Abstract
Diabetes leads to a more rapid development of diabetic cardiomyopathy (dbCM) and progression to heart failure in women than in men. Combination of high-fat diet (HFD) and freshly injected streptozotocin (STZ) has been widely used for diabetes induction; however, emerging data show that anomer-equilibrated STZ produces an early-onset and robust diabetes model. We designed a novel protocol using a combination of multiple doses of anomer-equilibrated STZ injections and HFD to develop a stable murine diabetes model featuring dbCM analogous to that in humans. Furthermore, we examined the effect of biological sex on the evolution of cardiometabolic dysfunction in diabetes. Our study included six experimental protocols (8 weeks) in male and female C57BL/6J mice (N = 109): fresh STZ + HFD, anomer-equilibrated STZ + HFD, HFD, fresh STZ, anomer-equilibrated STZ, and control diet + vehicle. Animals were characterized by extensive phenotyping in vivo and ex vivo. Anomer-equilibrated STZ + HFD led to induction of stable experimental murine diabetes characterized by impaired glucose homeostasis, cardiometabolic dysfunction, and altered metabolome of liver, skeletal muscle, kidney, and plasma. dbCM was more severe in female mice, including systolic dysfunction and reduced cardiac energy reserve. This study establishes a novel robust model of inducible murine diabetes and emphasizes the impact of biological sex on diabetes progression and severity.