Increased fatty acid metabolism attenuates cardiac resistance to ß-adrenoceptor activation via mitochondrial reactive oxygen species: A potential mechanism of hypoglycemia-induced myocardial injury in diabetes.

The mechanism of severe hypoglycemia (SH)-induced cardiovascular disease in diabetes remains unknown. Our previous study found that SH inhibits cardiac function and lipid metabolism in diabetic mice. Conversely, in nondiabetic mice, SH does not induce cardiac dysfunction but promotes cardiac lipid metabolism. This study aims to clarify the effect of increased fatty acid metabolism on the resistance of cardiomyocytes to ß-adrenoceptor activation during hypoglycemia in diabetes. Results revealed that cardiomyocytes with enhanced lipid metabolism were more vulnerable to damage due to ß-adrenoceptor activation, which presented as decreased cell viability, disorder of mitochondrial structure, dissipation of mitochondrial membrane potential, dysfunction of mitochondrial oxidative phosphorylation, nonapoptotic damage, and accumulation of ROS and calcium from mitochondria to cytoplasm, all of which were partially reversed by mitochondrial antioxidant Mito-TEMPO. The SH-induced cardiac dysfunction, and reduction of myocardial energy metabolism in diabetic mice were rescued by Mito-TEMPO. Our findings indicate that high fatty acid metabolism crippled cardiac resistance to ß-adrenoceptor hyperactivation, with mitochondrial ROS playing a pivotal role in this process. Reducing mitochondrial ROS in diabetes could disrupt this synergistic effect and prevent poor cardiac outcomes caused by SH.

Recurrent non-severe hypoglycemia aggravates cognitive decline in diabetes and induces mitochondrial dysfunction in cultured astrocytes.

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.

GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease.

OBJECTIVE: Astrocytes actively participate in energy metabolism in the brain, and astrocytic aerobic glycolysis disorder is associated with the pathology of Alzheimer's disease (AD). GLP-1 has been shown to improve cognition in AD; however, the mechanism remains unclear. The objectives of this study were to assess GLP-1's glycolytic regulation effects in AD and reveal its neuroprotective mechanisms. METHODS: The Morris water maze test was used to evaluate the effects of liraglutide (an analog of GLP-1) on the cognition of 4-month-old 5×FAD mice, and a proteomic analysis and Western blotting were used to assess the proteomic profile changes. We constructed an astrocytic model of AD by treating primary astrocytes with Aß1-42. The levels of NAD+ and lactate were examined, and the oxidative levels were assessed by a Seahorse examination. Astrocyte-neuron co-culture was performed to evaluate the effects of GLP-1 on astrocytes' neuronal support. RESULTS: GLP-1 improved cognition in 4-month-old 5×FAD mice by enhancing aerobic glycolysis and reducing oxidative phosphorylation (OXPHOS) levels and oxidative stress in the brain. GLP-1 also alleviated Aß-induced glycolysis declines in astrocytes, which resulted in reduced OXPHOS levels and reactive oxygen species (ROS) production. The mechanism involved the activation of the PI3K/Akt pathway by GLP-1. Elevation in astrocytic glycolysis improved astrocyte cells' support of neurons and promoted neuronal survival and axon growth. CONCLUSIONS: Taken together, we revealed GLP-1's capacity to regulate astrocytic glycolysis, providing mechanistic insight into one of its neuroprotective roles in AD and support for the feasibility of energy regulation treatments for AD.