{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:54:23Z","timestamp":1793836463616,"version":"4.6.1"},"reference-count":136,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AUB MPP","award":["320148"],"award-info":[{"award-number":["320148"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac autonomic neuropathy (CAN) is one of the earliest complications of type 2 diabetes (T2D), presenting a silent cause of cardiovascular morbidity and mortality. Recent research relates the pathogenesis of cardiovascular disease in T2D to an ensuing chronic, low-grade proinflammatory and pro-oxidative environment, being the hallmark of the metabolic syndrome. Metabolic inflammation emerges as adipose tissue inflammatory changes extending systemically, on the advent of hyperglycemia, to reach central regions of the brain. In light of changes in glucose and insulin homeostasis, dysbiosis or alteration of the gut microbiome (GM) emerges, further contributing to inflammatory processes through increased gut and blood\u2013brain barrier permeability. Interestingly, studies reveal that the determinants of oxidative stress and inflammation progression exist at the crossroad of CAN manifestations, dictating their evolution along the natural course of T2D development. Indeed, sympathetic and parasympathetic deterioration was shown to correlate with markers of adipose, vascular, and systemic inflammation. Additionally, evidence points out that dysbiosis could promote a sympatho-excitatory state through differentially affecting the secretion of hormones and neuromodulators, such as norepinephrine, serotonin, and \u03b3-aminobutyric acid, and acting along the renin\u2013angiotensin\u2013aldosterone axis. Emerging neuronal inflammation and concomitant autophagic defects in brainstem nuclei were described as possible underlying mechanisms of CAN in experimental models of metabolic syndrome and T2D. Drugs with anti-inflammatory characteristics provide potential avenues for targeting pathways involved in CAN initiation and progression. The aim of this review is to delineate the etiology of CAN in the context of a metabolic disorder characterized by elevated oxidative and inflammatory load.<\/jats:p>","DOI":"10.3390\/ijms21239005","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T22:00:33Z","timestamp":1606428033000},"page":"9005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Cardiac Autonomic Neuropathy: A Progressive Consequence of Chronic Low-Grade Inflammation in Type 2 Diabetes and Related Metabolic Disorders"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6403-9348","authenticated-orcid":false,"given":"Nour-Mounira Z.","family":"Bakkar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh 1107 2020, Beirut 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2514-2617","authenticated-orcid":false,"given":"Haneen S.","family":"Dwaib","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh 1107 2020, Beirut 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souha","family":"Fares","sequence":"additional","affiliation":[{"name":"Rafic Hariri School of Nursing, American University of Beirut, Riad El-Solh 1107 2020, Beirut 11-0236, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3004-5675","authenticated-orcid":false,"given":"Ali H.","family":"Eid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh 1107 2020, Beirut 11-0236, Lebanon"},{"name":"Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha 2713, Qatar"},{"name":"Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusra","family":"Al-Dhaheri","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, United Arab Emirates University, Al-Ain 15551, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3432-3038","authenticated-orcid":false,"given":"Ahmed F.","family":"El-Yazbi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh 1107 2020, Beirut 11-0236, Lebanon"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.2337\/dc15-0081","article-title":"Prevalence of cardiovascular autonomic neuropathy in a cohort of patients with newly diagnosed type 2 diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS)","volume":"38","author":"Zoppini","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.2337\/db19-0990","article-title":"Impairment in baroreflex sensitivity in recent-onset type 2 diabetes without progression over 5 years","volume":"69","author":"Strom","year":"2020","journal-title":"Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"956","DOI":"10.2337\/diacare.28.4.956","article-title":"Diabetic neuropathies: A statement by the American Diabetes Association","volume":"28","author":"Boulton","year":"2005","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e24","DOI":"10.1590\/S0066-782X2008000400014","article-title":"Diabetic cardiovascular autonomic neuropathy: Risk factors, clinical impact and early diagnosis","volume":"90","author":"Rolim","year":"2008","journal-title":"Arq. 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