Development and Characterization of a Novel Murine Model for Type 2 Diabetes: Elucidating the Impact on Systemic Metabolic Inflammation

Introduction. Diabetes is rapidly increasing in prevalence1, with Type 2 diabetes (T2D) being the most common of this metabolic disorder. T2D is characterized by chronic hyperglycemia due to both insufficient insulin action and impaired insulin production. The metabolic environment of T2D affects the immune cell landscape and the production of immune cells at the bone marrow2. The specific immune and hematopoietic changes underlying bone marrow dysfunction in diabetes. This study hypothesizes that diabetes induces significant alterations in bone marrow function, leading to an overproduction of leukocytes that infiltrate vital organs, thereby promoting chronic inflammation.

Materials and methods. The study involved two groups of male C57Bl/6 mice: a healthy group, and a diabetic group. To establish the T2D model, mice underwent a combined treatment of a high-fat diet (HFD) for seven weeks and intraperitoneal injections of low-dose streptozotocin (STZ) for five consecutive days during the fourth week. Control mice were fed a standard chow diet and received sodium citrate injections instead of STZ. Body weights and fasting blood glucose of mice were recorded weekly. Ex-vivo analyses included isolation of femur for histology and femoral bone marrow cells, and blood sample collection from the heart for analyses by flow cytometry.

Results. The T2D induction protocol successfully established a metabolic phenotype, with significant differences in blood glucose levels and body weight between the groups. Histological images confirmed that diabetes induced significant changes in cellularity within the distal metaphysis region of the femur. Flow cytometry analyses displayed a higher percentage of Lin-Sca-1(+)c-Kit(+) cells and Ki67 proliferation marker in the diabetic group. Finally, the diabetic mice model exhibited significantly expanded blood leukocyte populations, including monocytes and neutrophils, compared to healthy ones.

Conclusions. These findings suggest that the T2D treatment protocol effectively modulates the immune cell landscape and, potentially mirroring the inflammatory changes observed in human diabetic conditions. The upcoming research plans aim to elucidate the role of the pro-inflammatory Interleukin-6 (IL-6) crosstalk on systemic metabolic inflammation using noninvasive PET-CT imaging techniques.