Insulin physiology and metabolic control: current concepts and perspectives

Abstract

Type 2 diabetes (T2D) results from progressive failure of multiple interconnected metabolic nodes. This review synthesizes evidence that β-cell dedifferentiation, mediated by loss of PDX-1, MAFA, and NKX6.1 and by epigenetic silencing of their promoters, may represent a leading mechanism of β-cell dysfunction, potentially preceding apoptotic death. Reduced hepatic insulin clearance through CEACAM1-dependent clearance pathways may contribute to a feedback loop amplifying systemic hyperinsulinemia and worsening peripheral insulin resistance. Adipose tissue dysfunction has been proposed to initiate cascading hepatic and muscular resistance in a subset of T2D phenotypes. Emerging mechanisms include gut microbiota-derived metabolites regulating incretin secretion; cellular senescence and mitochondrial dysfunction as drivers of metabolic aging; and altered bile acid metabolism affecting gluconeogenic regulation. Subcutaneous insulin, reversing the physiological portal-to-peripheral gradient, generates hepatic hypoinsulinemia and peripheral hyperinsulinemia despite adequate total doses. These advances will potentially identify stage-matched therapeutic windows: early insulin resistance for lifestyle intervention and/or SGLT2 inhibitors (SGLT2i); compensatory phase for GLP-1Ra; advanced dedifferentiation for cell replacement. Precision medicine subtyping and multi-node targeting promise improved glycemic control and disease modification.

Keywords

Type 2 diabetes mellitus / β-cell / incretins / CEACAM1 / IDE / PDX-1 / precision medicine / geroscience

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