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Aims: This study examined the association between hypoglycemia and mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM) and identified risk factors for MCI in patients with hypoglycemia., Methods: In this retrospective study, 328 patients with T2DM were screened in 2019 and followed up in 2022. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). The diagnosis of MCI was based on established criteria. Risk ratio (RR) with 95 % confidence intervals (CI) was calculated to estimate the risk of MCI. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for MCI in those with hypoglycemia., Results: Patients with hypoglycemia had lower cognitive performance 3 years later. The RR of MCI was 2.221 (95 % CI 1.269-3.885). Multivariate logistic analysis showed that low grip strength, existing diabetic retinopathy (DR), and multiple hypoglycemia episodes were associated with higher odds of MCI in patients with hypoglycemia (adjusted odds ratio [OR] 0.909 [95 % CI 0.859-0.963]), 3.078 [95 % CI 1.158-12.358], and 4.642 [95 % CI 1.284-16.776], respectively, all P < 0.05)., Conclusions: Hypoglycemia increased MCI risk among patients with T2DM. Low grip strength, DR, and multiple hypoglycemia episodes may be potential risk factors for hypoglycemia-associated MCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Hypoglycemia is associated with cognitive dysfunction, but the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia could lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier (BBB) leakage. A streptozotocin T1D model (150 mg/kg, one-time intraperitoneal injection), using male C57BL/6J mice, was used to induce hypoglycemia. Brain tissue was extracted to examine for neuronal damage, permeability of BBB was investigated through Evans blue staining and electron microscopy, reactive oxygen species and adenosine triphosphate in brain tissue were assayed, and the functional changes of pericytes were determined. Cognitive function was tested using Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results showed that BBB leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present study aimed to determine the relationship between astrocytes and recurrent non-severe hypoglycemia (RH) 2 -associated cognitive decline in diabetes. RH induced cognitive impairment and neuronal cell death in the cerebral cortex of diabetic mice, accompanied by excessive activation of astrocytes. Levels of the neurotrophins BDNF and GDNF, together with BDNF and GDNF- related signaling, were downregulated by RH. In vitro, recurrent low glucose (RLG) 3 impaired cell viability and induced apoptosis of high-glucose cultured astrocytes. Accumulating mitochondrial ROS and dysregulated mitochondrial functions, including abnormal morphology, decreased membrane potential, downregulated ATP levels, and disrupted bioenergetic status, were observed in these cells. SS-31 mediated protection of mitochondrial functions reversed RLG-induced cell viability defects and neurotrophin production. These findings demonstrate that RH induced astrocyte overactivation and mitochondrial dysfunction, leading to astrocyte-derived neurotrophin disturbance, which might contribute to diabetic cognitive decline. Targeting astrocyte mitochondria might represent a neuroprotective therapy for hypoglycemia-associated neurodegeneration in diabetes., (Copyright © 2021. Published by Elsevier B.V.)