incretins and Cognitive-Dysfunction

Type 2 diabetes mellitus (T2DM) is a global disease that poses a significant threat to public health. The incidence of both diabetes and dementia has increased simultaneously. Researchers have found that a large proportion of dementia patients have T2DM. In recent years, increasing evidence has demonstrated a link between cognitive decline and T2DM. Although the exact pathogenesis of cognitive impairment in T2DM is still unknown, current studies suggest that hyperglycemia, cerebrovascular disease, brain insulin resistance, and changes in γ-aminobutyric acid (GABAergic) neurons may mediate the association between T2DM and cognitive impairment. These potential mechanisms may become targets for the treatment of cognitive disorders in patients with T2DM. Glucagon-like peptide-1 (GLP-1), a widely used anti-diabetic drug, has been shown to not only effectively lower blood glucose but also improve neurological function. Previous research has confirmed that GLP-1 and its analogues are effective in the treatment of cognitive impairment in patients with T2DM. This review describes current evidence on the mechanisms underlying the association between T2DM and cognitive impairment. In particular, this review focuses on recent advances in GLP-1 and its analogues for the treatment of T2DM-related cognitive impairment.

Topics: Cognitive Dysfunction; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins

Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown.. Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (N = 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSST ≥ 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that was ≥ 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed.. Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; P = 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; P < 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; P < 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; P < 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors.. Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial.

Topics: Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Risk Factors; Stroke

Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease.. The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed.. In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Cognition; Cognitive Dysfunction; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Incretins; Kidney; Kidney Diseases; Linagliptin; Male; Middle Aged; Treatment Outcome

Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Autophagy; Cognitive Dysfunction; Disease Models, Animal; Endoplasmic Reticulum Stress; Female; Incretins; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1

There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder.. In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy.. Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality.. Small sample size, open-label design, lack of a placebo group.. Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.

Topics: Adult; Affect; Bipolar Disorder; Cognition; Cognitive Dysfunction; Depressive Disorder, Major; Executive Function; Female; Humans; Incretins; Liraglutide; Male; Middle Aged; Mood Disorders; Nausea; Pilot Projects; Stroop Test; Treatment Outcome; Verbal Learning