Glucagon like peptide GLP is a glucose
Glucagon-like peptide-1 (GLP-1) is a glucose metabolic regulator, and GLP-1 and its analogues (exendin-4 and lixisenatide) may exert beneficial effects in diabetes and diabetes complications, especially dementia, because of its blood-brain barrier crossing abilities [, , ]. Several studies [4,, , , , , , , , , , , , ] demonstrated the potential neuroprotective activities of GLP-1 and its analogues. GLP-1 analogues were neuroprotective in well-characterized animal models of Alzheimer's disease [, , ], Parkinson's disease  and Huntington's disease . GLP-1 receptor agonists exhibited promising anti-stroke effects [21,23,24]. For example, preclinical evidence indicated that GLP-1 receptor activation reduced Tigecycline damage following stroke in transient middle cerebral artery occlusion models in Sprague-Dawley rats  and type 2 diabetic Goto–Kakizaki rats . GLP-1 receptor signaling is especially involved in the crosstalk between diabetes and the brain [25,26]. Our previous studies indicated that GLP-1 and its analogues alleviated brain neuronal injury in different dementia animal and cell models [4,, , , ], especially some diabetes-related factors, such as streptozotocin-  and AGEs-induced models [, , ]. Activation of the GLP-1 receptor (GLP-1R) in neurons inhibited the receptor for AGEs and reactive oxygen species pathways , which play crucial roles in metabolic memory. However, more direct evidence is needed to elucidate the relationship between metabolic memory and cognitive impairment as a diabetes-related disease. Further studies are also needed to examine the related underlying mechanisms of GLP-1R agonist (GLP-1RA). The present study established cell and mouse models to investigate metabolic memory-induced neuronal cell damage and the effects of GLP-1RA on this type of injury.
Materials and methods
Discussion The risks of diabetes and dementia increase with ageing. Epidemiological and pathological data suggest that the risk of developing dementia is higher in patients with diabetes and diabetes mellitus contributes to cognitive impairment [1,2]. Diabetes complications, including cognitive impairment, persist and progress despite the achievement of glycaemic control using antidiabetic drugs because of metabolic memory . Our previous studies indicated that GLP-1 and analogues played important roles in the treatment of dementia, especially diabetes-related dementia [4,, , , ]. We reported that GLP-1 and its analogue prevented neuron toxicity in the intracerebroventricular-streptozotocin rat model , AGEs-induced mouse model [, , ] and APP/PS1 mouse model . However, the specific effects of GLP-1RA on neuronal injury related to metabolic memory and the underlying mechanisms are not known, and further investigation is urgently needed. Therefore, the present study primarily focused on metabolic memory-induced neuronal damage and the effects of GLP-1 and its analogues. In vivo and in vitro models were established to mimic metabolic memory phenomenon and investigate the effects and mechanisms of GLP-1RA on metabolic memory-induced neurodegeneration. In vivo studies used db/db mice to investigate metabolic memory-induced neuronal cell damage, and the FDA-approved anti-diabetic drug metformin was used to normalize blood glucose levels in the present study. Several diabetes treatment drugs other than, in addition to GLP-1 and analogues were extensively examined in anti-dementia drug development because of the links between diabetes and dementia. Most of the data for insulin [, , ] and peroxisome proliferator-activated receptor-γ agonists rosiglitazone [, , ] and pioglitazone [, , ] in preclinical and clinical studies concerning dementia revealed beneficial effects on cognition. The effects of metformin on cognitive impairment were also investigated [, , , ]. However, the function of metformin on cognitive impairment remains controversial, and many of these studies did not demonstrate direct beneficial effects on dementia. An increased risk of dementia was attributed to the different adverse effects of metformin in these studies [, , ]. A previous study also indicated that different metformin doses may account for the different results . Metformin is recommended as the first-line glycaemic treatment [38,43], and a recent study investigated the protective effects of several anti-diabetes drugs on dementia risk in individuals with diabetes who were stable metformin users . We also used metformin to normalize blood glucose levels and evaluate the ameliorative effect of GLP-1RA on learning and memory decline in db/db mice with normalized blood glucose levels. Exendin-4 and lixisenatide produced significantly beneficial effects on learning and memory in the exendin-4/lixisenatide groups compared to the model group.