trends Endocrinol Metab"},{"key":"2022031302212569000_B29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.pain.2005.04.018","article-title":"Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain","volume":"116","author":"Zelenka","year":"2005","journal-title":"Pain"},{"key":"2022031302212569000_B30","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.pain.2005.11.011","article-title":"Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice","volume":"120","author":"Wolf","year":"2006","journal-title":"Pain"},{"key":"2022031302212569000_B31","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1093\/brain\/awr228","article-title":"The identification of gene expression profiles associated with progression of human diabetic neuropathy","volume":"134","author":"Hur","year":"2011","journal-title":"Brain"},{"key":"2022031302212569000_B32","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1056\/NEJMoa065213","article-title":"Interleukin-1-receptor antagonist in type 2 diabetes mellitus","volume":"356","author":"Larsen","year":"2007","journal-title":"N Engl J Med"},{"key":"2022031302212569000_B33","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1161\/CIRCULATIONAHA.112.122556","article-title":"Effects of interleukin-1\u03b2 inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial","volume":"126","author":"Ridker","year":"2012","journal-title":"Circulation"},{"key":"2022031302212569000_B34"},{"key":"2022031302212569000_B35"},{"key":"2022031302212569000_B36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S1359-6446(05)03637-8","article-title":"The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets","volume":"11","author":"Myers","year":"2006","journal-title":"Drug Discov Today"},{"key":"2022031302212569000_B37","doi-asserted-by":"crossref","first-page":"464","DOI":"10.2337\/dc07-1796","article-title":"Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA\/KORA Augsburg Surveys S2 and S3","volume":"31","author":"Ziegler","year":"2008","journal-title":"Diabetes Care"},{"key":"2022031302212569000_B38","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1212\/01.wnl.0000260606.36443.29","article-title":"Epidemiology of distal symmetrical neuropathies in the Italian elderly","volume":"68","author":"Baldereschi","year":"2007","journal-title":"Neurology"},{"key":"2022031302212569000_B39","doi-asserted-by":"crossref","first-page":"M236","DOI":"10.1093\/gerona\/56.4.M236","article-title":"High plasma insulin and lipids profile in older individuals: the Italian longitudinal study on aging","volume":"56","author":"Maggi","year":"2001","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2022031302212569000_B40","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1212\/01.WNL.0000149522.32823.EA","article-title":"Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation","volume":"64","author":"England","year":"2005","journal-title":"Neurology"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/36\/11\/3663\/617928\/3663.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/36\/11\/3663\/617928\/3663.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T06:33:06Z","timestamp":1647153186000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/36\/11\/3663\/38180\/Association-of-Subclinical-Inflammation-With"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,15]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2013,10,15]]},"published-print":{"date-parts":[[2013,11,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc13-0382","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,10,15]]}}}