Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration

Figures & data

Figure 1 Impaired insulin signaling/ secretion involved in the progression of dementia This schematic diagram depicts both normal and abnormal insulin signaling in the brain. Insulin activates signaling pathways such as AKT, PI3K, JNK, NF-KB, GLUT4 and GSK3. Synaptic plasticity and memory are both linked to the PI3K pathway. The PI3K pathway is linked to synaptic plasticity and memory. As a result, aberrant insulin binding can cause neuroinflammation by activating proinflammatory cytokines and lowering cognitive capacities via JNK and NF-KB. Long-term memory loss is caused by oxidative stress, mitochondrial dysfunction, and inflammation caused by GSK3 and its hyperphosphorylation. It also elevates the expression of caspase-3 and 9, which ultimately leads to neuronal cell death.

Figure 2 Insulin resistance in dementia is represented schematically by mitochondrial dysfunction, which leads to synaptic damage and neurodegeneration, glycosylated haemoglobin in intoxicated cognitive function due to failure in glucose transport for neurons, oxidative stress-induced amyloid beta and phosphorylated tau lineups via advanced glycation end products, inflammation caused by mitochondrial dysfunction and toxicities of amyloid-beta and glycation end products. Additionally, in both normal and impaired insulin signaling, Tau hyperphosphorylation was also observed, stimulates AKT, and inhibits tau hyperphosphorylation by inactivating GSK-3. Furthermore, the TOR pathway was also active for cellular growth and kept autophagy at a low level for cellular function. Black normal flow lines represent normal working mechanism; dotted red lines show inhibition of the pathway, and normal dark red flow lines show the overall cause of dementia.

Table 1 Impaired Insulin Signaling Dysfunction in the Progression of Dementia and Related Neurological Complications

S.No	Disease Model/Condition	Study Type	Brain Area Affected	Factors Involved	Duration of Study	Key Findings	References
1.	Central and peripheral insulin resistance	Preclinical study Tg2576, 3xTg-AD mice, WT mice Age: 10- and 16-months-old	Brain homogenates, Cerebral cortex, Hippocampal tissue	↓IRS-1 expression, ↑Inhibitory Ser612 phosphorylation, ↓Phosphorylation of AKT at Thr308, ↑AKT phosphorylation at Ser473	16 months	↑Cognitive deficits, ↑Extracellular plaques deposition	[^Citation191]
2.	Hypoglycaemia	Clinical study Population-based cohort study Propensity-Score Matched Analysis Senior South Korean cohort 7752 T2DM patients who had ever experienced hypoglycaemia, matched cohort	Cerebral cortex	↑Risk for all-cause dementia (HR 1.254), ↑Risk for AD dementia (HR 1.264), ↑ Risk for VD (HR 1.286)	14 years	Patients with a history of hypoglycaemia have an↑risk for dementia, AD dementia and VD	[^Citation192]
3.	Insulin dysregulation and diabetes	Clinical study 233 subjects Ethnicity: older Catholic clergy Mean age: 86 years, 45% male participants	Cerebral region, Cortical region, Subcortical region	↑ Cortical infarction, ↑ Subcortical infarction, ↑Risk of dementia	6 years	Diabetes morbidity ↑ the probability to develop cerebral infarctions, compared to those without diabetes	[^Citation193]
4.	T2DM	Clinical study Population-based cohort 2574 Japanese-American men, Number of diabetic subjects=900,	Cortex, Hippocampus	↑Risk for total dementia (IRR=1.6), ↑VD risk (IRR=2.0)	2.9 years	T2DM↑risk factor for AD and VD	[^Citation194]
5.	Diabetes mellitus	Clinical study Longitudinal cohort study 824 Catholic participants Age:≥55 years	Pre-frontal cortex, Frontal lobe	↓Cognitive ability, ↑Rate of decline in perceptual speed	9 years	Diabetes mellitus may be associated with an ↑ risk of developing AD and may affect cognitive systems differentially	[^Citation195]
6.	Diabetes mellitus	Clinical study Prospective population-based cohort study 6370 elderly subjects, with diabetes mellitus	Pre-frontal area	↑Risk of dementia (HR 1.3 to 2.8), ↑Risk of AD (HR 1.2 to 3.1)	2.1 years	Diabetes may ↑ the pathogenesis of dementia	[^Citation196]
7.	Hyperinsulinemia	Clinical study Longitudinal, cohort analyses 683 elderly subjects, without prevalent dementia Age: ≥65 years	Cerebral cortex, Hippocampus, Amygdala	↑Risk of AD (HR = 2.1; 95% CI: 1.5, 2.9), ↑Decline in memory-related cognitive scores in neuropsychiatric tests	5.4 years	Hyperinsulinemia is associated with an↑ risk of AD and ↓ in memory	[^Citation197]
8.	Diabetes	Clinical study Longitudinal cohort study in older Canadians, 5574 subjects without cognitive impairment at baseline	Cerebrum	↑Incident VCI (RR: 1.62; 95% CI: 1.12–2.33) and its subtypes, ↑ Risk of VD (RR: 2.03; 95% CI: 1.15–3.57), ↑ Risk of VCI (RR: 1.68; 95% CI: 1.01–2.78)	5 years	Diabetes was associated with ↑incidence of VCI	[^Citation198]
9.	Abnormal insulin level	Clinical study 25 patients with AD (6 apolipoprotein E homozygotes, 19 non-homozygotes), 14 healthy age-matched adults	Blood plasma, Cerebrospinal fluid	↓CSF insulin concentrations, ↑ Plasma insulin levels, ↓Ratio of CSF insulin levels to true plasma insulin levels	2 years	↓CSF insulin concentration led to more advanced dementia ↑ Plasma insulin levels signified more advanced dementia	[^Citation199]
10.	Diabetes mellitus	Clinical study Longitudinal, cohort study Dementia-free cohort, 1301 Stockholm, Sweden community dwellers Age: ≥75 years	Cerebellum, Hippocampus	↑Risk of dementia (HR=1.5), ↑Risk of AD (HR=1.3), ↑Risk of VD (HR=2.6)	6 years	Diabetes mellitus ↑risk of dementia, and VD The risk for dementia and VD↑ when diabetes mellitus occurs together with severe systolic hypertension/heart diseases	[^Citation200]
11.	Diabetes	Clinical study Epidemiological study 1892 Jewish male civil servant cohort, Mean age: 82 years	Cerebral cortex, Hippocampus, Amygdala	↑Risk of dementia (HR=2.83, 95% CI= 1.40 to 5.71)	5 years	Diabetes in midlife ↑risk factor for dementia	[^Citation201]
12.	Severe hypoglycaemia	Clinical study Prospective study 302 diabetic patients, with a history of severe hypoglycaemia, Age: ≥70 years	Cerebellum, Hippocampus	↑Risk of dementia (HR= 3.00, 95% CI 1.06–8.48)	5 years	Hypoglycaemia ↑ risk factor for dementia and vice-versa	[^Citation202]
13.	Diabetes with impaired insulin secretion and impaired glucose tolerance	Clinical study Population-based Uppsala Longitudinal cohort study, 2322 adult male participants, Mean age: 50 years old	Hippocampus	↑Cumulative risk of AD (HR= 1.31; 95% CI, 1.10–1.56), ↑ Risk of VD (HR= 1.45; 95% CI, 1.05–2.00), ↑ Risk of any-dementia or cognitive impairment	32 years	Impaired acute insulin response at midlife was associated with an ↑ risk of AD dementia	[^Citation203]
14.	Hypoglycaemic episodes	Clinical study Longitudinal cohort study 16,667 patients, Mean age: 65 years Morbidity: T2DM, without prior diagnoses of dementia or MCI	Cerebral cortex	↑ Risk of dementia (HR: 1.72–3.01%)	4.8 years	A history of severe hypoglycaemic episodes was associated with an ↑risk of dementia	[^Citation204]
15.	Diabetes mellitus with hypoglycaemic episodes	Clinical study 15,404 diabetic subjects, without prior dementia Mean age: 64.2 years	CNS	↑ Incidence rate of dementia	7 years	Adult diabetic patients with prior hypoglycaemia had a significantly ↑risk of dementia.	[^Citation205]
16.	Hypoglycaemia	Clinical study Prospective population-based study 783 old adults with diabetes, Mean age: 74.0 years; Ethnicity: Black race, 47.6% females	Hippocampus	↓Cognitive performance, ↑Risk for developing dementia in hypoglycaemic event (34.4%multivariate-adjusted HR= 2.1; 95% CI)	12 years	A bidirectional association occurs between hypoglycaemia and dementia in older adults with diabetes mellitus	[^Citation206]
17.	Hypoglycaemia	Clinical study Prospective observational Koreanstudy National Diabetes Program cohort, 4540 participants, Age: ≥60 years, without any history of hypoglycaemia or cognitive dysfunction	Hippocampus	↑Incidence of dementia (HR= 2.689; 95% CI, 1.080–6.694)	3.4 years	Hypoglycaemia significantly ↑the risk of dementia in Korean elderly patients	[^Citation207]
18.	Diabetes with hypoglycaemia	Clinical study Retrospective longitudinal cohort study, Age >65 years, diagnosed with T2DM, with no prior diagnosis of dementia	Cerebral cortex	↑Risk with the number of hypoglycemia episodes: one episode (HR = 1.26; 95% CI = 1.03–1.54)	3 years	Hypoglycaemia is associated with ↑ risk of dementia and may be responsible for the ↑ risk of dementia in patients with diabetes	[^Citation208]
19.	Diabetes	Clinical study Quantitative meta-analysis of longitudinal studies 6184 subjects with diabetes and 38,530 subjects without diabetes, subjects were without dementia or MCI at baseline	Hippocampus	↑Risk for AD (RR:1.46, 95% CI: 1.20–1.77), ↑Risk of VD (RR: 2.48, 95% CI: 2.08–2.96), ↑Risk of any dementia (RR: 1.51, 95% CI: 1.31–1.74) and ↑Risk of MCI (RR: 1.21, 95% CI: 1.02–1.45)	>3 years	Diabetes ↑risk factor for incident dementia (including AD, VD and any dementia) and MCI	[^Citation209]
20.	Severe hypoglycaemia in T2DM	Clinical study Prospective study 1066 men and women with T2DM Age: 60–75 years	Cerebral cortex, Hippocampus	↓Cognitive ability at baseline, ↑Cognitive decline during follow-up	4 years	Severe hypoglycaemia is associated with ↓initial cognitive ability and ↑cognitive decline	[^Citation210]
21.	T2DM and T1DM	Clinical study Retrospective national record linkage cohort study 3,43,062 people with T1DM; 18,55,141 people with T2DM; and a reference cohort Age: ≥30 years Ethnicity: English cohort	Pre-frontal cortex, Hippocampus	↑Risk for developing dementia in T1DM people (RR= 1.65; 95% CI 1.61, 1.68), ↑Risk for developing dementia in T2DM people (RR= 1.37), ↑Risk for VD by Two-folds	13 years	T1DM and T2DM significantly↑risk of dementia	[^Citation211]
22.	Lifetime history of severe hypoglycaemia (Self-reported)	Clinical study Cross-sectional, population-based study 1066 men and women Age: 60–75 years, with T2DM	Hippocampus	↓Late-life cognitive ability, ↑Age-related cognitive decline and dementia	5 years	Severe hypoglycaemia is associated with ↓late-life cognitive ability	[^Citation212]
23.	Diabetes-related factors (Insulin resistance, Hyperinsulinemia, Hyperglycaemia)	Clinical study Long-term prospective cohort study 135 autopsies of residents of Hisayama town (74 men and 61 women)	Middle frontal gyrus, Superior and middle temporal gyri, Inferior parietal lobule, Anterior cingulated gyrus, Amygdala, Hippocampus with entorhinal and trans entorhinal cortex Calcarine cortex, Basal ganglia	↑Risk for neuritic plaques, ↑Risk of AD pathology	5 years	Hyperinsulinemia and hyperglycaemia caused by insulin resistance ↑ neuritic plaque formation	[^Citation213]
24.	Diabetes mellitus	Clinical study Prospective observational Meta-analysis study 1,148,041study participants, 89,708 diabetic subjects, 1,058,333 non-diabetics subjects	Pre-frontal cortex, Amygdala, Hippocampus	3% ↑Risk of all type dementia, 56% ↑Risk of AD dementia, 127% ↑Risk of VD	13 years	↑Risk of all type dementia, AD and VD	[^Citation214,Citation216]
25.	Diabetes	Clinical study Systematic observational study Cohort of individuals reported on; cognitive function at baseline and at follow-up; and glucose status	Cerebral cortex	↑Rate of decline in cognitive function (1.2–1.7-fold, 95% CI), ↑Odds of future dementia (1.6 folds,95% CI 1.4–1.8)	20 years	People with diabetes have a ↑rate of cognitive dysfunction as compared to non-diabetics	[^Citation215,Citation217]

Notes: Symbols: (↑) Increases, (↓) Decreases, (%) Percent, (≥) Greater than or equal to.

Abbreviations: AD, Alzheimer’s disease; VD, Vascular dementia; CI, Confidence interval; HR, Hazard ratio; RR, Relative risk; IRS, Insulin receptor substrate; CNS, Central nervous system; IRR, Incident rate ratio; WT, Wild type; AKT, Protein kinase B; T2DM, Type 2 diabetes mellitus; T1DM, Type 1 diabetes mellitus; MCI, Mild cognitive impairment; CSF, Cerebrospinal fluid; VCI, Vascular cognitive impairment.

Table 2 Neuroprotective Role of GLP-1 Signaling Analogs in the Protection of Various Dementia Related Neurodegenerative Abnormalities

S. No	GLP-1 Signaling Activators	Brain Areas Affected	Neuro-Complications Prevented	Study Type	Dose and Route	Duration of Study	References
1.	Exendin-4 (GLP-1 agonist)	Cerebrum, Brain pericytes	↓Cerebral pathological neovascularization indices, ↑Learning and memory functions, ↓Diabetes-induced inflammation, ↓Oxidative stress, ↓Vascular-induced cognitive impairment and dementia	Pre-clinical study Control and diabetic mice, Human brain microvascular pericytes	Exendin-4: 30ng/kg per day	28 days	[^Citation226]
2.	Metformin (Direct, AMPK-dependent, GLP-1 activator)	CNS	↓Dementia risk in unmatched cohort (HR= 0.550; 95% CI), ↓Dementia risk in matched cohort (HR= 0.707; 95% CI)	Clinical study Retrospective, unmatched and matched-pair cohort study Mean age: 63 years, Morbidity: T2DM, no dementia at baseline	Prescribed doses	> 58.1 months	[^Citation225]
3.	Glitazone, Metformin (↑ GLP-1 in the plasma)	CNS	Glitazones ↓dementia risk (OR: 0.80), Metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with ↓dementia risk	Clinical study Retrospective, case-control study 8276 diabetes patients with dementia and 8276 diabetes patients without dementia, Mean age: 79.7 years, 56.2% women candidates	Prescribed doses	5 years	[^Citation223]
4.	Dipeptidyl-Peptidase 4 Inhibitors (↑ level of incretins like GLP-1)	CNS	↓Risk of dementia compared to sulphonyl urea use (HR= 0.66), ↓Risk of AD dementia (HR=0.64), ↓Risk of VD non-significantly (HR= 0.66)	Clinical study Population-based, retrospective observational cohort study, 7552 users of sulfonylureas and 7552 users of DPP-4 inhibitors, Age >60 years, with T2DM, dementia-free at baseline	Prescribed doses	1362 days	[^Citation216]
5.	Pioglitazone and Metformin	CNS	↓ Risk of dementia compared with those on metformin +sulfonylurea (HR 0.56; 95% CI 0.34, 0.93)	Clinical study Retrospective cohort study, 2,04,323 individuals with T2DM, receiving metformin-based dual therapy, Age: ≥18 years and ≥65 years, Dementia-free at baseline	At prescribed doses	3 months	[^Citation227]
6.	Pioglitazone (GLP-1activator)	CNS	↓ Dementia risk, Greater ↓ in dementia risk on prolonged use	Clinical study Retrospective cohort study 11,011 pioglitazone users, 11,011 never-users of pioglitazone Mean age: 59 years, No dementia at baseline	Prescribed doses	>20 months	[^Citation225]
7.	Exenatide (Long-acting, GLP-1 receptor agonist)	Caudate, Putamen	↑Neuronal survival pathways, ↑Mitochondrial function, ↓Neuro-inflammation	Clinical study Randomized, double-blind, placebo-controlled trial Age: 25–75 years	Exenatide- 2 mg, once weekly, subcutaneous injections	48 weeks exposure period, 2 weeks washout period	[^Citation228]
8.	Sitagliptin (DPP-4 inhibitor, ↓GLP-1 degradation and ↓glucagon secretion)	CNS	↑Glycemiccontrol, ↓Insulin requirement, ↑Cognitive function in elderly diabetic patients,	Clinical study Prospective, observational study 253 elderly patients with T2DM, with and without AD	Regular prescribed doses	6 months	[^Citation222]
9.	Pioglitazone (PPAR-γ agonist, activates GLP-1 receptor)	Substantia nigra, Striatum	↓Dementia incidence	Clinical study Prospective cohort study 1,45,928 subjects Age: ≥60 years	Prescribed doses, oral route	2 years	[^Citation229]
10.	Liraglutide (a novel GLP-1 analog)	Frontal cortex	↓ Insulin receptor aberrations, ↓Amyloid-β plaque load, ↓ IRS-1 pS^616 levels, ↓Glial activation, ↓Astrocytosis	Pre-clinical study APPSWE/PS1dE9 mouse model of AD Age: 7 months	25 nmol/kg body weight, i.p., once daily	8 weeks	[^Citation230]
11.	Liraglutide (GLP-1 analog)	Hippocampus	↓Memory impairment, ↓Neuronal loss, ↑Synaptic plasticity, ↓Amyloid plaque deposition by 40–50%, ↓Inflammatory response, ↓Activated microglial cell numbers	Pre-clinical study AD transgenic mice APP/PS1 and WT littermate controls Age: 7-months-old	Systemic administration 25 nmol/kg body weight, i.p., once daily	8 weeks	[^Citation231]
12.	Liraglutide, Exenatide (GLP-1 receptor agonists)	Cerebral cortex, Hippocampus	↑ Axonal transport ↓Hippocampal IRS-1pSer, ↑Behavioral measures of cognition	Pre-clinical study Model: APP/PS1 Tg mice and WT controls Age: 13 to 14 months old	25 nmol/kg body weight, i.p. route	3 weeks	[^Citation232]
13.	GLP-1, Exendin-4 (a stable analog of GLP-1)	Hippocampus	↓Endogenous levels of amyloid peptide, ↓Dementia like-effect of amyloid β oligomers, ↓Neuronal death induced by amyloid β	Pre-clinical study In vitro: PC12 cell culture, In vivo: db+/db+mice	PC12 cells: GLP-1 (3.3, 33, and 330 ng/mL), exendin-4 (0.1, 1.0, and 10 µg/mL) Mice: GLP-1 (3.3 ng, 6.6 ng), exendin-4 (0.2 ng), via bilateral infusion	18 days	[^Citation233]
14.	Liraglutide (GLP-1 agonist)	Cerebral cortex	↑ Cerebral microvasculature, ↓Cerebral microaneurysms and leakage	Pre-clinical study Transgenic mice APP/PS1 and WT mice Age: 7-months old	Liraglutide - 25 nmol/kg body weight, saline (0.9% w/v), via i.p.injection, once daily	8 weeks	[^Citation219]
15.	Liraglutide (Novel GLP-1 analog, pre-treatment)	Hippocampal CA1 region	↓Aβ25–35-induced impairment of spatial learning and memory, ↑Late-phase long-term potentiation, ↑Intracellular cAMP level	Pre-clinical study Adult, male, Sprague Dawley rats Weight:230–250 grams	Liraglutide:2 µL, injected at a rate of 0.2 L/min, and 25 nmol/kg body weight by i.p. injection	2 weeks	[^Citation218]
16.	GLP-1	Hippocampus	↑Intracellular calcium levels, ↓ Calcium responses to glutamate, ↓Membrane depolarization, ↓Neuronal death induced by glutamate, ↑ Neuronal plasticity, ↑ Cell survival	Pre-clinical study In-vitro study Dissociated hippocampal cell cultures, Density: 80–100 cells/mm^Citation2	10 nM GLP-1 treatment	10 days	[^Citation234]
17.	GLP-1 receptor agonists	Substantia nigra, Striatum	↓Inflammatory response ↑ Insulin receptor signaling ↓Proinflammatory cytokine levels	Clinical study Meta-analysis of randomized controlled trials Adult participants, Body mass index: 25 or higher; with or without T2DM	Exenatide: twice daily and once weekly, Liraglutide: once daily at clinically relevant doses	20 weeks	[^Citation235]
18.	GLP-1 analog (Liraglutide)	Temporal lobe, Occipital lobe, Parietal lobe, Cerebellum	↑Glucose metabolism, ↓Decline of brain glucose consumption	Clinical study Randomized, placebo-controlled, double-blinded study, 38 AD patients	Liraglutide- 0.6 mg subcutaneously daily for 1 week, then 2 mg daily for 1 week, and then 1.8 mg daily	26 weeks	[^Citation221]
19.	Intra-nasal insulin detemir	Hippocampus, Amygdala, Pre-frontal cortex	↑Verbal memoryin APOE-€4 positive carriers, ↑Working memory in the 40 IU group, ↑Visuospatial working memory	Clinical study Total: 60 old subjects, 39 participants with amnestic MCI and 21 participants with probable AD with Mini-Mental State Examination scores >15	20 IU and 40IU, daily treatment for 3 weeks, via nasal drug delivery device	2 years	[^Citation220]
20.	Geniposide (a novel agonist for GLP-1)	Pheochromocytoma	↑Anti-apoptotic Bcl-2 protein level, ↑ Heme oxygenase-1, ↑Phosphorylation of c-Raf, MEK ↑Phosphorylation of MAPK, and p90RSK ↓Oxidative damage	Pre-clinical study In-vitro study Rat PC12 cell line, cultured in Dulbecco’s modified Eagle’s medium, at 37°Celsius with 5% CO2	GLP-1: 33 mg/l, Geniposide: 50 mg/l,	4 hours	[^Citation227,Citation236]

Notes: Symbols: (↑) Increases, (↓) Decreases, (>) Greater than, (≥) Greater than or equal to, (<) Less than, (%) Percent.

Abbreviations: IU, International unit; OR, Odds ratio; HR, Hazard ratio; CI, Confidence interval; APP/PS1, Amyloid precursor protein/presenilin 1mutant form of Alzheimer’s disease; GLP-1, Glucagon like peptide-1; CA1, Cornu ammonis1; CNS, Central nervous system; cAMP, Cyclic AMP; i.p., Intra-peritoneal; AD, Alzheimer’s disease; VD, Vascular dementia; DPP-4, Dipeptidyl peptidase-4; IRS, Insulin receptor substrate; WT, Wild type; PC12, Pheochromocytoma cell 12; Bcl-2, B cell lymphoma-2; c-Raf, c-Rapidly accelerated fibrosarcoma; MEK, Mitogen-activated protein kinase kinase; MAPK, Mitogen-activated protein kinase; CO₂, Carbon dioxide; T2DM, Type 2 diabetes mellitus; APOE-€4, Apolipoprotein E, type epsilon 4 allele; MCI, Mild cognitive impairment; AMPK, AMP-activated protein kinase; PPAR-γ, Peroxisome proliferator-activated receptor gamma.

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