The Role Of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) in Diabetes-Related Neurodegenerative Diseases Part 1

Abstract:

Recent clinical guidelines have emphasized the importance of screening for cognitive impairment in older adults with diabetes, however, there is still a lack of understanding about the drug therapy. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are widely used in the treatment of type 2 diabetes and potential applications may include the treatment of obesity as well as the adjunctive treatment of type 1 diabetes mellitus in combination with insulin.
Growing evidence suggests that GLP-1 RA has the potential to treat neurodegenerative diseases, particularly diabetes-related Alzheimer’s disease (AD) and Parkinson’s disease (PD). Here, we review the molecular mechanisms of the neuroprotective effects of GLP-1 RA in diabetes-related degenerative diseases, including AD and PD, and their potential effects.

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Keywords:

Glucagon-like peptide-1, diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, cognition.

Introduction

Type 2 diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia caused by relatively insufficient insulin secretion. It is estimated that about 415 million people had diabetes in 2015, and this number may continue to rise to 642 million by 2040.1 Diabetes-related neurodegenerative disease (ND) is of particular importance due to the cognitive impairment it causes in older patients with type 2 diabetes. 

The risk of incident mild cognitive impairment (up to 60%) and dementia (50–100%) is higher in patients with type 2 diabetes than in those without.2 Recent clinical guidelines have emphasized the importance of screening for cognitive impairment in older adults with diabetes;3 however, there is still a lack of understanding about drug therapy. 

Therefore, an urgent goal is to develop effective neuroprotective drugs that act on the common mechanisms of diabetes-related NDs, thereby slowing the disease progression.

Glucagon-like peptide 1 (GLP-1) is a 30-amino-acid peptide hormone produced in intestinal epithelial endocrine L-cells by the processing of proglucagon.4 GLP-1 is widely used in the treatment of type 2 diabetes because it not only controls blood glucose but may also reduce body weight. Future uses of GLP-1 may also include the treatment of obesity, as well as the adjunctive treatment of type 1 diabetes mellitus in combination with insulin.5 Natural GLP-1 degrades within 2–3 min in circulation, thus greatly limiting its effects. 

Various GLP-1 receptor agonists (GLP-1 RAs) have been developed to provide long-term effects. GLP-1 RA functions by activating the GLP-1 receptor (GLP-1R), and GLP-1R is widely located throughout the brain.6,7 The ability of GLP-1 and its agonists to cross the blood–brain barrier8–10 suggests its therapeutic potential for NDs. 

A large number of studies have demonstrated the neuroprotective ability of GLP-1 RA, resulting in the improvement of cognitive and non-cognitive dysfunction of the central nervous system (CNS).

The proposed mechanisms of diabetes-related NDs include cerebral insulin resistance (IR), vascular endothelial dysfunction, inflammation, blood–brain barrier injury, white matter disease of vascular origin, demyelination and axonal loss, and peroxidative membrane injury.11 

Among these mechanisms, brain IR may play a primary role, and it is worth noting that neurologic complications may already occur with prediabetes IR.12 Oxidative stress,13 mitochondrial dysfunction,14 and endoplasmic reticulum (ER) stress15 are all involved in NDs induced by brain IR. 

In this review, we discuss the accumulating evidence concerning the effects of GLP-1 RA in diabetes-related NDs.

The GLP-1 RA and Its Relationship with Brain Insulin Resistance

Brain IR can be defined as the failure of brain cells to respond to insulin, and the lack of response may be due to the downregulation of insulin receptors, an inability of insulin receptors to bind insulin or faulty activation of the insulin signaling cascade.16 

Insulin receptors are distributed throughout the brain but have the highest concentration in the olfactory bulb, cerebral cortex, hypothalamus, hippocampus, and cerebellum.17 Insulin binds to the insulin receptor, phosphorylates the insulin receptor substrate (IRS), activates the phosphoinositide-3 kinase (PI3K) and mitogen-activated kinase (MAPK) pathways, and modifies the activity of several downstream effectors. 

PI3K activates protein kinase B (Akt), which inactivates several important substrate proteins, such as glycogen synthase kinase 3β (GSK-3β)18 and forkhead box O,19 and activates mammalian target of rapamycin (mTOR).20 As a result, it modulates some cellular processes, such as cell survival, proliferation, apoptosis, protein synthesis, inflammation, ER stress, mitochondrial function, and autophagy in neurodegenerative disorders.18–20 

Akt also promotes B-cell lymphoma 2 and B-cell lymphoma extra-large transcription by activating cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB).21 Thereafter, it regulates learning, memory,22 and neuron survival.23 MAPK regulates various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity.24 Impairment of insulin signaling is common in diabetes-related NDs.

GLP1-R is a class B G protein-coupled receptor,25 and its expression has been reported in the cerebral cortex, especially the occipital and frontal lobes, hypothalamus, and thalamus, whereas lower levels are found in the caudate putamen, globus pallidus, and hippocampus.21 GLP-1 and its RA cross the blood–brain barrier, with exendin-4 considered as one of the best based on the rate of brain influx, percentage of reaching the brain that accumulates in the brain parenchyma, and percentage of the systemic dose taken per gram of brain tissue.8 

Small amounts of GLP-1 may also be produced by preproglucagon neurons, located in the nucleus tractus solitarii of the brainstem26,27 and projected to other brain regions, such as the nuclei of the hypothalamus, including the arcuate and paraventricular nuclei.28 In the case of diabetes or obesity-related IR, GLP-1 secretion in the brain29 and peripheries30 may be impaired, which may contribute to the pathogenic change in neurodegeneration and cognitive decline; however, exogenous GLP-1 may help treat these diseases. 

When GLP-1 binds to the receptor, adenosine cyclase is activated and intracellular cAMP increases, thereby activating protein kinase A (PKA) and PI3K. The downstream pathways are mainly the PI3K and MAPK pathways; hence, the GLP-1 signaling and insulin signaling pathways are similar and partially overlapping (Figure 1).

Consequently, exogenous drugs that act on GLP-1Rs increase insulin sensitivity, possibly because GLP-1R stimulation compensates for some of the impaired insulin signaling. Among these drugs, liraglutide has been reported to have neuroprotective effects by ameliorating damage to the insulin pathway. In vitro experiments proved that it reversed the phosphorylation status of IRS1, Akt, and GSK-3β and reduced beta-amyloid formation and tau hyperphosphorylation in the human neuroblastoma cell line, SH-SY5Y.31 In vivo experiments proved that liraglutide prevented the dysregulation of Akt and GSK-3β and Alzheimer-associated tau phosphorylation in the brains of diabetic mice.32,33 Besides, it prevents the loss of brain insulin receptors in an Alzheimer’s disease (AD) model.34 Exenatide also has a similar effect on impaired insulin signaling pathways.35,36

The GLP-1 RA and Mitochondrial Dysfunction and/or Oxidative Stress

Mitochondria are the main energy production systems of most eukaryotic cells and are responsible for energy conversion, tricarboxylic acid cycle, oxidative phosphorylation, calcium storage, etc. Mitochondrial dysfunction has negative effects on the body and is believed to be an important factor in aging and disease. It has been found that insulin receptor knockout mice show reduced mitochondrial oxidative phosphorylation activity.37 Abnormal mitochondrial calcium transport was observed in the myocardium and visceral adipose tissue of obese mice.38,39 

In the hippocampal tissue of type 2 diabetic mice, the expression of mitochondrial dynamin-related protein 1 (Drp1) increased, whereas inhibition of Drp1 restored neuronal function.40 In diabetic models, peroxisome proliferator-activated receptor c coactivator 1a (PGC-1a), an important factor in diabetic mitochondrial biosynthesis, is often found to be abnormally expressed, whereas PGC-1a is critical for synaptic growth and CNS function. 

Reduced levels of the mitochondrial autophagy-associated protein Parkin in the substantia nigra may contribute to the development of Parkinson’s disease (PD) in db/db mice and high-fat diet-induced diabetic mice.41 As discussed above, mitochondrial dysfunction (mitochondrial bioenergetics, calcium buffering) and mitochondrial quality control systems (mitochondrial dynamics, mitophagy, mitochondrial biogenesis) may be involved in the pathological mechanisms of diabetes-related NDs.

Oxidative stress refers to a state of imbalance between oxidation and antioxidant effects in the body, favoring oxidation, leading to inflammatory infiltration of neutrophils, increased protease secretion, and production of a large number of oxidative intermediates. Mitochondria are key sites for aerobic metabolism and reactive oxygen species (ROS) production in cells and are also one of the most important organelles related to oxidative stress. 

Some experts believe that cerebral IR is the result of ceramide accumulation in brain tissue, and ROS overproduction occurs due to metabolic abnormalities accompanying peripheral IR and impaired mitochondrial activity in the IR brain.13 Studies have shown that ROS can cause age-related synaptic loss and ultimately cognitive impairment,42 where ROS interactions with inflammation may play a role. 

Oxidative products, including lipid and protein oxidation, are promoters of brain inflammation.43 Nuclear transcription factor-κB (NF-κB) Inflammatory pathway signaling plays a key role in regulating the amount of ROS in the cell.44 Excessive ROS can inhibit IRS1 activation by activating inflammation-related protein kinase C, inhibitor kappa B kinase β (IKKβ), c-Jun N-terminal kinase (JNK), and p38 MAPK, thereby aggravating IR,45 creating a vicious cycle.

In the nervous system, the regulatory effect of GLP-1 RA on mitochondrial function and oxidative stress is involved in the remission of diabetes-related NDs. 

In diabetes-related AD, GLP-1 promotes mitochondrial biogenesis and the antioxidant system by regulating the PGC-1a signaling pathway in vivo to directly reverse tau hyperphosphorylation.46 GLP-1(9-36) (amide) reduced elevated levels of mitochondrial-derived ROS in the hippocampus of AD model (APP/ PS1) mice.47 

Exendin-4 significantly increased amyloid β protein (Aβ)-induced reduction in mitochondrial function, integrity, respiratory control rate, and mitochondrial P/O ratio in all brain regions and decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV, and V activities in all brain regions.36 Exenatide also improved hippocampal mitochondrial morphology and dynamics and reduced oxidative stress in the hippocampus of AD model (5xFAD) mice.48

The mechanism by which GLP-1 RA regulates mitochondrial function and oxidative stress has not been well elucidated. GLP-1 signaling may improve mitochondrial biogenesis via PGC-1a/nuclear respiratory factor-1/mitochondrial transcription factor A signaling regulated by adiponectin/ adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK)49 and elevates the expression of NAD-dependent protein deacetylase sirtuin 1 (SIRT1), which increases the expression of Parkin, leading to mitophagy activation.50 Evidence strongly suggests that GLP-1 increases ERmitochondria communication, resulting in higher mitochondrial activity.51 Upregulating SIRT3 expression and activation of the extracellular signal-regulated kinase-Yes-associated protein (ERK-Yap) signaling pathway, as well as the CREB/ adiponectin axis, may also be involved in the protection of mitochondria by GLP-1.52,53 The improvement of antioxidant stress through GLP-1 signaling seems to be related to the activation of the GLP-1 R/cAMP/PKA signaling pathway and nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling pathway.54,55

The GLP-1 RA and Endoplasmic Reticulum (ER) Stress

The ER is the basic organelle for the synthesis of a series of important biological molecules, such as proteins, lipids (such as triglycerides), and carbohydrates. ER stress refers to the activation of ER responses, such as the unfolded protein response (UPR) and apoptosis signaling pathway, through the accumulation of misfolded and unfolded proteins and the disorder of calcium balance after various stress agents are applied to cells. The early role of UPR is to reduce translation to lessen the need for new protein folding, degrade unfolded proteins to minimize damage and increase the expression of chaperone proteins to assist protein folding. The UPR is thought to promote cell homeostasis. 

However, if this mechanism persists, it may lead to different metabolic diseases56 and NDs.57 UPR is mainly involved in the activation of three transmembrane proteins, inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF6), and protein kinase R (PKR)-like ER kinase (PERK). Normally, these three proteins are associated with luminal binding immunoglobulin protein (BiP), also known as 78-kDa glucose-regulating protein (GRP78), and are inactive. Under stress conditions, BiP is released and thus activates the IRE-1, ATF6, and PERK signaling cascades.58

ER, stress plays a role in the occurrence and development of diabetes and IR in peripheral tissues such as the pancreas, liver, adipose tissues, and skeletal muscle.58–63 Although some of the effects of ER stress are tissue-specific, there are some commonalities in the damage to insulin signaling. Under the action of unhealthy metabolic factors (obesity, diabetes), ER stress is initiated, and IRE-1 is activated, which in turn leads to the phosphorylation of IRS1 at the serine 307 residue by activating JNK, thereby impairing insulin signaling.64–66 A similar pattern was observed in the brain. 

Evidence indicates that ER stress was increased, thereby resulting in impaired insulin receptor signaling in the hippocampus and frontal cortex of obese rats, which is also caused by the activation of JNK.67 Therefore, diabetes and ER stress are vicious cycles in the brain, and IR is the key link. ER stress is also involved in the degenerative brain changes caused by diabetes. Elevated expression of ER stress markers, including GRP78, ATF-6, X-box binding protein1, C/EBP homologous protein (CHOP), and phospho-Jun N-terminal kinase (p-JNK), was evident in the hippocampal CA1 of diabetic rats,68 which may ultimately affect synaptic plasticity.

ER, stress has always been considered a result of NDs, but previous studies have shown that it is a more complex process by interfering with UPR to affect disease progression.69 GLP-1 RA has been shown to interfere with UPR to protect against NDs. Liraglutide treatment reduced neuroinflammation and ameliorated ER stress in the inferior olive of the aged Wolfram syndrome rat model.70 Moreover, it can prevent the disease before the appearance of metabolic symptoms.71 Liraglutide may engage Akt and signal transducer and activator of transcription 3 signaling to favor adaptive responses and shift cell fate from apoptosis to survival under chronic ER stress conditions in nerve cells.72 Our team used palmitic acid stimulation to induce neuronal IR, confirming that ER stress is involved in the functional damage of neurons induced by IR, and exendin significantly alleviates both ER stress and neuronal damage (data not shown).

However, it is not clear how GLP-1 RA regulates ER stress. Inhibiting the PI3K/Akt signaling pathway may eliminate the protective effect of GLP-1R by increasing ER stress, suggesting that this pathway may be involved in the effect of GLP-1 on ER stress.73 Besides, the PKA pathway may also be involved in GLP-1, attenuating the ER stress signaling pathway and protecting cells from apoptosis.74–76 Evidence suggests that PKA-dependent protection of GLP-1 is mediated through enhanced ATF4-CHOP-growth arrest and DNA damage-inducible gene 34 (GADD34) signaling, resulting in eukaryotic initiation factor 2 alpha dephosphorylation and translational recovery.76

However, some researchers believe that exendin-4 protects β-cells against free fatty acids and salubrinal-induced ER stress and apoptosis, not through ATF4-CHOP- GADD34 feedback signaling but through enhancing cellular defense mechanisms (eg, BiP, Bcl-2, and JunB).77 In addition, other studies have investigated the mechanism by which GLP-1 regulates ER stress. Exendin-4 enhances the binding of heat shock factor 1 to the promoter of heat shock protein (HSP) genes through SIRT1-mediated deacetylation, which then increased the expression of molecular chaperones HSP70 and HSP40 to alleviate lipid-induced hepatic ER stress.78 ER oxidoreductase mediates the inhibitory effects of exendin-4 on ER stress, ameliorating hyperhomocysteinemia-induced endothelial dysfunction.79 ER protein 46, a new member of the thioredoxin family, highly expressed in pancreatic β-cells, may mediate GLP-1 regulation of ER stress and thus increase the protection of pancreatic β cells.80,81 These studies suggest the complexity of GLP-1 RA in regulating ER stress.

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