{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T20:06:35Z","timestamp":1779307595941,"version":"3.51.4"},"reference-count":80,"publisher":"Endocrinology Research Centre","issue":"2","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.probl-endojournals.ru\/jour\/about\/editorialPolicies#openAccessPolicy"}],"content-domain":{"domain":["www.probl-endojournals.ru"],"crossmark-restriction":true},"short-container-title":["Probl Endokrinol (Mosk)"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM), projected to affect 700 million individuals by 2045, may be driven by a hypothesized physiological axis where impaired hepatic insulin clearance, mediated by CEACAM1 endocytosis, links proinsulin misfolding to chronic hyperinsulinemia, exacerbating T2DM, obesity, and non-alcoholic fatty liver disease (NAFLD). Approximately 50\u201380% of proinsulin, synthesized at ~6000 molecules per second, undergoes 5\u201310% misfolding due to disrupted disulfide bonds (B7-A7, B19-A20, A6-A11) under endoplasmic reticulum (ER) stress, compounded by glutathione (GSH) depletion, which primarily impairs protein disulfide isomerase (PDI) function critical for insulin synthesis. Hepatic clearance involves CEACAM1 binding, insulin receptor isoform B (IR-B) tyrosine 960 autophosphorylation, AP-2\/clathrin\/dynamin vesicle formation, Rab5-mediated acidification (pH 5.5), Rab7 trafficking, and lysosomal cathepsin B\/D hydrolysis, supported by IR-B\u2013IRS-1 tyrosine 608\u2013PI3K\u2013PDK1\u2013Akt (Ser473)\u2013GSK3\u03b2 signaling. ER stress activates the unfolded protein response (UPR: IRE1\u03b1-XBP1, PERK-eIF2\u03b1, ATF6), increasing clearance demand.<\/jats:p>\n                  <jats:p>When clearance fails, misfolded proinsulin accumulates, driving hyperinsulinemia, which promotes insulin resistance, activates mTORC1\u2013SREBP-1c-mediated lipogenesis and VLDL export, and contributes to NAFLD and obesity, as observed in\u00a0CEACAM1 knockout models. The Hepatic Insulin Clearance Index (HICI), derived from a 50-g glucose challenge yielding a C-peptide\/insulin ratio&lt;1, may diagnose impaired clearance with greater sensitivity than HOMA-IR. Emerging tools, such as cryo-EM and portal vein proteomics, could quantify misfolded aggregates and elucidate NAFLD connections. Potential therapeutic strategies, including CEACAM1 enhancers and IR-B agonists, may target this clearance axis. This hypothesis underscores hepatic insulin clearance as a potential mediator of insulin resistance and its role in diseases linked to chronic hyperinsulinemia.<\/jats:p>","DOI":"10.14341\/probl13658","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T19:22:08Z","timestamp":1779304928000},"page":"69-77","update-policy":"https:\/\/doi.org\/10.14341\/crossmarkpolicy2018","source":"Crossref","is-referenced-by-count":0,"title":["Failure of Hepatic Insulin Clearance via CEACAM1-Mediated Endocytosis: The Missing Physiological Link Between Proinsulin Misfolding, Hyperinsulinemia, and Metabolic Complications in Type 2 Diabetes, Obesity, and NAFLD"],"prefix":"10.14341","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-1688","authenticated-orcid":true,"given":"Maher Monir","family":"Akl","sequence":"first","affiliation":[{"name":"Faculty of Medicine, National Research Lobachevsky State University of Nizhny Novgorod"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-236X","authenticated-orcid":true,"given":"Amr","family":"Ahmed","sequence":"additional","affiliation":[{"name":"The public health department, Riyadh First Health Cluster, Ministry of Health"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"5458","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Tanase, D. 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