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

Figure 1 Integrated signaling networks mediating centrosome amplification under diabetic conditions. Under the pathological microenvironment of type 2 diabetes mellitus, multiple metabolic stressors - including high glucose, insulin, palmitic acid/free fatty acids, and advanced glycation end products - activate converging signaling cascades that collectively drive centrosome amplification (CA). The core pro-CA axes include: (1) The proliferating cell nuclear antigen-Rho-associated protein kinase 1 (ROCK1) axis, which promotes assembly of the centrosomal ROCK1/14-3-3σ complex via upstream reactive oxygen species/protein kinase B signaling; (2) The Wnt6/plasma membrane receptor frizzled 4/β-catenin pathway, in which secreted Wnt6 binds to the membrane receptor plasma membrane receptor frizzled 4 and activates nuclear β-catenin to transcriptionally upregulate ROCK1 and 14-3-3σ; (3) Diabetic stimuli promote centrosome amplification by enhancing ROCK1 binding to dynactin subunit 2 and kinesin family member 2A; (4) The protein kinase C alpha-p38 mitogen-activated protein kinase-cellular myelocytomatosis oncogene/cellular Jun proto-oncogene transcriptional cascade, which activates the transcription of centrosome duplication-related genes; (5) The nucleophosmin-histone H2B complex pathway, where the nuclear nucleophosmin-histone H2B complex translocates to the centrosome and disrupts centrosome duplication control; (6) The peroxisome proliferator-activated receptor gamma-spindle-and kinetochore-associated complex subunit 1 regulatory axis, which modulates centrosome homeostasis via transcriptional upregulation of spindle-and kinetochore-associated complex subunit 1; (7) the advanced glycation end products-receptor for advanced glycation end-products-Krüppel-like factor 5-mouse double minute 2 signaling axis, which facilitates CA through mouse double minute 2-mediated degradation of p53 and Rb; and (8) The c-Jun N-terminal kinase 1-signal transducer and activator of transcription 3-14-3-3σ pathway serves as an endogenous negative feedback loop to restrain excessive CA. Symbols: Solid arrow (→) = promotion, activation, or transcriptional upregulation; blunt-ended line (⊣) = inhibition. T2DM: Type 2 diabetes mellitus; FFA: Free fatty acids; PCNA: Proliferating cell nuclear antigen; ROCK1: Rho-associated coiled-coil-containing protein kinase 1; DCTN2: Dynactin subunit 2; KIF2A: Kinesin family member 2A; JNK1: C-Jun N-terminal kinase 1; STAT3: Signal transducer and activator of transcription 3; PPARγ: Peroxisome proliferator-activated receptor gamma; SKA1: Spindle-and kinetochore-associated complex subunit 1; PKCα: Protein kinase C alpha; c-Myc: Cellular myelocytomatosis oncogene; c-Jun: Cellular Jun proto-oncogene; AGEs: Advanced glycation end-products; RAGE: Receptor for advanced glycation end-products; KLF5: Krüppel-like factor 5; MDM2: Mouse double minute 2; NPM-H2B: Nucleophosmin-histone H2B complex; p-JNK1: Phosphorylated c-Jun N-terminal kinase 1; p-STAT3: Phosphorylated signal transducer and activator of transcription 3; p-PKCα: Phosphorylated protein kinase C alpha; Rb: Retinoblastoma protein; NPM: Nucleophosmin; AGEs: Advanced glycation end-products.

Figure 2 Distinct pathogenic effects of centrosome amplification in proliferating vs terminally differentiated cells. The functional consequences of centrosome amplification (CA) are highly dependent on cell cycle status. In proliferating vascular cells (endothelial cells and vascular smooth muscle cells), CA primarily induces mitotic defects including multipolar spindle formation, chromosomal instability and aneuploidy, as well as cellular senescence and dysregulated proliferation/migration, which collectively drive diabetic macrovascular complications and microvascular endothelial injury. In terminally differentiated metabolic parenchymal cells (pancreatic β-cells, hepatocytes, adipocytes, and podocytes), CA exerts pathogenic effects mainly through disrupting interphase microtubule organization, intracellular vesicle trafficking, primary ciliogenesis, and Golgi positioning, contributing to β-cell dysfunction, systemic insulin resistance, and diabetic kidney disease. Solid black arrow: Supported by in vitro primary-cell experimental evidence; Grey dashed arrow: Hypothesized pathogenic cascade without direct evidence from metabolic tissues. VSMC: Vascular smooth muscle cell; CA: Centrosome amplification; CIN: Chromosomal instability.