Hypothalamic dysfunction can lead to irregularities in glucose metabolism, a major contributor to the development of type 2 diabetes mellitus (T2DM). The interplay between autophagy and apoptosis is critical for cellular and tissue balance, and this process may become impaired in T2DM. Given that propionic acid (PA) has neuroprotective properties, this study aimed to explore its impact on the regulation of the apoptosis/autophagy balance in the ventromedial hypothalamus (VMH) of rats with type 2 diabetes mellitus (T2DM). Male Wistar rats were categorized into the following experimental groups: 1) control, 2) T2DM, and 3) treatment groups that received oral doses for 14 days of: 4) metformin (60 mg/kg), 5) sodium salt of propionic acid (PA, 60 mg/kg), and 6) a combination of PA and metformin. Various methods were employed to analyze the effects, including Western blot analysis for proteins such as Bax, Bcl-xl, LC3, Beclin-1, and caspase-3; RT-PCR to quantify gene expression of Bax, Bcl-xl, LC3, and Beclin-1; transmission electron microscopy for ultrastructural assessment; and immunohistochemistry for Bax and Bcl-xl expression in ventromedial hypothalamus (VMH) samples. In rats with T2DM, apoptosis and mitoptosis were observed in the ventromedial hypothalamus (VMH), alongside an enlargement of endoplasmic reticulum (ER) tubules and cisterns. This was accompanied by an imbalance between pro-apoptotic and anti-apoptotic factors, marked by increased levels of Bax and caspase-3, and a reduction in the autophagy marker LC3 and the anti-apoptotic protein Bcl-xl. Treatment with metformin and propionic acid (PA) partially alleviated these ultrastructural changes in the VMH, as evidenced by reduced mitochondrial swelling and fewer apoptotic neurons. Metformin was effective in preventing neuronal apoptosis but also triggered reactive astrogliosis and an accumulation of lipofuscin granules. The increase in the number of autophagosomes was associated with higher levels of LC3, Beclin-1, and Bcl-xl, as well as a decrease in Bax and caspase-3 compared to T2DM alone. PA shifted the cellular response from apoptosis to autophagy by boosting LC3 and Beclin-1 expression, while also elevating Bcl-xl levels. These changes may represent an adaptive mechanism to counteract T2DM-induced apoptosis. Combined treatment with PA and metformin reduced the relative area of ER membranes and cisterns compared to the control, T2DM, and metformin groups. This combined treatment also appeared optimal in restoring the balance between pro-apoptotic, anti-apoptotic, and autophagy markers. Type 2 diabetes mellitus (T2DM) is linked to the activation of apoptosis, which results in functional impairments in the ventromedial hypothalamus (VMH). Physical activity, when combined with metformin, may effectively protect against diabetes-induced neuronal death by shifting the cellular process from apoptosis to autophagy in the VMH.
