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Lessons from bariatric surgery: Can increased GLP-1 enhance vascular repair during cardiometabolic-based chronic disease?

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Abstract

Type 2 diabetes (T2D) and obesity represent entangled pandemics that accelerate the development of cardiovascular disease (CVD). Given the immense burden of CVD in society, non-invasive prevention and treatment strategies to promote cardiovascular health are desperately needed. During T2D and obesity, chronic dysglycemia and abnormal adiposity result in systemic oxidative stress and inflammation that deplete the vascular regenerative cell reservoir in the bone marrow that impairs blood vessel repair and exacerbates the penetrance of CVD co-morbidities. This novel translational paradigm, termed ‘regenerative cell exhaustion’ (RCE), can be detected as the depletion and dysfunction of hematopoietic and endothelial progenitor cell lineages in the peripheral blood of individuals with established T2D and/or obesity. The reversal of vascular RCE has been observed after administration of the sodium-glucose cotransporter-2 inhibitor (SGLT2i), empagliflozin, or after bariatric surgery for severe obesity. In this review, we explore emerging evidence that links improved dysglycemia to a reduction in systemic oxidative stress and recovery of circulating pro-vascular progenitor cell content required for blood vessel repair. Given that bariatric surgery consistently increases systemic glucagon-like-peptide 1 (GLP-1) release, we also focus on evidence that the use of GLP-1 receptor agonists (GLP-1RA) during obesity may act to inhibit the progression of systemic dysglycemia and adiposity, and indirectly reduce inflammation and oxidative stress, thereby limiting the impact of RCE. Therefore, therapeutic intervention with currently-available GLP-1RA may provide a less-invasive modality to reverse RCE, bolster vascular repair mechanisms, and improve cardiometabolic risk in individuals living with T2D and obesity.

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Abbreviations

AGE:

Advanced Glycation End Product

ALDH:

Aldehyde Dehydrogenase

BMI:

Body Mass Index

CNS:

Central Nervous System

CRP:

C-Reactive Protein

CV:

Cardiovascular

CVD:

Cardiovascular Disease

DPP4:

Dipeptidyl Peptidase 4

eNOS:

Endothelial Nitric Oxide Synthase

EC:

Endothelial Cell

EPC:

Endothelial Progenitor Cell

GLP-1:

Glucagon-like Peptide 1

GLP-1R:

Glucagon-like Peptide 1 Receptor

GLP-1RA:

Glucagon-like Peptide 1 Receptor Agonist

HbA1c:

Glycated Hemoglobin

HPC:

Hematopoietic Progenitor Cell

HUVEC:

Human Umbilical Vein Endothelial Cell

iNOS:

Inducible Nitric Oxide Synthase

MI:

Myocardial Infarction

MPC:

Mesenchymal Progenitor Cell

NLRP3:

NOD-like Receptor, Pyrin domain-containing 3

NO:

Nitric Oxide

oxLDL:

Oxidized Low-Density Lipoprotein

RCE:

Regenerative Cell Exhaustion

RCT:

Randomized Controlled Trial

ROS:

Reactive Oxygen Species

RYGB:

Roux-en Y Gastric Bypass

SIRT1:

Sirtuin 1

SG:

Sleeve Gastrectomy

SSC:

Side Scatter

T2D:

Type 2 Diabetes

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Acknowledgements

The authors would like to thank M. G. Rudakevich MSc (BMC) of Synapse Visuals for generating the original illustrations. E.B. was the recipient of a University of Toronto Banting & Best Diabetes Centre-Novo Nordisk Studentship. S.V. has a Tier 1 Canada Research Chair in Cardiovascular Surgery. D.A.H. is the Sheldon H. Weinstein Chair in Diabetes Research at the Schulich School of Medicine, Western University.

Funding

This work was supported by funding from the Canadian Institutes of Health Research (CIHR) grant (MOP#378189). S.V. reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; he is also the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. No other authors have anything to disclose.

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Authors and Affiliations

  1. Division of Cardiac Surgery, St. Michael’s Hospital, Toronto, ON, Canada

    Ehab Bakbak, Daniella C. Terenzi, Justin Z. Trac, Hwee Teoh, Adrian Quan, Subodh Verma & David A. Hess

  2. Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON, Canada

    Mohammed Al-Omran

  3. Division of Endocrinology and Metabolism, St. Michael’s Hospital, Toronto, ON, Canada

    Hwee Teoh & Ori D. Rotstein

  4. Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada

    Ehab Bakbak, Daniella C. Terenzi, Justin Z. Trac, Hwee Teoh, Adrian Quan, Ori D. Rotstein, Mohammed Al-Omran, Subodh Verma & David A. Hess

  5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Ehab Bakbak, Justin Z. Trac, Mohammed Al-Omran, Subodh Verma & David A. Hess

  6. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Daniella C. Terenzi, Ori D. Rotstein, Mohammed Al-Omran & Subodh Verma

  7. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Mohammed Al-Omran & Subodh Verma

  8. Molecular Medicine Research Laboratories, Robarts Research Institute, London, ON, Canada

    David A. Hess

  9. Department of Physiology and Pharmacology, Western University, London, ON, Canada

    David A. Hess

  10. Department of Internal Medicine, Humber River Hospital, Toronto, ON, Canada

    Stephen A. Glazer

  11. Division of Endocrinology and Metabolism, Queen’s University, Kingston, ON, Canada

    Stephen A. Glazer

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S.V. reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; he is also the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. No other authors have anything to disclose.

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Glossary important terms:

Abnormal Adiposity:

the condition of being severely overweight or obese.

Advanced Glycation End Products (AGE):

Molecules formed by the non-enzymatic and irreversible reaction of reducing sugars and the amino group of a protein, lipid or nucleic acid. AGE levels are often elevated during hyperglycemia and contribute to chronic oxidative stress.

Aldehyde dehydrogenase (ALDH):

An intracellular enzyme that protects progenitor cells from oxidative stress and alkylating agents. As progenitor cells differentiate and mature, ALDH expression decreases.

Atherosclerosis:

an inflammatory disease of the arteries characterized by the deposition of plaques of fatty material on their inner walls.

Body-mass Index (BMI):

A measurement of an individuals’ weight in relation to their height. BMI is often used clinically to classify obesity and is defined as body mass divided by the square of an individual’s height [Kg/m2].

Diabesity:

A term used to describe the overlapping pathophysiology of diabetes and obesity. Although distinct metabolic conditions, diabetes and obesity share many common features such as increased systemic inflammation and oxidative stress.

Dipeptidyl Peptidase 4 (DPP4):

A ubiquitously expressed serum protease responsible for the N-terminal cleavage of bioactive substrates. Particularly, DPP4 is responsible for degradation of the incretin class of peptides such as GLP-1.

Endothelial Progenitor Cell (EPC):

As building blocks of new blood vessels, circulating EPC function facilitates vessel repair and are critical in the prevention of ischemic complications.

Glucagon-like Peptide 1 (GLP-1):

Belonging to the incretin family, this peptide hormone is secreted primarily by L-cells expressed throughout the gastrointestinal tract. GLP-1s primary function is to promote insulin secretion by β-cells, and inhibit glucagon secretion by α-cells of the pancreas.

Dysglycemia:

abnormality in blood glucose level stability.

Hematopoietic Progenitor Cell (HPC):

A multipotent cell line capable of differentiating into both myeloid, and lymphoid blood cell types. Their function is critical for promoting vessel repair and maintaining homeostasis..

Mesenchymal Progenitor Cell (MPC):

A multipotent cell line capable of differentiating into pericytes and smooth muscle cells. Once in the peripheral circulation, these cells envelop blood vessels, stabilize new capillaries and promote vascular integrity.

NOD-like Receptor, Pyrin Domain-containing 3 (NLRP3):

Expressed mostly in macrophages, this protein is a vital component of the NLRP3 inflammasome. Upon activation, the NLRP3 inflammasome catalyzes the activation of pro-inflammatory cytokines that modulate inflammation and apoptosis.

Reactive Oxygen Species (ROS):

A class of oxygen-containing, and highly reactive, free-radical produced as a product of mitochondrial oxidative phosphorylation. A buildup of ROS, characteristic of cardiometabolic disease, can result in cellular damage and promote systemic inflammation.

Regenerative Cell Exhaustion (RCE):

A state characterized by the depletion and dysfunction of pro-vascular progenitor cell, which ultimately results in decreased vessel repair. RCE is the result of chronic inflammation and oxidative stress and can be detected in the bone marrow of individuals with cardiometabolic disease.

Sodium Glucose Cotransporter-2 (SGLT2):

A transport protein found in the proximal tubule of the kidney. Inhibition of this transporter with pharmacological agents promotes glucose excretion, combatting hyperglycemia.

Type 2 Diabetes (T2D):

A metabolic condition characterized by glucotoxicity as a result of decreased insulin sensitivity and chronic hyperglycemia. T2D is an important risk factor for developing ischemic cardiovascular comorbidities.

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Bakbak, E., Terenzi, D.C., Trac, J.Z. et al. Lessons from bariatric surgery: Can increased GLP-1 enhance vascular repair during cardiometabolic-based chronic disease?. Rev Endocr Metab Disord 22, 1171–1188 (2021). https://doi.org/10.1007/s11154-021-09669-7

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