Primary ObjectiveTo validate biomarkers of response to bariatric surgery and to develop algorithms, which combine these variables, to predict individual responses. Secondary Objectives* To establish the predictive value of selected preoperative…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Appetite and general nutritional disorders
- Gastrointestinal therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are the preoperative blood samples and urine used for
GWAS analysis, urine samples will be collected to evaluate predictors of
response to surgery , based on results of GWAS analysis and omics analyses
performed in previous SOPHIA studies.
Secondary outcome
- To study the predictive value of the measured preoperative biomarkers
metabolic response and weight loss 3, 18 and 60 months after bariatric surgery.
Specifically, we will assess:
* pro- and anti-inflammatory circulating cytokines and chemokines
* fasting insulin and glucose to calculate insulin sensitivity index and HbA1C
* cardiorespiratory fitness and handgrip strength
* questionnaires to assess eating behavior and psychological traits
Metabolic response is defined as an improvement in insulin
sensitivty assessed by HOMA-IR.
- To get more mechanistic insight, the following metabolic assessment will be
performed after an overnight fast:
* Resting energy expenditure and substrate oxidation using indirect
calorimetry after an overnight fast and during the hyperinsulinemic euglycemic
clamp
* Assessment of hepatic and muscle tissue insulin sensitivity using a stable
isotope tracer (6,6 2H2 glucose) during a 2-step hyperinsulinemic euglycemic
clamp
* Assessment of adipose tissue insulin sensitivity by calculating the adipose
tissue insulin resistance index and by measuring the percentage suppression of
fatty acids during low dose insulin infusion (this method was previously
validated by our group)
* Assessment of the insulin signaling pathway in biopsies of skeletal muscle
and subcutaneous fat by measuring mRNA expression and phosphorylation of key
insulin signalling proteins
* Assessment of liver fat and NAFLD criteria, mRNA expression and
phosphorylation of the insulin signaling pathway as well as mRNA expression of
key components (transcription factors and enzymes) in the de novo lipogenesis
pathway in liver biopsies harvested during bariatric surgery
Background summary
Obesity is the result of a complex interplay between genetic and epigenetic
predisposition, environment, physical activity, nutrition and psychology. It is
a debilitating disorder and a risk factor for the development of metabolic
disorders such as dyslipidaemia, hypertension and hyperglycaemia as well as
certain cancers. Bariatric surgery has proven to be the most effective
treatment for morbid obesity with established long-term results of weight loss,
remission of comorbid conditions and the improvement of Quality of Life (QoL).
However, variability in these results after bariatric surgery is well known.
Identifying preoperative predictors of postoperative weight loss and metabolic
health is of clinical priority. Predictors could help further improve the
efficacy of care for obesity by tailoring treatment to the individual, based on
their predicted response and therefore optimize outcome after bariatric
surgery. This study is part of an international multicentre European research
project: SOPHIA (Stratification of Obese Phenotypes to Optimize Future Obesity
Therapy).
Study objective
Primary Objective
To validate biomarkers of response to bariatric surgery and to develop
algorithms, which combine these variables, to predict individual responses.
Secondary Objectives
* To establish the predictive value of selected preoperative biomarkers and
changes in biomarkers to predict metabolic response and weight loss 3, 18 and
60 months after bariatric surgery.
* To study changes in psychological factors (depression, anxiety, binge eating,
eating behavior, food craving, body image) and how these factors are associated
with weight loss, metabolic health and improvement of QoL 3, 18 and 60 months
after bariatric surgery.
* Assessment of hepatic, muscle and adipose tissue insulin sensitivity using
stable isotope tracers and assessment of insulin signaling pathways and protein
kinase C family in tissue biopsies.
* To determine the correlation of preoperative measured candidate predictors
with selected gene and protein expression (metabolic pathways involved in
substrate metabolism) in insulin sensitive tissues (liver, muscle and adipose
tissue) in a subset of 40 patients.
Study design
Prospective follow up cohort study.
Study burden and risks
Laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy surgery will be
performed following current procedure protocols and in accordance with Dutch
legislations (Wet op de Geneeskundige Behandelings Overeenkomst).
Hyperinsulinemic, euglycemic clamps have been performed by our research group
in multiple studies. The stable isotope [6,6-2H2]glucose is used as a tracer,
and has no radioactive properties. It behaves like its natural substrate and
has been previously used without adverse effects when infused in tracer
amounts47-50. During the hyperinsulinemic clamp there is a risk for
hypoglycaemia. This is minimized by close monitoring of plasma glucose levels
and adjustment of iv glucose, every 5-10 minutes
Surgery will be performed according to standard procedures and current
guidelines by an experienced surgeon. During the surgery, biopsies will be
taken from the liver, muscle and adipose tissue compartments in the subset of
subjects. The number and volume of tissue biopsies will be kept to a minimum.
Earlier studies in our group showed that these procedures are safe and were
without adverse events.
Possible adverse events related to these procedures are damage to surrounding
organs, increased infection risk, pain at biopsy site, and local hematoma and
bleeding from the sample site. It should be stated, however, that these adverse
events have been described for percutaneous biopsy of abdominal organs, and
that taking biopsies during surgery is safer than taking percutaneous biopsies:
* Biopsies are taken under direct vision; surrounding organs can be easily
spared;
* All procedures are performed under general anesthesia and under strict
sterile conditions in the operating room; there is no increased infection risk;
* There is no percutaneous entry site for liver and adipose tissue biopsies;
* The day(s) after the muscle biopsies, participants will experience a sore
feeling at the biopsy location. Local hemostasis can be checked directly after
the biopsy and during the surgery: in case of bleeding from the sample site
(0.1 to 1% for percutaneous liver biopsy), the surgeon can control this easily
and under direct vision.
To further minimize the risk, subjects that use anticoagulants or have
coagulation disorders will be excluded from the subgroup and surgeons will
check for local hemostasis twice.
It has to be stated that the operative procedure itself is not part of the
protocol, but regular patient care.
Placing intravenous cannulas for study purposes can be an unpleasant experience
for the subjects. There is a low risk of phlebitis at the intravenous injection
sites, this is unpleasant, but not harmful, of temporary nature and
self-limiting.
The hyperinsulinemic, euglycemic clamps are generally well tolerated
Meibergdreef 30
Amsterdam 1105AZ
NL
Meibergdreef 30
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
* Ability to provide informed consent
* Patient is >= 18 and <= 75 years old
* BMI >= 40 kg/m2 or >= 35 kg/m2 with obesity related comorbidity
* Scheduled for primary bariatric procedure: Roux-en-Y gastric bypass (RYGB) or
Sleeve Gastrectomy (SG)
* Stable weight 3 months prior to inclusion weight (<10% change in body weight
for 3 months prior to assessments)
In order to be eligible to participate in the subgroup of this study, we will
use the following inclusion criteria:
* We will include only patients who will undergo RYGB;
* Patients who are insulin resistant (impaired fasting glucose (> 5.6 mmol/L)
or fasting insulin > 74 pmol/L)
* Postmenopausal women (to prevent bias due to the effect of sex homones on
insulin sensitivity)
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
* Patients who do not understand the patient information letter
* Any actual medical condition except for obesity related health issues or well
treated hypothyroidism
* Pregnancy anticipated in the first two years following surgery
A potential subject who meet the following criteria will be excluded from
participation in the subgroup of this study:
* Coagulation disorders and/or use anticoagulants
* Use of any medication except for statins, antihypertensives (except for ACE-
or angiotensin receptor blockers) and thyroid hormone
* Diabetes mellitus type 2
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| CCMO | NL77692.018.21 |