Glucagon Like Peptide-1 and Its Receptor in Human Brain: Distribution of Expression, Functional Implications, Age Related Changes & Species Specific Characteristics

Emerging evidence has shown that the Glucagon like peptide-1 (GLP-1) agonist can be used for treating Alzheimer’s disease, but knowledge of its neural targets is limited. To understand the neural substrates of GLP-1, we have done whole brain mapping for GLP-1 and its receptor (GLP-1R), in 30 human brains. GLP-1 expression was studied by immuno-histochemistry and confirmed by western blot method. GLP-1R gene expression was studied by RT-PCR. GLP-1 expression was seen in most of the cortical areas (maximum in frontal, prefrontal & parietal cortex), diencephalon and brainstem, but not in cerebellum. Protein expression studies validated these results. Highest expression of GLP-1R was found in the frontal cortex. The orbito-frontal cortex and cerebellum had negligible expression. Hippocampus demonstrated significant presence of GLP-1R but patchy immunoreactivity to GLP-1. GLP-1R presence in most of the human cortical regions and absence in cerebellum is the major deviation from the animal brain. Sites which might be of interest in Alzheimer’s have been identified. GLP-1 demonstrated age related decline in most of the areas after 5thdecade. At 60yrs GLP-1 was not found in any of the cortical areas except in the prefrontal cortex but it was present in the sub-cortical areas. Age related profiling of GLP-1 in various brain areas has been analysed, which can have important bearing on understanding the Alzheimer’s. This study provides detailed description of GLP-1 and GLP-1R locations by complete human brain mapping for the first time and may lead to novel treatment options targeting the GLP-1 receptors.

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Effects of glucagon-like peptide 1 receptor agonists on comorbidities in older patients with diabetes mellitus

Therapeutic Advances in Chronic Disease ◽

10.1177/2040622319862691 ◽

2019 ◽

Vol 10 ◽

pp. 204062231986269 ◽

Cited By ~ 14

Author(s):

Olusola F. Onoviran ◽

Dongming Li ◽

Sarah Toombs Smith ◽

Mukaila A. Raji

Keyword(s):

Cognitive Deficits ◽

Adverse Drug Events ◽

Case Discussion ◽

Receptor Agonists ◽

Age Related ◽

Patients With Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Treatment Of Obesity ◽

Multiple Conditions

Elderly patients with diabetes are at high risk of polypharmacy because of multiple coexisting diseases and syndromes. Polypharmacy increases the risk of drug–drug and drug–disease interactions in these patients, who may already have age-related sensory and cognitive deficits; such deficits may delay timely communication of early symptoms of adverse drug events. Several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved for diabetes: liraglutide, exenatide, lixisenatide, dulagluatide, semaglutide, and albiglutide. Some are also approved for treatment of obesity. The current review of literature along with clinical case discussion provides evidence supporting GLP-1 RAs as diabetes medications for polypharmacy reduction in older diabetes patients because of their multiple pleiotropic effects on comorbidities (e.g. hyperlipidemia, hypertension, and fatty liver) and syndromes (e.g. osteoporosis and sleep apnea) that commonly co-occur with diabetes. Using one medication (in this case, GLP-1 RAs) to address multiple conditions may help reduce costs, medication burden, adverse drug events, and medication nonadherence.

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Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1601745113 ◽

2016 ◽

Vol 113 (32) ◽

pp. 9105-9110 ◽

Cited By ~ 191

Author(s):

Kirstie J. Whitaker ◽

Petra E. Vértes ◽

Rafael Romero-Garcia ◽

František Váša ◽

Michael Moutoussis ◽

...

Keyword(s):

Human Brain ◽

Brain Maturation ◽

Association Cortex ◽

Projection Neurons ◽

Consolidation Process ◽

Developmental Variation ◽

Cortical Areas ◽

Brain Connectome ◽

Age Related ◽

High Incidence

How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14–24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial- and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence.

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Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

Frontiers in Neuroenergetics ◽

10.3389/fnene.2013.00002 ◽

2013 ◽

Vol 5 ◽

Cited By ~ 17

Author(s):

Michael Gejl ◽

Susanne Lerche ◽

Lærke Egefjord ◽

Birgitte Brock ◽

Niels Møller ◽

...

Keyword(s):

Human Brain ◽

Brain Glucose ◽

Hexokinase Activity ◽

Glucose Transfer ◽

Blood Brain ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Brain Metabolic Alterations in Rats Showing Depression-Like and Obesity Phenotypes

Neurotoxicity Research ◽

10.1007/s12640-019-00131-w ◽

2019 ◽

Vol 37 (2) ◽

pp. 406-424 ◽

Cited By ~ 1

Author(s):

Katarzyna Głombik ◽

Jan Detka ◽

Joanna Góralska ◽

Anna Kurek ◽

Bogdan Solnica ◽

...

Keyword(s):

Frontal Cortex ◽

Prenatal Stress ◽

High Fat Diet ◽

Current Data ◽

High Fat ◽

Metabolic Disturbances ◽

Animal Model Of Depression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

AbstractCurrent data suggest an important role of brain metabolic disturbances in the pathogenesis of depression and obesity, diseases that frequently co-occur. Our aim was to determine whether there are changes in markers characterizing glucose metabolism in prenatal stress (PS; animal model of depression), in rats fed a high-fat diet (HFD), and especially in the model of depression and obesity co-occurrence. The changes in glucose-6-phosphate, glycogen, glucose transporters (GLUT1, GLUT4), glucagon-like peptide-1 receptor (GLP-1R), and mitochondrial complexes levels in the frontal cortex and/or hippocampus were observed. In the case of the coexistence of depression and obesity, the most important changes were (1) the decrease in the membrane form of GLUT4, which may suggest weaker insulin action in the frontal cortex, and (2) the diminished GLP-1R, which could cause neurodegenerative changes in the hippocampus. However, presented results suggested that HFD weakened the PS effect of uncoupling oxidative phosphorylation in the frontal cortex.

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Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats.

Journal of Clinical Investigation ◽

10.1172/jci119482 ◽

1997 ◽

Vol 99 (12) ◽

pp. 2883-2889 ◽

Cited By ~ 117

Author(s):

Y Wang ◽

R Perfetti ◽

N H Greig ◽

H W Holloway ◽

K A DeOre ◽

...

Keyword(s):

Glucose Tolerance ◽

Age Related ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Lipoproteins and Cardiovascular Disease: An Update on the Clinical Significance of Atherogenic Small, Dense LDL and New Therapeutical Options

Biomedicines ◽

10.3390/biomedicines9111579 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1579

Author(s):

Ali A. Rizvi ◽

Anca Pantea Stoian ◽

Andrej Janez ◽

Manfredi Rizzo

Keyword(s):

Cardiovascular Disease ◽

Cardiometabolic Risk ◽

Treatment Options ◽

Low Density Lipoproteins ◽

Lipid Lowering ◽

Small Dense Ldl ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Therapeutical Options ◽

Pathophysiologic Mechanisms

Dyslipidemia is a potent risk factor for the genesis and progression of cardiovascular disease (CVD), and both the concentration and type of low-density lipoproteins (LDL) augment this association. The small, dense LDL (sdLDL) subfraction is the subtype which is most strongly predictive of atherosclerosis and cardiovascular events. In addition to the traditionally available lipid-lowering treatment options, certain novel therapies have been shown to favorably impact sdLDL, among them the antidiabetic class of agents known as glucagon-like peptide 1 receptor agonists (GLP1-RAs). These drugs seem to alter the pathophysiologic mechanisms responsible for the formation and accumulation of atherogenic lipoprotein particles, thus potentially reducing cardiovascular outcomes. They represent a uniquely targeted therapeutic approach to reduce cardiometabolic risk and warrant further study for their beneficial nonglycemic actions.

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SUN-602 Weight Loss After Glucagon-Like Peptide-1 Receptor Agonist Treatment in Childhood Obesity with Diabetes and Cirrhosis Associated with a Homozygous MC4R Mutation

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.611 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Philippe Klee ◽

Mirjam Dirlewanger ◽

Valérie McLin ◽

Maria Teresa Carminho ◽

Valerie M Schwitzgebel

Keyword(s):

Liver Transplantation ◽

Weight Loss ◽

Pulmonary Hypertension ◽

Portal Hypertension ◽

Treatment Options ◽

Liver Fat ◽

Loss Of Function ◽

Induce Weight Loss ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Background Mutations in the melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity. Treatment options are limited but glucagon-like peptide-1 receptor agonists (GLP-1 RA) may be of use to induce weight loss. Methods Exome of the patient was captured using the Agilent SureSelect QXT Human All Exon V5 kit and sequenced on Illumina. Clinical findings and results We report obesity-associated diabetes and cirrhosis in a 13-year girl born from consanguineous parents of Afghan origin. Past medical history revealed mild mental retardation and excessive weight gain since infancy. Linear growth was normal. Her father was obese and no diabetes was found in the family. The girl was initially investigated for hoarseness and found to have pulmonary hypertension, later accepted to be secondary to cirrhosis and portal hypertension. Physical examination revealed obesity (BMI 34.9kg/m2) and acanthosis nigricans. Blood exams showed leucopenia and thrombocytopenia without anemia, compatible with portal hypertension. Chest CT revealed important dilatation of the pulmonary arteries, a nodular liver and splenomegaly. Liver biopsy confirmed cirrhosis. An extensive workup including whole exome sequencing identified a homozygous MC4R variant [NM_005912.2 (MC4R): c.63_64del, p.(Tyr21*)], classified as pathogenic according to the ACMG guidelines. Both parents were heterozygous for this variant. An endocrinological workup showed insulin resistance with a HOMA-IR index of 7.27 and diabetes with peak blood glucose of 11.5mmol/l. HbA1c was 5.1% (32mmol/mol). Thyroid tests, leptin, proinsulin levels (3.5pmol/l, n <11.0pmol/l) were normal. The mutation being homozygous with a predicted complete loss of function (https://www.mc4r.org.uk/), no treatment with a MC4R agonist was tried. At the age of 15 years (BMI 36.0kg/m2), the patient underwent liver transplantation because of progressive portal hypertension and to halt the progression of pulmonary hypertension. At the age of 16 years (BMI 33.2kg/m2, HbA1c 4.9% (30.0 mmol/mol), HOMA-IR 5.3) a treatment with GLP-1 RA (liraglutide) was started at a dosage of 0.6mg and progressively increased to 3mg, in an attempt to induce weight loss, avoid the accumulation of liver fat and to protect the graft. GLP-1 RA is supposed to exerts its effects on appetite independently of the MC4R pathway. 2 months after liraglutide introduction, no side effects, a weight loss of 4kg and a decrease of appetite were observed (BMI 31.6kg/m2, HbA1c 4.5% (26mmol/mol), HOMA-IR 3.14). Conclusion Obesity-associated MCR4 mutations, in homozygous state, may lead to diabetes, liver cirrhosis and porto-pulmonary hypertension. Treatment options are scarce, but GLP-1 RA seem to have a rapid, positive effect on weight and metabolic control. Would earlier treatment have prevented progression to end-stage-liver disease and need for liver transplantation?

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