Centrosome amplification in type 2 diabetes mellitus: Putative mechanisms, clinical research implications, and investigational therapeutic perspectives

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by progressive pancreatic β-cell failure, systemic insulin resistance, and multiorgan complications driven by sustained hyperglycemia, lipotoxicity, oxidative stress, and chronic low-grade inflammation. Centrosome amplification (CA), defined as a numerical increase of centrosomes (typically ≥ 3 mature centrosomes or ≥ 4 centrioles per cell), is distinct from centrosome structural defects, fragmentation, or primary ciliary dysfunction. Accumulating preclinical and clinical evidence suggests a bidirectional association between T2DM and CA: The pathological microenvironment of T2DM induces CA in multiple cell types via several reported signalling cascades, including the protein kinase B-reactive oxygen species-Rho-associated coiled-coil-containing protein kinase 1/14-3-3 protein sigma axis, Wnt6-frizzled 4-β-catenin pathway, and peroxisome proliferator-activated receptor γ-spindle and kinetochore-associated protein 1 transcriptional regulatory axis; in turn, CA may contribute to β-cell dysfunction, systemic insulin resistance, and the progression of diabetic macrovascular and microvascular complications. This narrative review aims to summarize the molecular regulation of centrosome homeostasis, the inducing factors and signaling networks underlying T2DM-associated CA, and the cellular mechanisms whereby CA may participate in T2DM pathogenesis and target-organ damage. Notably, much of the mechanistic data are derived from tumour-derived cell lines, and direct in vivo evidence from key metabolic tissues remains scarce, while clinical evidence supporting CA as a biomarker is still limited. We further synthesize available evidence from in vitro studies, animal models, and clinical cohorts, discuss investigational therapeutic strategies targeting CA for T2DM and its complications, and highlight current limitations and future research directions. This work provides a conceptual framework for exploring novel cellular mechanisms of T2DM and for developing centrosome-targeted interventions that remain to be validated for disease-modifying effects.

Keywords: Centrosome; Centrosome amplification; Type 2 diabetes mellitus; Pancreatic β-cell; Insulin resistance; Diabetic complications; Biomarkers; Oxidative stress; Rho-associated protein kinase 1

Core Tip: In vitro studies indicate that the diabetic microenvironment can induce Centrosome amplification (CA) via multiple interconnected signalling cascades, including protein kinase B-reactive oxygen species(Rho-associated coiled-coil-containing protein kinase 1/14-3-3 protein sigma, Wnt6-frizzled 4, protein kinase C-p38 and peroxisome proliferator-activated receptor γ-spindle and kinetochore-associated protein 1 axes. Putative links between CA and pancreatic β-cell failure, systemic insulin resistance, as well as diabetic macro-and microvascular complications remain largely hypothetical, owing to limited direct in vivo evidence from human metabolic tissues. Peripheral-blood-mononuclear-cell CA correlates with glycated haemoglobin and complication severity within a single observational clinical cohort; these associations cannot support prognostic inference, and it remains purely an exploratory research biomarker and is not ready for clinical application. Modulation of centrosome homeostasis represents a pre-clinical investigational direction; therapeutic benefits of polo-like kinase 4 inhibitors, Rho-associated coiled-coil-containing protein kinase blockers and antidiabetic agents related to CA suppression still await formal experimental verification.