Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: Role of suppression of autophagy and modulation by anti-diabetic drugs.

Prediabetes is a highly prevalent stage of early metabolic dysfunction that poses a high risk for cardiovascular and cognitive impairment without a clear pathological mechanism. Here, we used a non-obese prediabetic rat model previously developed in our laboratory to examine this mechanism. These rats were subjected to a mild metabolic challenge leading to hyperinsulinemia without hyperglycemia or obesity. This was associated with impaired hippocampal-dependent cognitive functions together with an augmented cerebrovascular myogenic tone. Consequently, hippocampal expression of hypoxia-inducible factor-1α increased, together with markers of mitochondrial dysfunction and oxidative stress. In parallel, the phosphorylation of Akt and mTOR increased in the prediabetic rat hippocampus alongside increased expression of p62 and LC3 puncta indicating a possible repression of autophagic flux. Neuroinflammation and neuronal apoptosis were detected in the hippocampal CA1 area as increased CD68 and IBA-1 staining, as well as increased TUNEL staining and caspase-3 activity, respectively. Treatment with metformin or pioglitazone, at a previously determined vasculoprotective non-hypoglycemic dose, reversed the cerebrovascular and hippocampal molecular alterations and ameliorated cognitive function. The present study proposes a mechanistic framework whereby prediabetic cerebrovascular impairment potentially leads to a mild hypoxic state that is exacerbated by the metabolic dysfunction-driven suppression of neuronal autophagy leading to cognitive impairment.