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.

Keywords: cognitive function; functional near‐infrared spectroscopy; liraglutide; metabolic changes; type 2 diabetes mellitus.

Conflict of interest statement

None.

Figures

Figure 1. The grand averaged oxyhemoglobin concentration in relevant channels during verbal fluency task between baseline and 12 weeks after glucagon‐like peptide‐1 treatment.

The thick curves showed the averaged oxyhemoglobin concentration over patients in significant channels (channels 2, 8, 13, and 17). The shaded area indicated the SEM. The extracted mean oxyhemoglobin concentration during verbal fluency task in relevant channels after glucagon‐like peptide‐1 treatment were expressed as median with interquartile range and were compared using the Wilcoxon matched‐pairs signed‐rank test. T‐map of mean oxyhemoglobin concentration changes for 12‐week vs 0‐week contrast in glucagon‐like peptide‐1 group with the distribution of the significant channels was presented in the middle row panel (P<0.05). The mean oxyhemoglobin concentration differences (between 0 and 12 weeks) as a function of significant channels and time of all patients in glucagon‐like peptide‐1 group was presented in the middle row right panel. Ch2, Ch8, Ch13, and Ch17 indicate Channels 2, 8, 13 and 17; DLFPC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; and OxyHb, Oxyhemoglobin.

Figure 2. The grand averaged oxyhemoglobin concentration in relevant channels during verbal fluency task at 12weeks between control and GLP‐1 groups, and the correlation of significant channels with metabolic factors and cognitive tests.

The thick curves showed the averaged oxyhemoglobin concentration over patients in significant channels (channels 13 and 15) in both groups. The shaded area indicated the SEM. T‐map of mean oxyhemoglobin concentration difference at 12 weeks of GLP‐1 group vs control group contrast with the distribution of the significant channels was presented in the upper row right panel (P<0.05). The comparisons of grand mean oxyhemoglobin concentration in significant channels at 12‐weeks between control and GLP‐1 groups. Data were expressed as median with interquartile range. The correlations of metabolic parameters and cognitive assessments with the mean oxyhemoglobin concentration in significant channels were presented by heat map in the lower row panel. ANT indicates Animal Naming Test; BMI, body mass index; BP, blood pressure; Ch13, and Ch15, Channels 13 and 15; CDT, Clock Drawing Test; DST, Digit Span Test; GLP‐1, glucagon‐like peptide‐1; HbA1c, glycated hemoglobin; HDL‐c, high‐density lipid cholesterol; LDFR, long‐delay free recall; LDL‐c, low‐density lipid cholesterol; MES, Memory and Executive Screening; MMSE, Mini‐Mental State Examination; OxyHb, Oxyhemoglobin; TC, total cholesterol; TG, triglycerides; and TMT, Trail Making Test.