Effect of Weight Loss Surgery on Stem Cells.

October 16, 2019 updated by: Subodh Verma, Unity Health Toronto

Impact of Bariatric Surgery on Circulating Inflammatory and Pro-vascular Progenitor Cell Populations.

Obesity and diabetes are linked to increased risk for health problems such as heart attack, stroke, and death. At the cellular level, obesity and diabetes increase levels of harmful inflammatory cells (M1 macrophages) and decreases levels of protective stem cells (circulating progenitor cells) in the blood.

Bariatric (weight loss) surgery is an effective treatment that leads to significant weight loss and improved health in patients with obesity. However, it is unknown if weight loss surgery also replenishes healthy stem cells and decreases inflammatory cells in the body. Therefore, the purpose of this research study is to compare levels of these stem and inflammatory cells before and after bariatric surgery, and to compare to a control group of healthy normal weight participants.

The investigators anticipate that inflammatory cell levels will be reduced and stem cell levels and function will be restored after bariatric surgery, similar to levels of healthy normal weight individuals.

Study Overview

Detailed Description

The escalating pandemics of obesity and type 2 diabetes mellitus (T2DM) are among the most devastating health crises worldwide. The prevalence of obesity (body mass index (BMI) > 30kg/m^2) is nearly 1 billion individuals worldwide and estimated by the Center for Disease Control at 37.7 percent of the adult population in the United States. The International Diabetes Federation estimates that over 400 million individuals worldwide have T2DM and this number is expected to increase to over 600 million by the year 2040. Diet, exercise, and medications such as metformin have long been the cornerstone of T2DM therapy. Unfortunately, long-term success in the control of T2DM remain disappointing, and even with new medications such as glucagon-like peptide-1 (GLP-1) analogues (Liraglutide) and sodium-glucose co-transporter 2 (SGLT2) inhibitors (Gliflozins), adequate glycemic control remains elusive. Ultimately, T2DM patients will develop severe cardiovascular complications such as peripheral artery disease, heart attack, and stroke. Due to aging population demographics, and the paucity of curative therapies in this area, the prevalence and economic burden of obesity and T2DM is on the rise. Currently, the costs of medical care for obesity-related illnesses in the United States are estimated at $147 - 185 billion per year. Therefore, the search for curative therapies to combat obesity and T2DM are continually sought.

Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, and improved metabolic health. Permanent loss of 20-25 percent body weight (35 - 45 kilograms) is common for patients receiving Roux-en-y Gastric Bypass (RYGB) or Vertical Sleeve Gastrectomy (VSG) compared to <5 percent in best non-surgical medical therapy patients. The mechanisms of weight loss following bariatric surgery are multifactorial and include changes in food intake, satiety, alterations in gut hormones and bile acid adaptations. Such drastic weight loss is also associated with improvement in chronic inflammatory diseases, including atherosclerosis and T2DM. Indeed, bariatric surgery leads to improved glycemic control and potential remission of T2DM. Recently, studies have independently reported significant reductions in fasting blood glucose and glycated hemoglobin (HbA1C) in >80 percent of patients receiving bariatric surgery. Amelioration of T2DM commonly occurs within days to weeks of surgery even before substantial weight loss is observed. Finally, adverse cardiovascular events, usually associated with obesity and T2DM, were reduced after bariatric surgery compared to conventional therapies. Despite these phenomenal successes, the mechanisms governing the reversal of diabetes after bariatric surgery remains largely unknown.

Obesity, atherosclerotic plaque formation and the development of T2DM are all associated with heightened inflammation. Obesity involves increases in inflammatory immune cells (M1 macrophages) that are present during the remodeling of adipose tissue. In functional opposition to heightened immunity is the reparative role of tissue-specific stem cells. Central to all regenerative processes, stem cells can be found within every tissue in the body with the capacity to self-renew, and to generate new cell types that promote tissue maintenance or repair. In this capacity, stem cells can be considered "conductors of the orchestra" that co-ordinate the myriad cells and signals involved in the regenerative response. However, during chronic diseases such as T2DM, relentless inflammation and oxidative damage results in stem cell depletion and dysfunction, and the severity of injury overwhelms the capacity to respond. For example, adipose tissue contains a heterogenous mixture of stem and progenitor cells which are likely affected by the inflammation associated with obesity. Similarly, circulating hematopoietic and endothelial progenitor cells, involved in blood vessel maintenance and repair, show aberrant secretory and vessel formative functions that are negatively impacted by chronic hyperlipidemia and hyperglycemia. This concept termed "stem cell exhaustion" is becoming increasingly recognized during chronic diseases, as circulating stem and progenitor cell number and/or regenerative function is altered by the inflammatory environment within obesity/T2DM patients.

What remains unclear is whether reduced circulating stem cell number or aberrant regenerative function can be restored following bariatric surgery. The investigators have recently established novel methodologies to assess inflammatory status (M1 / M2 macrophage status) and circulating progenitor cell content and function by performing detailed flow cytometric analyses using aldehyde dehydrogenase (ALDH, a detoxification enzyme and conserved stem cell function) in combination with cell surface marker analyses. Notably, the investigators have shown that circulating progenitor cell content and inflammatory M1 macrophage content are increased in patients with T2DM compared to age-matched healthy controls. For the first time, the effectiveness of bariatric surgery at the cellular level can be evaluated and regenerative stem cell functions that impact obesity and T2DM can be explored. Elucidating the status of stem cells following bariatric surgery will provide insight into the likelihood of T2DM relapse or reverting to an obese state and provide a potential mechanism for the improvements in cardiovascular health. This study will be able to establish a relationship between the reversal of obesity, T2DM and adverse cardiovascular events with the restoration of regenerative stem cell associated with anti-inflammatory and pro-angiogenic function.

The investigators hypothesize that bariatric surgery will augment circulating, pro-vascular progenitor cell content and will reduce systemic inflammation via restoration of M1 / M2 macrophage balance.

Study Type

Observational

Enrollment (Actual)

38

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Ontario
      • Toronto, Ontario, Canada, M5B 1W8
        • St. Michael's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Community Sample/Residents mainly from the Greater Toronto Area.

Description

Inclusion Criteria:

  • Individuals undergoing bariatric surgery
  • Must be able to provide two visits, before and after surgery

Exclusion Criteria:

  • Unable to provide written consent
  • Unable to provide two visits for blood collection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Normal weight control
Individuals who are generally healthy and have a body mass index less than 25 kg/m^2.
Bariatric Surgery Group
Individuals electing to undergo bariatric surgery (generally with a body mass index between 35 and 40 kg/m^2 with an additional co-morbidity such as type 2 diabetes, or individuals with a body mass index greater than 40 kg/m^2) and who are willing to participate for 2 visits, one before and one after surgery. The intervention in this group is bariatric surgery.
Surgical intervention for weight reduction, whereby the stomach is resected and the gastrointestinal tract is rerouted in the case of Roux-en-y gastric bypass, or the stomach is only resected in the case of sleeve gastrectomy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in the frequency of circulating cells with aldehyde dehydrogenase activity.
Time Frame: Baseline and after surgery, 3-4 months
Baseline and after surgery, 3-4 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in the frequency of circulating cells with aldehyde dehydrogenase activity and cell surface marker expression.
Time Frame: Baseline and after surgery, 3-4 months
Baseline and after surgery, 3-4 months

Other Outcome Measures

Outcome Measure
Time Frame
Changes in the concentration of oxidative stress and inflammatory markers
Time Frame: Baseline and after surgery, 3-4 months
Baseline and after surgery, 3-4 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Subodh Verma, MD, Unity Health Toronto
  • Principal Investigator: David A Hess, PhD, Robart's Research Institute, London, Ontario

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2018

Primary Completion (Actual)

June 25, 2019

Study Completion (Actual)

August 13, 2019

Study Registration Dates

First Submitted

October 10, 2019

First Submitted That Met QC Criteria

October 16, 2019

First Posted (Actual)

October 18, 2019

Study Record Updates

Last Update Posted (Actual)

October 18, 2019

Last Update Submitted That Met QC Criteria

October 16, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All IPD that underlie results in a publication

IPD Sharing Time Frame

Starting 6 month following publication.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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