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

Table 1 Summary of key studies investigating centrosome amplification in diabetes and metabolic disorders

Ref.	Experimental model	Sample size/cell line	CA definition	Diabetic experimental condition	CA-related quantitative outcome	Main findings	Evidence type
He et al[16], 2020	In vitro cell model	HCT116 human colon carcinoma cells	≥ 3 centrosomes per cell (γ-tubulin immunofluorescence)	High glucose + high insulin + FFA metabolic stress	Increased percentage of cells harbouring supernumerary centrosomes under diabetic-like stimulation	Wnt6-FZD4-β-catenin signalling acts upstream of ROCK1/14-3-3σ to drive diabetes-associated CA	Tumour-derived cell-line direct evidence
Liu et al[19], 2019	In vitro cell model	HCT116 human colon carcinoma cells	≥ 3 centrosomes per cell (γ-tubulin immunofluorescence)	High glucose + high insulin + FFA metabolic stress	Elevated proportion of CA-positive cells under diabetic-like conditions upon PPARγ overexpression	Diabetic-like stimuli up-regulate PPARγ; PPARγ transcriptionally activates SKA1 to promote diabetes-related CA	Tumour-derived cell-line direct evidence
Lu et al[17], 2019	In vitro cell model	HCT116 cells	≥ 3 centrosomes per cell	High glucose + high insulin + FFA metabolic stress	PCNA overexpression further elevates CA frequency under diabetic-like stress; JNK1-STAT3 activation reduces the percentage of CA-positive cells	PCNA promotes whereas JNK1-STAT3 suppresses diabetes-associated CA via targeting the ROCK1/14-3-3σ complex	Tumour-derived cell-line direct evidence
Xu et al[18], 2022	In vitro cell model	HCT116 human colon carcinoma cells	≥ 3 centrosomes per cell (γ-tubulin immunofluorescence)	High glucose + high insulin + FFA metabolic stress	Enhanced CA frequency upon diabetic-like stress, diminished after disruption of NPM-H2B interaction	NPM-H2B complex translocates from nucleus to centrosome under metabolic stress and mediates CA induction	Tumour-derived cell-line direct evidence
Wu et al[20], 2020	In vitro cell pharmacological intervention model	HCT116 human colon carcinoma cells	≥ 3 centrosomes per cell (γ-tubulin immunofluorescence)	High glucose + high insulin + FFA ± resveratrol treatment	Resveratrol dose-dependently reduced percentage of CA-positive cells under diabetic-like stress	Resveratrol attenuates diabetes-triggered CA by inhibiting PKCα-p38-c-MYC/c-JUN signalling cascade	Tumour-derived cell-line direct evidence (pharmacological assay)
Kushner et al[51], 2014	In vitro primary cell functional assay	Primary HUVECs	Supernumerary centrosomes (immunofluorescence)	No diabetic stimulus; experimental artificial centrosome over-abundance	Supernumerary centrosome-bearing cells display defective migration phenotype	Excess centrosomes disrupt endothelial cell polarity and migratory capacity	Primary-cell in vitro direct evidence
Huang-Doran et al[7], 2011	Human monogenic genetic study	Patients carrying biallelic PCNT loss-of-function mutations	Centrosomal structuralfunctional defect (not numerical acquired CA)	No experimental metabolic intervention; natural human germline mutation	Not applicable (structural defect, no quantitative CA count)	Pericentrin congenital deficiency causes severe human insulin resistance independent of adiposity	Human genetic indirect mechanistic evidence
Wang et al[15], 2018	Clinical cross-sectional cohort + in vitro cell model	30 T2DM patients, 30 age-matched healthy controls; HUVECs	≥ 3 centrosomes per cell (γ-tubulin immunofluorescence)	Clinical: Patients with established T2DM	PBMC CA frequency: 2-3-fold higher in T2DM patients vs controls; elevated CA rate observed in metabolically-stressed cultured endothelial cells	CA frequency in PBMCs is markedly increased in T2DM; glucolipotoxic stress induces CA via AKT-ROS-ROCK1/14-3-3σ signalling axis	Human observational-cohort direct evidence + primary-cell in vitro direct evidence
				In vitro: High glucose + high insulin + FFA stimulation

Studies are grouped into two broad categories: (1) Upper panel: Experiments investigating acquired numerical centrosome amplification under diabetic-like conditions; and (2) Lower-panel entry: Human monogenic disease reflecting congenital centrosome structural-functional defects, representing indirect mechanistic background evidence and not evidence for acquired numerical centrosome amplification in sporadic type 2 diabetes mellitus. CA: Centrosome amplification; FFA: Free fatty acids; FZD4: Frizzled-4; ROCK1: Rho-associated coiled-coil-containing protein kinase 1; PPARγ: Peroxisome proliferator-activated receptor gamma; SKA1: Spindle-and kinetochore-associated complex subunit 1; PCNA: Proliferating cell nuclear antigen; JNK1: C-Jun N-terminal kinase 1; STAT3: Signal transducer and activator of transcription 3; NPM: Nucleophosmin; H2B: Histone H2B; PKCα: Protein kinase C alpha; c-MYC: Cellular myelocytomatosis oncogene; c-JUN: Cellular Jun proto-oncogene; HUVECs: Human umbilical vein endothelial cells; T2DM: Type 2 diabetes mellitus; PBMCs: Peripheral blood mononuclear cells; AKT: Protein kinase B; ROS: Reactive oxygen species.