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Introduction Vascular inflammation with elevated circulating white blood cell (WBC) counts is a key driver of cardiovascular disease, particularly in diabetes (1). The bone marrow (BM) is the primary source of these short-lived WBCs, and enhanced BM activity in cardiovascular risk states such as metabolic syndrome, obesity, and hypertension has been visualized as increased 18F-fluorodeoxyglucose (18F-FDG) uptake on PET/CT imaging (2). However, in diabetes, no increase in BM 18F-FDG uptake was observed (2). 18F-FDG is a glucose analogue, hyperglycemia and insulin resistance may limit tracer uptake through substrate competition and altered glucose utilization (3). We therefore tested whether BM 18F-FDG uptake in diabetes reflects hematopoietic activity under hyperglycemic conditions.Methods Patients with diabetes and age-matched non-diabetic controls (n=18/group) underwent 18F-FDG PET/CT; BM activity was quantified in lumbar vertebrae using standardized uptake values, and circulating leukocytes were measured in peripheral blood. In parallel, male C57BL/6J mice with experimental diabetes and controls (n=5/group) underwent 18F-FDG PET imaging. Peripheral leukocytes were quantified by flow cytometry. BM activation was quantified by hematopoietic stem/progenitor (LSK) frequency, Ki-67 proliferation, and BM cellularity. Cohorts were stratified by non-diabetic versus diabetic status.Results Diabetic patients displayed significantly lower BM 18F-FDG uptake (figure 1A), with SUV mean difference of -0.3131 ±0.1216 (p<0.05), yet elevated circulating WBC counts compared with controls (figure 1B). Diabetic mice recapitulated this discordance, showing reduced BM 18F-FDG signal (figure 1C), with %ID/g mean difference of -0.5363 ± 0.1221 (p<0.01), but increased WBC leukocyte compared with controls (figure 1D). Direct BM analyses in mice demonstrated increased LSK frequencies (p <0.05), higher Ki-67 positivity (p <0.0001), and increased BM cellularity (p <0.05) - consistent with heightened hematopoietic activation even when glucose-based PET readouts were attenuated. An unpaired t-test with p<0.05 was considered significant.Conclusions Diabetes is associated with increased BM hematopoietic activation even though BM 18F-FDG uptake appears reduced. This mismatch indicates that 18F-FDG PET can underestimate BM inflammatory activity in hyperglycemic state, likely reflecting altered substrate utilization rather than reduced hematopoiesis. These findings have important implications for interpretation of BM PET imaging in cardiometabolic disease and for risk stratification based on inflammatory imaging biomarkers. These findings support metabolism-aware interpretation of BM PET signals and motivate development of non-glucose-based tracers to improve detection of BM activation in cardiometabolic disease.References Kohutek ZA, et al. Circ Res 2020.Devesa A, et al. Eur Heart J 2022.Dudoignon D, et al. Cancer Imaging 2020.Abstract 157 Figure 1(A) Bone marrow uptake. Representative whole-body 18F-FDG PET images of a control (left) and a diabetic patient (right). The control shows increased 18F-FDG uptake in the bone marrow (arrowheads) compared to the diabetic patient. (B) WBC count. Unpaired t-test shows a significant difference, between the two groups, with higher WBC count in diabetic patients. (C) Bone marrow uptake in mice. Representative segmented whole-skeleton 18F-FDG PET images of a control (left) and a diabetic mouse (right). The control shows increased 18F-FDG uptake in the bone marrow (arrowheads) compared to the diabetic mouse. (D) Frequency of WBC from live cells. Unpaired t-test shows a significant difference between the two groups, with higher %WBC in diabetic mice.