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.

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 50-80% of proinsulin, synthesized at ~6000 molecules per second, undergoes 5-10% 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-IRS-1 tyrosine 608-PI3K-PDK1-Akt (Ser473)-GSK3β signaling. ER stress activates the unfolded protein response (UPR: IRE1α-XBP1, PERK-eIF2α, ATF6), increasing clearance demand.When clearance fails, misfolded proinsulin accumulates, driving hyperinsulinemia, which promotes insulin resistance, activates mTORC1-SREBP-1c-mediated lipogenesis and VLDL export, and contributes to NAFLD and obesity, as observed in CEACAM1 knockout models. The Hepatic Insulin Clearance Index (HICI), derived from a 50-g glucose challenge yielding a C-peptide/insulin ratio<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.