A mouse model of uterine exposure to long-term hyperglycemia and a high-fat diet^*

A growing body of literature has shown that type 1 diabetes (T1D) and high-fat diet (HFD) affect female reproductive function and may be involved in a chronic inflammatory state. Our previous studies indicated that T1D as well as HFD may evoke perturbations in the receptor for advanced glycation end products (RAGE) signaling pathway. The aim of the study was to determine the amount of RAGE protein and its proinflammatory ligands in uterine tissues harvested from T1D and HFD/pre-diabetic mice (n = 5 per group). We sought the impact of T1D and HFD on the activity of the RAGE signaling pathway in uterine tissues during the estrous cycle. The abundance of RAGE and its ligands were estimated using immunohistochemical staining. However, we also performed nerve conduction velocity studies to confirm diabetic neuropathy. The highest amount of RAGE and its ligands were observed in uterine tissues of T1D mice. Moreover, myometrial activity of the RAGE signaling pathway was increased in HFD in comparison to the control group (P≤0.05). We observed a strong relationship between RAGE, Nε-(carboxymethyl)lysine (CML) and tumor necrosis factor alpha (TNFα) proteins in mice myometrium. These data suggest that T1D and HFD could modulate the activity of RAGE and thus RAGE signaling pathway in uterine tissues during estrous cycle. Long-term diabetes and HFD may induce malfunctions in the uterine milieu. In the future RAGE protein may serve as a molecular marker in the diagnosis of malfunctions in pre- and diabetic uterus milieu.