Exercise Conditioning Enhances Insulin Sensitivity with Metabolic and Glycemic Control Driven by Hepatic Silencing of HMGB1 in Type 2 Diabetic Mice

Bravo, G. M.; Paramasivam, P.; Jacquez, Q.; Sandoval, G.; Beason, H.; Ramirez, E. B.; Chi, J.; Gu, H.; Magalhaes, F. D. C.; Alvidrez, R. I. M.

doi:10.1101/2025.04.27.650052

bioRxiv · 10.1101/2025.04.27.650052

Exercise Conditioning Enhances Insulin Sensitivity with Metabolic and Glycemic Control Driven by Hepatic Silencing of HMGB1 in Type 2 Diabetic Mice

Bravo, G. M.·Paramasivam, P.·Jacquez, Q.·Sandoval, G.·Beason, H.·Ramirez, E. B.·Chi, J.·Gu, H.·Magalhaes, F. D. C.·Alvidrez, R. I. M.

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Abstract

Type 2 Diabetes (T2D) is characterized by chronic insulin resistance and inflammation. Exercise induces hyperglycemia control in T2D more than pharmacologic therapies alone. High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear factor for T2D progression. We hypothesize that hepatic silencing of HMGB1 in T2D and exercise will increase insulin sensitivity and shift metabolic routes, decrease liver damage and improve metabolic health in T2D mice. MethodsLiver HMGB1 KO (HMGB1{Delta}) was induced with AAV8-TBG in HMGB1 flox mice (AAV8-EGFP was used as wildtype controls). T2D mice were induced with a low-dose STZ and a high-fat diet. T2D mice ran for four weeks (1hr daily). Dual Energy X-Ray Absorptiometry (DEXA), A1C, glycemia, HMGB1, metabolomics and metabolic cage analysis were performed pre- and post-exercise. RT-PCR, immunoblotting and immunohistochemistry for glucose metabolism markers were performed in tissue samples. ResultsT2D HMGB1{Delta} mice show 20% less hyperglycemia compared to controls with a strong correlation between reduced HMGB1 levels and lower A1C following exercise. Additionally, fat percentage, liver damage, and glycogen storage were significantly reduced. These findings highlight the high potential effect of exercise potentiated has via HMGB1 governed mechanisms and highlights HMGB1 as a therapeutic target for managing hyperglycemia in T2D. ARTICLE HIGHLIGHTSHMGB1 hepatic silencing in Type 2 Diabetic mice is a promising therapeutic target for enhancing Insulin sensitivity. Combination of hepatic HMGB1 silencing and exercise potentiates the metabolic benefits and liver protection in Type 2 Diabetic mice. Shift in metabolic routes and carbohydrate metabolism due to regulation of hepatic HMGB1 expression makes HMGB1 an ideal target for pharmacologic intervention. However, our study also underscores the value of exercise as the primary focus of diabetic glucose control aided by enhanced therapeutic targeting of HMGB1 for chronic inflammation and hyperglycemia.

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Bravo, G. M., Paramasivam, P., Jacquez, Q., Sandoval, G., Beason, H., Ramirez, E. B., Chi, J., Gu, H., Magalhaes, F. D. C., Alvidrez, R. I. M.. 2025-04-27. Exercise Conditioning Enhances Insulin Sensitivity with Metabolic and Glycemic Control Driven by Hepatic Silencing of HMGB1 in Type 2 Diabetic Mice. https://doi.org/10.1101/2025.04.27.650052

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