Diabetic encephalopathy (DE) is a common central nervous system complication resulting from diabetes mellitus (DM). While the exact pathogenesis remains unclear, a homeostatic imbalance of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) within neurons has been shown to be closely associated with the dysfunctional cognitive pathology of this condition. Our previous work has revealed that phosphatidate phosphatase Lipin1 plays a critical role in the cognitive processes of DE via regulating mitochondrial function. In this study, we reported that the integrity of neuronal MAMs was disrupted in DE mice, which was accompanied by a decrease in the expression of hippocampal Lipin1. With a knock-down of hippocampal Lipin1 in normal mice, ER stress was induced, MAMs structures were impaired and Ca