Activation of Glucagon‐Like Peptide‐1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism‐Independent Pathway

Abstract

Background Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon‐like peptide‐1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon‐like peptide‐1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. Methods and Results Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near‐infrared spectroscopy. At 12 weeks, patients in the glucagon‐like peptide‐1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention ( P =0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions ( P =0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions ( P <0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. Conclusions We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. Registration URL: https://www.ClinicalTrials.gov ; Unique identifier: NCT03707171.

Relationship between glycemic control and cognitive impairment: A systematic review and meta-analysis

“…Ten studies that did not meet the inclusion criteria, three studies with incomplete data, and seven studies that did not meet the outcome criteria were excluded. Finally, 13 relevant studies were included ( Hanyu et al, 2009 ; Plastino et al, 2010 ; Sato et al, 2011 ; Cukierman-Yaffe et al, 2014 , 2020 ; Guo et al, 2014 ; Isik et al, 2017 ; Köbe et al, 2017 ; Furie et al, 2018 ; Lin et al, 2018 ; Biessels et al, 2021 ; Cummings et al, 2021 ; Li et al, 2021 ). The specific literature screening process is shown in Figure 1 .…”

Impact of glucagon-like peptide 1 analogs on cognitive function among patients with type 2 diabetes mellitus: A systematic review and meta−analysis

“…Finally, 34 articles were eligible for full-text review and data assessment. A total of 5 studies comprising three randomized controlled trials ( 18 – 20 ) and two prospective cohort studies ( 21 , 22 ) that met the inclusion criteria were analyzed ( Figure 1 ). Consequently, a “snowball search” was performed based on the citation lists of all the included studies.…”

Recurrent moderate hypoglycemia accelerates the progression of Alzheimer’s disease through impairment of the TRPC6/GLUT3 pathway

“…Similar results were seen with PC12 cells, as GLUT3 expression was significantly inhibited by BAPT-AM and Compound C but increased upon AMPK activation by AICAR. We recently showed that the GLP-1 receptor agonist, liraglutide, can improve the cognitive function of patients with type 2 diabetes mellitus ( 49 ). Thus, the protective effects of hyperforin on cognitive function should be further tested in patients with diabetes.…”