OPEN ACCESS
`
`EDITED BY
`Christoph Thiemermann,
`Queen Mary University of London,
`United Kingdom
`
`REVIEWED BY
`Marcin Filip Osuchowski,
`Ludwig Boltzmann Institute for
`Experimental and Clinical Traumatology,
`Austria
`Basilia Zingarelli,
`Cincinnati Children’s Hospital Medical
`Center, United States
`
`*CORRESPONDENCE
`Jesse Roth
`jroth2@northwell.edu
`
`†These authors have contributed
`equally to this work and share
`first authorship
`
`RECEIVED 19 January 2023
`ACCEPTED 26 April 2023
`PUBLISHED 17 May 2023
`
`CITATION
`Mehdi SF, Pusapati S, Anwar MS,
`Lohana D, Kumar P, Nandula SA,
`Nawaz FK, Tracey K, Yang H, LeRoith D,
`Brownstein MJ and Roth J (2023)
`Glucagon-like peptide-1: a multi-faceted
`anti-inflammatory agent.
`Front. Immunol. 14:1148209.
`doi: 10.3389/fimmu.2023.1148209
`
`COPYRIGHT
`© 2023 Mehdi, Pusapati, Anwar, Lohana,
`Kumar, Nandula, Nawaz, Tracey, Yang,
`LeRoith, Brownstein and Roth. This is an
`open-access article distributed under the
`terms of the Creative Commons Attribution
`License (CC BY). The use, distribution or
`reproduction in other forums is permitted,
`provided the original author(s) and the
`copyright owner(s) are credited and that
`the original publication in this journal is
`cited, in accordance with accepted
`academic practice. No use, distribution or
`reproduction is permitted which does not
`comply with these terms.
`
`TYPE Review
`PUBLISHED 17 May 2023
`DOI 10.3389/fimmu.2023.1148209
`
`Glucagon-like peptide-1:
`a multi-faceted
`anti-inflammatory agent
`
`Syed Faizan Mehdi 1†, Suma Pusapati 1†,
`Muhammad Saad Anwar 1, Durga Lohana 1, Parkash Kumar 1,
`Savitri Aninditha Nandula 1, Fatima Kausar Nawaz 1,
`Kevin Tracey 1, Huan Yang 1, Derek LeRoith 2,
`Michael J. Brownstein 3 and Jesse Roth 1*
`
`1The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States,
`2Division of Endocrinology, Diabetes & Bone Disease, Icahn School of Medicine at Mt. Sinai,
`New York, NY, United States, 3Azevan Pharmaceuticals, Bethlehem, PA, United States
`
`Inflammation contributes to many chronic conditions. It is often associated with
`circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate
`with disease severity. They are often elevated and can serve as markers of
`inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-
`MSH and ACTH have receptor-mediated anti-inflammatory properties that can
`rescue cells from damage and death. These peptides have been studied well in
`the past century. In contrast, GLP-1 and its anti-inflammatory properties have
`been recognized only recently. GLP-1 has been proven to be a useful adjuvant
`therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It
`also lowers HbA1C and protects cells of the cardiovascular and nervous systems
`by reducing inflammation and apoptosis. In this review we have explored the link
`between GLP-1, inflammation, and sepsis.
`
`KEYWORDS
`
`GLP-1 - glucagon-like peptide-1, incretin, GLP-1 agonists, hormone, inflammation,
`anti-inflammation
`
`1 Introduction to GLP-1
`
`Glucagon-like peptide-1 (GLP-1) is a peptide hormone that is produced in the intestine
`and in multiple other sites that are known for their role in regulating glucose metabolism.
`GLP-1 is also involved in multiple other physiological processes including appetite,
`cardiovascular function, and inflammation (1).
`Acute Inflammation is central to in-vivo responses to a wide range of challenges
`including viral and bacteriological infections, and to host repair processes. Chronic
`inflammation, on the other hand, is associated with conditions like type 2 diabetes,
`metabolic syndrome, obesity, cancer, arthritis, and bowel diseases like Crohn’s disease and
`
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`ulcerative colitis (2). Our recent studies have revealed the anti-
`inflammatory properties of several peptide hormones such as hCG,
`oxytocin, ghrelin, and vasopressin.(3-6) In this review article, we
`focus on the anti-inflammatory properties of the incretin hormone
`‘Glucagon-like Peptide-1 (GLP-1). Known for promoting glucose
`homeostasis and weight loss, the anti-inflammatory properties of
`GLP-1 suggest that it may also blunt inflammation and protect
`against organ damage (3–6).
`
`2 Functions of GLP-1 and its receptors
`
`Glucagon-like peptide-1 (GLP-1) is a 30-31 amino acid long
`incretin that is produced when proglucagon undergoes post-
`translational processing. This glucose-lowering agent is secreted
`by intestinal enteroendocrine L-cells in response to nutritional and
`inflammatory stimuli and by neurons in the nucleus of the solitary
`tract in the brainstem. GLP-1 activates a seven transmembrane G
`protein coupled receptor, GLP-1R. GLP-1 receptors are expressed
`in pancreatic islet b-cells, pulmonary epithelial cells, atrial cardiac
`myocytes, vagal afferent neurons, neurons in a number of brain
`regions, as well as cells lining gastric pits and small intestinal
`mucosa. The GLP-1R can couple to the Gs or Gq proteins,
`leading to increases in intracellular cAMP and/or Ca2+ levels and
`activation of PKA, Epac-2, phospholipase C and ERK1/2 signal
`transduction pathways. Activation of GLP-1R by GLP-1 or other
`exogenous agonists, including exendin-4 and liraglutide, decreases
`inflammatory responses in several animal models like rat heart and
`whole animal model. The hypoglycemic activity of GLP-1 is
`associated with the stimulation of glucose-dependent insulin
`secretion, inhibition of glucagon production and regulation of
`islet cell proliferation, differentiation, and survival. Under
`physiological conditions, GLP- 1 is rapidly degraded by dipeptidyl
`peptidase-4 (DPP- 4) after it is released (7).
`
`3 Discovery of GLP-1
`
`In 1923, Charles Kimball and John Murlin, in an attempt to
`purify commercial insulin, precipitated a pancreatic fraction that had
`a hyperglycemic effect (8). Identifying it as a secreted factor, they
`named it ‘Glucagon’ or ‘Glucose Agonist’. In 1959, Roger Unger et al.,
`developed the first antibody that could be used in a
`radioimmunoassay to detect glucagon in tissue samples and blood
`(9, 10). In 1966, Ellis Samols, Vincent Marks and others confirmed
`the presence of glucagon-like immunoreactivity in extra-pancreatic
`tissue, especially the intestine. Subsequently in 1967, Samols and
`Marks reported glucagon-like material
`in pancreatectomized
`humans, indicating its extra-pancreatic origin (11). In 1968, Roger
`Unger demonstrated that intraduodenal administration of glucose
`increased the levels of a circulating glucagon-like substances (9, 10).
`In contrast to glucagon, the intestinal glucagon-like material
`stimulated the release of insulin. It was clear that glucagon and the
`g l u c a g o n - l i k e m a t e r i a l w e r e d i s t i n c t e n t i t i e s , a n d
`immunohistochemical studies revealed that intestinal cells that
`were positive for the glucagon-like material had a different
`
`morphology from glucagon secreting a-cells. The cells that made
`glucagon-like material were called L-cells. In 1970 the glucagon
`precursor, proglucagon, was identified. In the pancreas,
`proglucagon undergoes post-translational cleavage yielding two
`fragments. One was a mature glucagon and the other was called
`the proglucagon fragment. In 1980, the intestinal glucagon-like
`material, glicentin, was identified along with a smaller species
`named oxyntomodulin in 1982. Collectively, these studies suggested
`that proglucagon undergoes tissue-specific processing resulting in
`formation of glicentin and oxyntomodulin in the intestine, and
`glucagon plus the N-terminal fragment of glicentin in the pancreas.
`In the 1980s Joel Habener described a new glucagon-related peptide
`encoded in the anglerfish preproglucagon cDNA. Subsequently two
`glucagon-related peptides were identified in rat, bovine, hamster, and
`human proglucagon. These two peptides are now called glucagon-like
`peptides 1 and 2 (GLP-1 and GLP-2) as shown in Figure 1 “The
`proglucagon precursor (12–16).
`
`4 GLP-1 receptor
`
`The GLP-1 receptor is a member of the secretin subfamily (B1)
`of G-protein coupled receptors (GPCRs). It consists of 463 amino
`acids (17). These amino acids are arranged in seven transmembrane
`(7TM) alpha-helices with an N-terminal domain that is located
`extracellularly and a C-terminal domain that is intracellular. The
`transmembrane helices are connected by three extracellular and
`three intracellular loops (17, 18). Ligand binding to its receptor
`occurs in two stages. The first step involves the binding of the
`extracellular domain to the C-terminus of the ligand. This causes a
`conformational shift that leads to attachment of the N-terminus of
`the ligand to the 7TM domain (18–20). (Figure 2) for a more
`detailed figure, refer to reference 18.
`GLP-1 receptor signaling occurs primarily through the Gas
`stimulatory G protein (21). Coupling of Gas and Gaq in beta cells
`of pancreas lead to an increase in cAMP by activation of adenylyl
`cyclase and phosphoinositol 3 kinase (PI3K) pathway. cAMP
`activates PKA and Epac-2 signal transduction pathways (22).
`PKA and Epac-2 inhibit the K-channel, altering Kv currents
`leading to calcium influx as well as calcium release from the
`endoplasmic reticulum. This results in calcium-induced release of
`insulin granules (23). PKA and Epac-2 also activate cyclin D and
`CREB,
`leading to beta-cell proliferation, differentiation, and a
`decrease in endoplasmic reticulum stress response (24). Exenatide
`decreases ER stress in response to synthetic stressors (25). In mouse
`models, exendin-4 increases beta cell proliferation by activation of
`epidermal growth factor receptors (26). Human beta cells exposed
`to GLP-1 show increased beta cell proliferation (24, 25) (Figure 3).
`Activation of the GLP-1 pathways decreases the inflammatory
`response in multiple models. GLP-1 Analog liraglutide improves
`vascular function in polymicrobial sepsis by reduction of oxidative
`stress and inflammation (24, 27–31). Exendin in diabetic mice
`diminishes inflammatory responses by increasing the expression
`of regulatory T cells (32). Liraglutide has anti-inflammatory effects
`on endothelial cells by decreasing activation of NF-kB, inhibiting
`TNF-alpha, and increasing nitric oxide production (28). Like GLP-1
`
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`FIGURE 1
`GLP-1 synthesis: In the intestine — The proglucagon precursor gives rise to oxyntomodulin, GLP1 (and its two equipotent, truncated derivatives) and
`GLP-2. Like the GLPs, the intervening peptides (IP-1 and IP-2) may also have physiological functions (12, 13). In the pancreas, the proglucagon
`precursor yields glucagon and the glicentin-related pancreatic peptide (GRPP) (12–16) Figure modified from article 12. Figure from Open access
`(Molecular Metabolism) permissible to re-use under a CC-BY 4.0 license.
`
`agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, which block the
`degradation of GLP-1, also cause attenuation of the inflammatory
`responses. Sitagliptin decreases the LPS-inflammatory response by
`inhibiting the NF-kB pathway. This leads to decreased production
`of proinflammatory cytokines including TNF-a, IL-6, IL-1b and
`decreased expression of COX-2 in cardiomyocytes (33).
`
`5 GLP-1 and various organs
`
`GLP-1 has been shown to carry out numerous protective and
`regulatory functions in different organ systems. The functions are
`illustrated in the Figure (Figure 4).
`
`6 GLP-1: anti-inflammatory effects
`
`6.1 Cardiovascular system
`
`The antioxidant and anti-inflammatory effects of GLP-1 protect
`the cardiovascular system. GLP-1 levels are elevated in patients post
`myocardial infarction. Administration of GLP-1 analogs (or DPP-4
`inhibitors, which inhibit the degradation of GLP-1), decreased
`cardiovascular and thrombotic complications in animal models of
`LPS-induced sepsis. They also suppressed inflammation and
`formation of reactive oxygen species (ROS) in vasculature,
`resulting in vasorelaxation and amelioration of hypotension.
`Moreover, reduced organ damage by thrombotic occlusion in the
`
`FIGURE 2
`(Original by authors of the manuscript): The seven transmembrane alpha-helices are bound to G-protein subunits (19). These consist of alpha
`subunit and beta-gamma subunit complexes bound to GDP. In the inactive state, the a-subunit is bound to GDP. Upon binding of GLP-1, GDP is
`replaced by GTP, which then activates the a-subunit. The a-subunit and GTP complex activate signaling cascades through adenylyl cyclase and
`phospholipase C (20).The third intracellular loop is most important in receptor signaling.
`
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`FIGURE 3
`GLP-1 receptor signaling (21-26). Figure modified from article 23. Figure from Open access (Gastroenterology) permissible to re-use under a CC-BY
`4.0 license.
`
`lung has been reported in LPS-induced sepsis due to improvement
`in microvascular circulation by GLP-1 analogs. In a polymicrobial
`model of sepsis induced by cecal ligation and puncture, a GLP-1
`analog ameliorated vascular inflammation and oxidative stress by
`improving endothelial function (28)
`In a cardiac fibrosis model, the GLP-1 analogue liraglutide
`reduced vascular reactivity, cardiac hypertrophy, fibroblast
`accumulation, collagen deposition and MCP-1 production (40).
`
`Another GLP-1 analogue, exendin-4, also prevented cardiac
`remodeling and diastolic dysfunction in an experimental diabetes
`model. This was associated with a reduction in macrophage
`infiltration, lower expression of IL-1b and IL-6, and an increase
`in IL-10 in the heart (41).
`GLP-1 improved left ventricular function in patients with
`chronic heart failure and in dogs with dilated cardiomyopathy.
`Survival rates after myocardial infarction also improved after GLP-1
`
`FIGURE 4
`(Original by authors of the manuscript): Effects of GLP-1 on various organ systems (34–39).
`
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`administration. Sitagliptin, a DPP-4 inhibitor, improves myocardial
`response in coronary artery disease patients. LPS-induced cardiac
`dysfunction recovered in DPP-4 deficient rats after treatment with
`sitagliptin. Exendin-4 and DPP-4 de ficiency prevented
`vasoconstriction and multiple organ injury after LPS treatment,
`and improved survival in endotoxemic rats (31).
`In animal studies, GLP-1 and its analogs reduced macrophage
`infiltration in blood vessels, and production of pro-inflammatory
`cytokines such as IL-6, IL-1b, TNF-a, and CRP. It has been
`speculated that liraglutide, a GLP-1 analog, suppresses cytokine
`release in bacterial septic shock and in SARS-CoV-2 viral sepsis.
`GLP-1 analogs and DPP-4 inhibitors have shown promise in animal
`models of cardiovascular disease. Studies in humans should be done
`(42, 43) (Table 1).
`
`6.2 Gastrointestinal system
`
`GLP-1 is secreted into the distal intestine by enteroendocrine L
`cells in response to nutrient ingestion (42). GLP-1 receptors are
`widely distributed in the gastrointestinal tract, pancreas, heart, lungs,
`kidneys, and nervous system. These receptors contribute to the wide
`range of physiological functions (45). Besides metabolic effects, GLP-
`
`1 improves mucosal integrity and diminishes inflammation (42, 46).
`Exendin-4, a GLP-1 mimetic peptide, decreases the production of
`pro-inflammatory cytokines, and diminishes the enteric immune
`response. GLP-1 decreases production of pro-inflammatory
`cytokines, mainly by downregulating NF-kB phosphorylation and
`nuclear translocation (45).
`Several recent studies have suggested that GLP-1 should be
`considered as a treatment for a wide range of intestinal diseases,
`including Inflammatory bowel diseases, intestinal mucositis, coeliac
`disease and short bowel syndrome (45). GLPs, (including GLP-1,
`GLP-2 and DPP-4) have recently gained increased attention from
`researchers studying Inflammatory bowel diseases (IBDs).
`IBDs including Crohn’s disease and ulcerative colitis are
`chronic relapsing-remitting diseases with multifactorial etiologies
`and complex pathogenesis. The Incidence and prevalence of IBDs
`are rising globally. GLPs including GLP-1 regulate weight and
`glycemia. GLP-1 also inhibits gastric emptying, decreases food
`ingestion, and increases crypt cell proliferation. It also improves
`intestinal growth and nutrient absorption. GLPs have been
`proposed to improve tissue healing of injured epithelium, regulate
`T-cell growth and function, control innate immune cells such as
`macrophages and dendritic cells, and lower pro-inflammatory
`cytokines in IBD (47) (Table 2).
`
`Nephropathy¶
`
`RetinopathyD
`
`Cardiovascular
`Overall
`mortality
`
`Benefit
`
`Benefit
`
`?
`
`Benefit
`
`Benefit
`
`Neutral
`
`?
`
`Neutral
`
`Neutral
`
`Unexpected increase
`in retinopathy
`outcomes◊
`
`Benefit
`
`?
`
`Benefit
`
`Benefit
`
`Benefit
`
`?
`
`Benefit
`
`?
`
`TABLE 1 Efficacy of GLP-1 agonists efficacy (adapted from UpToDate) (44).
`
`Elimination
`half-life
`
`Glycemic
`efficacy (reduction
`in
`A1C in
`% points)*
`
`Cardiovascular out-
`comes
`ASCVD/HF
`
`Long-acting GLP-1 receptor agonists (more pronounced effect on fasting glucose)
`
`Dulaglutide
`
`5 days
`
`Efpeglenatide
`
`6 to 7 days
`
`Exenatide
`
`8 to 14 days
`
`Liraglutide
`
`11 to 15 hrs
`
`–1 to –1.5
`
`–1 to –1.11
`
`–1.5 to –1.6
`
`–0.8 to –1.5
`
`Semaglutide
`
`6 to 7 days
`
`–1.5 to –2
`
`Benefit
`
`Benefit
`
`Neutral
`
`Benefit
`
`Benefit
`
`Short-acting GLP-1 receptor agonists (more pronounced effect on postprandial glucose)
`
`Exenatide
`
`2 to 3 hrs
`
`–1
`
`Lixisenatide
`
`3 to 5 hrs
`
`–0.8 to –1
`
`Dual-acting GLP-1 and GIP receptor agonists
`
`?
`
`Neutral
`
`Tirzepatide
`
`5 days
`
`–2 to –2.5
`
`?§
`
`?
`
`Neutral
`
`?
`
`?
`
`?
`
`?
`
`GLP-1, glucagon-like peptide 1; A1C, glycated hemoglobin; ASCVD, atherosclerotic cardiovascular disease; HF, heart failure; SubQ, subcutaneously; ?, inadequate data; GIP, glucose-dependent
`insulinotropic polypeptide; eGFR, estimated glomerular filtration rate.
`*Reduction in A1C is dependent upon a number of factors, such as baseline A1C and background therapy. In trials directly comparing shorter- versus longer-acting GLP-1 receptor agonists,
`longer-acting had better glycemic efficacy.
`¶Nephropathy is defined as elevated albuminuria, reduced eGFR (usually <60 mL/min/1.73 m2), or both.
`DRetinopathy outcomes were not systematically evaluated or adjudicated.
`◊The higher rate of retinopathy complications with subcutaneous semaglutide was unexpected and may be a consequence of rapid glycemic control similar to that seen in other settings. If
`subcutaneous semaglutide is prescribed to a patient with diabetic retinopathy, titrate slowly to avoid rapid declines in A1C and perform retinal screening within 6 months of drug initiation to
`detect progression of retinopathy.
`§In preliminary trials, tirzepatide did not increase the risk of major cardiovascular events.
`
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`6.3 Hepatobiliary system
`
`GLP-1 based therapies have shown promise in liver diseases e.g.
`non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
`steatohepatitis (NASH). In recent years, the prevalence of non-
`alcoholic fatty liver disease (NAFLD) has continued to rise, and
`10%-25% of NAFLD cases progress to non-alcoholic steatohepatitis
`
`(NASH). 10%-15% of NASH cases will develop into hepatocellular
`carcinoma, approximately 700,000 people die from the disease each
`year (53).
`Nonalcoholic steatohepatitis is associated with inflammation
`of the liver, driven by an aberrant accumulation of fat. In rats fed
`with a high-fat diet, treatment with liraglutide, a GLP-1R analog,
`reduced steatosis and lobular inflammation compared to the
`
`TABLE 2 GLP-1 analogues under investigation in vitro and in vivo (animal and human studies).
`
`Models
`
`Treatments
`
`In-vitro study
`Macrophage RAW
`264.7
`cell culture
`
`Pre-treated with
`exendin-4 for 6hrs
`followed by LPS for
`24hrs
`
`Exendin-4 inhibits production of many LPS-induced inflammatory factors, thereby decreasing production
`of ROS reactive oxygen species.
`
`(Lu et al.,
`2019) (27)
`
`Results
`
`References
`
`GLP-1 self-
`associated with
`PEGylated
`phospholipid
`micelles i.p
`
`—
`
`GLP-1-SSM (sterically stabilized phospholipid micelles) improve architecture of the intestine, partially
`preserve goblet cell number, decrease IL1-b secretion and improve diarrhea induced by DSS.
`
`(Anbazhagan
`et al., 2017)
`(48)
`
`I.P or I.V administration of LPS caused a significant rise in plasma levels of GLP-1 through the TLR-4
`mechanism.
`
`(Lebrun et al.,
`2017) (46)
`
`Exendin-4 (GLP-1
`agonist) s.c.
`
`DSS-induced colitis in GLP-1 R knockout mice showed dysregulation of intestinal gene expression, as
`well as abnormal representation of microbes in feces and increased sensitivity to intestinal injury. Also,
`Exendin-4 administration caused significantly increased expression of genes encoding cytokines and
`chemokines in gut injury.
`
`(Yusta et al.,
`2015) (49)
`
`LPS+/-Exendin-4
`
`Exendin-4 Inhibited production of pro-inflammatory cytokines including TNF-a and IL-1 a in LPS-
`induced inflammation in mouse model.
`
`(Al-Dwairi
`et al., 2018)
`(50)
`
`(Işbil
`Büyükcoşkun
`et al., 2007)
`(51)
`
`In-vivo animal
`studies
`DSS-induced colitis
`in
`mouse model
`
`DSS-induced colitis
`in
`mouse model
`— Ischemia/
`reperfusion
`
`DSS-induced colitis
`in
`mouse with GLP-
`1R
`knockout
`
`Colonic smooth
`muscle
`cells of male
`BALB/c
`mice cultured in
`DMEM
`
`Wistar rat model
`
`MPTP-treated
`Parkinson
`Disease mouse
`model
`Human A53T
`a-synuclein
`transgenic
`PD mouse
`model
`(MPTP=1-methyl-
`4-phenyl-1,2,3,6-
`tetrahydropyridine)
`
`Human study
`a) Healthy
`volunteers
`b)Ischemia/
`reperfusion injury
`model of human
`gut
`
`a) GLP-1 injected
`i.c.v
`b) GLP-1 receptor
`antagonist, Exendin
`9-39
`I.c.v and i.p
`
`CCK analogues
`or
`Liraglutide and
`GLP-1 analogues
`i.p
`
`—
`
`Centrally injected Exendin 9-39 inhibited the gastroprotective effects of GLP-1 agonists,
`suggesting that this effect is managed by central mechanisms.
`
`CCK analogues or GLP-1 analogues restored the disruption of intestinal tight junction, reduced colonic
`inflammation, inhibited colonic dopaminergic neuron reduction and the accumulation of a-synuclein
`oligomers in the colon of both PD mouse models.
`
`(Su et al.,
`2022) (52)
`
`3hrs after LPS injection
`a)
`plasma GLP-1 levels
`rose significantly.
`b)
`45 min after ischemia
`in the human intestine,
`GLP-1 levels rose
`significantly and
`returned to baseline
`after reperfusion.
`
`(Lebrun et al.,
`2017) (46)
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`saline-injected group. Exendin-4, a GLP-1R agonist, was shown in
`another study to lower hepatic production of the inflammatory
`markers TNF-, IL-1, and IL-6, as well as macrophage markers
`cluster of differentiation 68 (CD68), and F4/80 in mice fed a
`western-type (high fat) diet (54).
`C-reactive-protein (CRP) is produced by the liver and is a
`marker of inflammation. Liraglutide produced a significant decrease
`in the mean concentration of CRP in a retrospective investigation of
`110 obese patients with type 2 diabetes mellitus, indicating its
`potential as an anti-inflammatory drug. Exenatide plus metformin
`caused a significant reduction in baseline CRP and TNF-a. These
`findings show that GLP-1-based treatments improve fatty liver
`disease in rats and humans via reducing inflammation (42).
`NAFLD is associated with cell death and fibrosis that ultimately
`progress to cirrhosis. In obese patients with NAFLD, Fibroblast
`growth factor-21 protein (FGF21) and RNA levels are higher in the
`liver. Treatment with GLP-1R agonists reduced the level of FGF21.
`This supports its use in cirrhosis. Note that 80% of patients who
`develop hepatocellular carcinoma had cirrhosis beforehand (55, 56).
`GLP-1RA significantly reduced cell necrosis and apoptosis, the
`two major forms of liver cell death. Hepatic cell death mainly
`includes two forms: apoptosis and cell necrosis. Gupta et al. showed
`that a GLP-1RA significantly reduced cell necrosis and
`apoptosis.The reduction of abdominal visceral adiposity by GLP-
`1RAs results in a reduction in liver fat content that can alleviate
`NAFLD. The ability of GLP-1 to reduce fat is due to its binding to a
`specific GLP-1R present in adipose tissue (57). Vendrell et al.
`confirmed the expression of GLP-1R in mature adipose cells by
`the detection of the mRNA and protein (58). A 6-month-long
`treatment with GLP-1RAs in obese patients with T2DM resulted in
`significant reductions in intrahepatic lipids (IHL). In addition, the
`median relative reduction in IHL was 42% (53) (Figure 5).
`
`6.4 Central nervous system
`
`Glucagon-like peptide-1 is produced in the brainstem and has
`numerous functions, including neuroprotection (59–61) GLP-1 and
`GLP-1 analogs can cross the blood-brain barrier (62–68) GLP-1
`receptors have been observed in the neurons of the nucleus tractus
`solitarius that project to GLP-1R–expressing regions in the
`hindbrain, hypothalamus, including the paraventricular nucleus
`(PVN), dorsal medial nucleus of the hypothalamus, and arcuate
`nucleus (ARC) (42, 64, 66, 67, 69, 70). GLP-1-based therapies have
`anti-inflammatory effects on multiple tissues (42, 53, 71–73).
`Chronic inflammation is a significant risk factor for many
`neurodegenerative disorders, e.g., Alzheimer’s disease and
`Parkinson’s disease (42, 74–78).
`
`6.4.1 Parkinson’s disease
`The prevalence of Parkinson’s disease has been rising in recent
`years (79, 80). It
`is the second most common chronic
`neurodegenerative disease and affects between 1% - 2% of people
`above age 60 and 4% of those above age 80 (81–87). Parkinson’s
`disease occurs when dopaminergic neurons in the substantia nigra
`pars compacta form Lewy bodies and gradually die (88–90). The
`Lewy body is an abnormal aggregate containing alpha-synuclein.
`Most Parkinson’s disease treatments focus on managing symptoms
`by replacing dopamine and improving dopaminergic signaling, but
`these treatments fail to address the underlying cellular degeneration
`(64, 91). Since dopamine breaks down to form reactive oxygen
`species, it may contribute to disease progression (92, 93). Activation
`of microglia plays a crucial role in spontaneous Parkinson’s Disease
`in humans (64, 94–96). MPTP (1-methyl-4-phenyl-1,2,3,6-
`tetrahydropyridine) induces Parkinson’s disease in rodents.
`MPTP is a pro-drug for the neurotoxin MPP+ (1-methyl-4-
`
`FIGURE 5
`Effects of glucagon-like peptide-1 receptor agonist on non-alcoholic fatty liver disease. PPAR-a, Peroxisome proliferator-activated receptor; IHL,
`intrahepatic lipids; AMPK, AMP-activated protein kinase; CRP, C reactive protein; AGEs, Advanced glycation and end products; JNK, c-Jun NH2-
`terminal kinase; GLP-1RA, Glucagon-like peptide-1 receptor agonist; NAFLD, Non-alcoholic fatty liver disease (53). Modified figure from reference
`53. Figure from Open access (World Journal of Gastroenterology) permissible to re-use under a CC-BY 4.0 license).
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`phenylpyridinium). This agent destroys dopaminergic neurons in
`the substantia nigra (81, 97–104).Exendin- 4, a GLP-1 R agonist,
`has inhibitory effects on microglial activation and greatly reduces
`the expression of TNF-a and IL-1b caused by MPTP (67, 105–107).
`Exendin-4 inhibits 6-hydroxydopamine (6-OHDA)-induced
`dopaminergic cell death in neuronal culture. The intraventricular
`administration of GLP-1 protects mice from MPTP-induced
`dopaminergic cell loss (64, 86, 108, 109).
`
`6.4.2 Alzheimer’s disease
`Alzheimer’s disease is the most common form of dementia; it is
`responsible for 60–70% of cases (110, 111). About 1 person in 9
`(10.8%) in the US population age 65 and older has AD (112). People
`65+ years of age in Europe had a pooled incidence rate of AD of 19.4
`per 1000 person-years (113–115). The Alzheimer’s disease
`population increased by 5% from age 65 to 73, 13.1% from age 75
`to 84, and 32% from age 85 and older (112, 116). Alzheimer’s
`disease was the seventh-leading cause of death in 2020 and
`2021 (112).
`In AD, IL-1 beta is significantly increased in the frontal cortex
`and hippocampus and may contribute to cognitive dysfunction by
`promoting the synthesis of amyloid precursor protein (117, 118).
`GLP-1 therapies may have preventive and restorative effects on
`Alzheimer’s disease (42, 119). Exogenous GLP-1 (7–36) amide
`administration inhibited IL-1 beta transcription and prevented
`beta-induced amnesia and cell death (36, 59, 113, 114). Also, it
`restores learning and memory by stimulating LTP (long-term
`( 6 0, 1 2 0– 1 2 2 ) .
`p o t e n t i a t i o n )
`I n a r o d e n t m o d e l ,
`neuroinflammation was reduced due to suppression of TNF-alpha
`when GLP-1 exenatide (20 ug/kg/day) was given intraperitoneally.
`The peptide improved memory and prevented the loss of
`hippocampal neurons (111, 123). Treatment with liraglutide in a
`
`mouse model of Alzheimer’s disease reduced the inflammatory
`response in the cortex by decreasing the number of activated
`microglia (60, 65, 107, 124, 125). Mice that express two human
`mutant genes linked to early-onset Alzheimer’s disease develop a
`chronic inflammatory response (126). In these animals, D-Ala2-
`GIP reduces the activation of microglia and astrocytes in the brain,
`decreasing the release of pro-inflammatory cytokines and oxidative
`stress (127).Microglia and astroglia express GIP receptors (128,
`129). Activating them reduces central inflammatory responses. GIP
`receptor activation increases microglia expression of key growth
`factors such as brain-derived neurotrophic factor(BDNF), glial cell-
`line derived neurotrophic factor (GDNF), and nerve growth factor
`(NGF) in a phosphoinositide 3-kinase (PI3K) and protein kinase A
`(PKA) dependent manner (130) (Figure 6).
`Brain irradiation has been demonstrated to increase the
`expression of IL-6, IL-1b, and IL-12p70 cytokines. Liraglutide
`reduces the proinflammatory cytokine gene expression caused by
`X-ray irradiation (42, 131).
`In a study on rats, when cultured astrocytes were stimulated by
`LPS, IL-1b mRNA expression increased temporally. GLP-1 therapy
`decreased IL-1b mRNA production compared to the LPS alone-
`treated cultures (67, 72). The GLP-1 suppresses TNF-alpha and
`associated cytokines in microglia (Figure 7).
`
`6.5 Stroke models
`
`Strokes in the elderly can cause permanent neurological damage
`and are among the leading causes of death. Patients who have
`hyperglycemia and diabetes mellitus type 2 (T2DM) have a higher
`stroke frequency than those who do not have these conditions (132,
`133). Stimulating GLP-1Rs with exendin-4 reduces brain damage
`
`FIGURE 6
`Overview of the main pathways induced by GLP-1 in neurons. Activation of the GLP-1R activates adenylyl cyclase and increases cAMP levels. This
`activates PKA and other downstream kinases related to growth factor signaling. GLP-1 supports neurogenesis, reduces inflammation, and inhibits
`apoptosis while improving learning and memory in the hippocampus.(modify from reference 130) (AATP, adenosine triphosphate; cAMP, Cyclic
`adenosine monophosphate; CREB, cAMP response element binding protein; PKA, protein kinase A; PI3K, phosphatidylinositol-3 kinase; PKC, protein
`kinase c; mTOR, Mammalian target of rapamycin; ERK, extracellular signal-regulated kinase; BRAF, v-raf murine sarcoma viral oncogene homolog
`B1.) Figure modified from reference 130, Open access (Peptides journal) permissible to re-use under a CC-BY 4.0 license).
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`muscle tissues (142). Covid victims who took GLP-1R agonists had
`fewer hospital admissions (143).
`
`7 GLP-1 in obstructive lung disease
`and asthma
`
`Asthma affects about 25 million people in the US and more than
`330 million people world-wide (144). GLP-1 receptor agonists
`decreased allergic responses in asthma by preventing the activation
`of NF-kB leading to decreased release of proinflammatory cytokines
`(IL-5, IL-13, IL-33) and neutrophils, eosinophils, basophils and CD4
`+ T cell numbers (142, 145). Exendin-4 also relaxes bronchial smooth
`muscles by acting on the cAMP-PKA pathway (144).
`A recent study demonstrated that GLP-1 agonists improve survival
`and lung function in mouse models of asthma and COPD. The results
`showed that GLP-1R agonists have therapeutic potential in the
`treatment of ch