Relationship between Metabolic Remodeling of Pancreatic β-cells and Pancreatic Histology in Type 2 Diabetes

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ID: 323802
2026
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Abstract
Abstract Background 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a key glycolytic regulator involved in the compensation for β-cell dysfunction under diabetic conditions, but its upstream regulation is incompletely understood. Here, we have characterized the relationship between the underlying pancreatic pathology and PFKFB3 expression in pancreatic β-cells. Methods Pancreatic sections from deceased individuals with and without type 2 diabetes (T2D) were immunostained for PFKFB3. The ratios of PFKFB3-positive β and α cells were compared, and the relationships with islet amyloid and pancreatic fibrosis were assessed. PFKFB3 expression was also evaluated in caerulein-treated mice and INS-1 832/13 cells co-cultured with pancreatic stellate cells (PSCs), as models of fibrosis. Results Eighteen individuals with and 18 without T2D were evaluated. The proportion of PFKFB3-positive β-cells, but not α-cells, was higher in those with T2D (23.9%±16.1% vs. 8.7%±6.3%, p < 0.05). PFKFB3 expression negatively correlated with β-cell mass (ρ=−0.34, p < 0.05). Both the amyloid deposition and area of fibrosis positively correlated with the proportion of PFKFB3-positive β-cells (ρ=0.50 and 0.84, respectively; p < 0.05). In mice, β-cell PFKFB3 positivity was higher in the fibrosis model versus controls (20.5%±10.5% vs. 5.6%±5.1%, p < 0.05). Additionally, Pfkfb3 expression in INS-1 cells was significantly higher after co-culture with PSCs. In this co-culture model, RNA sequencing identified transforming growth factor (TGF)-β-related gene clusters; ELISA confirmed high TGF-β levels, and western blotting showed greater phosphorylation of Smad. Conclusions PFKFB3-mediated metabolic remodeling occurs in the β-cells of individuals with T2D, and is linked not only to β-cell overload, but to pancreatic fibrosis and local TGF-β/Smad signaling.
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Authors Rimi Izumihara, Hiroshi Nomoto, Koki Chiba, Hiraku Kameda, Akinobu Nakamura, Hiroki Mizukami, Tatsuya Atsumi
Journal the journal of clinical endocrinology & metabolism
Year 2026
DOI
10.1210/clinem/dgag315
URL
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