Effect of Weight Loss Surgery on Stem Cells.
Condition: Obesity, Morbid; Stem Cells; Cardiovascular Morbidity
MeSH terms: Obesity, Morbid
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Bariatric (weight loss) surgery
Intervention type(s): Procedure
Intervention description(s): 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.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Community Sample/Residents mainly from the Greater Toronto Area.
      
Biospecimen description: 
      Serum was collected and stored.
    
Keywords: Stem Cells; Obesity; Cardiovascular Events; Type 2 Diabetes