Intestinal Metabolic Reprogramming as a Key Mechanism of Gastric Bypass in Humans
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Obesity Weight Loss, Endocrine, Endocrine, Diabetes, Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 10/7/2018 |
| Start Date: | February 2016 |
| End Date: | September 2020 |
The purpose of this research study is to determine how gastric bypass surgery effects
metabolism in obesity and Type 2 Diabetes. One mechanism that has been investigated in animal
models is change to the biology of the small intestine (Roux limb) and how glucose and other
fuels are metabolized (or how the body digests and uses sugar and other fuels). This study
will evaluate the role of the intestine in the beneficial metabolic effects of gastric bypass
surgery. It specifically will examine whether the intestine increases its metabolism and its
activity, and whether this results in an increase in fuel utilization. Thirty two (32)
subjects will be recruited (18 with and 14 without Type 2 Diabetes). At the time of gastric
bypass surgery, a small piece of intestine that is usually discarded will be collected. At
three time points over the first year after surgery, intestinal samples will be obtained by
endoscopy or insertion of a lighted flexible tube through the mouth. Blood samples will be
taken at all time points, as well. All samples will undergo comprehensive metabolic analyses.
Comparisons will be made between the two groups to understand the metabolic changes over time
and if there are differences between the two groups.
metabolism in obesity and Type 2 Diabetes. One mechanism that has been investigated in animal
models is change to the biology of the small intestine (Roux limb) and how glucose and other
fuels are metabolized (or how the body digests and uses sugar and other fuels). This study
will evaluate the role of the intestine in the beneficial metabolic effects of gastric bypass
surgery. It specifically will examine whether the intestine increases its metabolism and its
activity, and whether this results in an increase in fuel utilization. Thirty two (32)
subjects will be recruited (18 with and 14 without Type 2 Diabetes). At the time of gastric
bypass surgery, a small piece of intestine that is usually discarded will be collected. At
three time points over the first year after surgery, intestinal samples will be obtained by
endoscopy or insertion of a lighted flexible tube through the mouth. Blood samples will be
taken at all time points, as well. All samples will undergo comprehensive metabolic analyses.
Comparisons will be made between the two groups to understand the metabolic changes over time
and if there are differences between the two groups.
Several studies have concluded that Roux-en-Y gastric bypass surgery (RYGBS) is the best
current treatment option for obesity-related Type 2 Diabetes Mellitus (T2DM). The mechanisms
underlying RYGBS-induced improvement in glycemic control remain unclear. Many investigators
have advocated that this effect does not depend upon body weight loss, based on clinical
observations that improvement in glucose homeostasis occurs early in the postoperative
period, often prior to hospital discharge. Understanding the mechanisms underlying the
metabolic effects of RYGBS will help to engineer ways to improve RYGB or to produce these
effects without surgery.
This study will examine the concept of intestinal metabolic reprogramming as one of the key
mechanisms of action for diabetes improvement following Roux-en-Y gastric bypass surgery
(RYGBS) in humans. It is hypothesized that the reconfigured intestine is characterized by an
increase in energetically expensive processes, such as structural remodeling, cytoskeletal
reorganization, and cellular proliferation. To accommodate the increased bioenergetics
demands, the intestinal epithelium increases its metabolic activity and reprograms its fuel
utilization. Specifically, glucose, cholesterol and amino acid metabolism are all
dramatically altered to increase anabolic pathways and generate building blocks for cellular
growth and maintenance.
It has not previously been possible to test this hypothesis in humans as: A) the adaptive
processes of the intestine in patients undergoing RYGBS have not been thoroughly
characterized, B) it is not known whether the intestinal reprogramming appears early enough
to explain the prompt improvement in glucose metabolism observed after RYGBS in humans, and
C) the variability of the degree of intestinal metabolic adaptation, which could account for
the variability in remission of T2DM, has not been studied. This study will perform a
longitudinal, comprehensive metabolic analysis of the Roux limb in human subjects with and
without T2DM undergoing RYGBS and determine the time course of the adaptive metabolic
changes.
Eighteen (18) subjects with and fourteen (14) subjects without T2DM (total 32 subjects), who
have been scheduled to undergo RYGBS as standard of care, will be recruited. For each
enrolled subject, data collection will include an intestinal tissue sample (Roux limb tissue
sampling from discarded tissue) at the time of RYGBS, from the mucosa of the jejunum, within
40 cm from the gastrojejunal anastomosis. Postoperatively, tissue sampling from the same area
will be performed by an Upper GI endoscopy, at 1 month (±15 days), 6 months (±1 month) and 12
months (±2 months) after RYGBS. Tissue samples will be processed for histo-morphological
examination and for RNA, protein and metabolomics analyses. A blood sample will be obtained
at all time points and analyzed for metabolic biomarkers. Data analysis will include
description and comparison of the morphological, gene protein and metabolite signatures of
the intestinal (Roux limb) tissue and the blood biomarkers from each time point.
Additionally, these outcome measures will be compared between the two groups (T2DM and
Non-T2DM). Finally, a correlation of the intestinal adaptive changes with metabolic status,
some eating behaviors, adverse symptomatology, and quality of life will be undertaken.
current treatment option for obesity-related Type 2 Diabetes Mellitus (T2DM). The mechanisms
underlying RYGBS-induced improvement in glycemic control remain unclear. Many investigators
have advocated that this effect does not depend upon body weight loss, based on clinical
observations that improvement in glucose homeostasis occurs early in the postoperative
period, often prior to hospital discharge. Understanding the mechanisms underlying the
metabolic effects of RYGBS will help to engineer ways to improve RYGB or to produce these
effects without surgery.
This study will examine the concept of intestinal metabolic reprogramming as one of the key
mechanisms of action for diabetes improvement following Roux-en-Y gastric bypass surgery
(RYGBS) in humans. It is hypothesized that the reconfigured intestine is characterized by an
increase in energetically expensive processes, such as structural remodeling, cytoskeletal
reorganization, and cellular proliferation. To accommodate the increased bioenergetics
demands, the intestinal epithelium increases its metabolic activity and reprograms its fuel
utilization. Specifically, glucose, cholesterol and amino acid metabolism are all
dramatically altered to increase anabolic pathways and generate building blocks for cellular
growth and maintenance.
It has not previously been possible to test this hypothesis in humans as: A) the adaptive
processes of the intestine in patients undergoing RYGBS have not been thoroughly
characterized, B) it is not known whether the intestinal reprogramming appears early enough
to explain the prompt improvement in glucose metabolism observed after RYGBS in humans, and
C) the variability of the degree of intestinal metabolic adaptation, which could account for
the variability in remission of T2DM, has not been studied. This study will perform a
longitudinal, comprehensive metabolic analysis of the Roux limb in human subjects with and
without T2DM undergoing RYGBS and determine the time course of the adaptive metabolic
changes.
Eighteen (18) subjects with and fourteen (14) subjects without T2DM (total 32 subjects), who
have been scheduled to undergo RYGBS as standard of care, will be recruited. For each
enrolled subject, data collection will include an intestinal tissue sample (Roux limb tissue
sampling from discarded tissue) at the time of RYGBS, from the mucosa of the jejunum, within
40 cm from the gastrojejunal anastomosis. Postoperatively, tissue sampling from the same area
will be performed by an Upper GI endoscopy, at 1 month (±15 days), 6 months (±1 month) and 12
months (±2 months) after RYGBS. Tissue samples will be processed for histo-morphological
examination and for RNA, protein and metabolomics analyses. A blood sample will be obtained
at all time points and analyzed for metabolic biomarkers. Data analysis will include
description and comparison of the morphological, gene protein and metabolite signatures of
the intestinal (Roux limb) tissue and the blood biomarkers from each time point.
Additionally, these outcome measures will be compared between the two groups (T2DM and
Non-T2DM). Finally, a correlation of the intestinal adaptive changes with metabolic status,
some eating behaviors, adverse symptomatology, and quality of life will be undertaken.
Inclusion Criteria:
- Patients who elect to undergo gastric bypass surgery
- Standard bariatric surgery criteria (A BMI 35 to 40 kg/m2, with an obesity comorbid
condition, OR BMI 40 kg/m2 or >).
Exclusion Criteria:
- Prior bariatric or foregut surgery
- Documented history of Type 1 Diabetes
- Poor overall general health
- Impaired mental status
- Drug and/or alcohol addiction
- Currently smoking
- Pregnant or plans to become pregnant
- Portal hypertension and/or cirrhosis
We found this trial at
1
site
300 Halket St.
Pittsburgh, Pennsylvania 15213
Pittsburgh, Pennsylvania 15213
1-866-MyMagee (696-2433)
Magee-Womens Hospital of UPMC Magee-Womens Hospital of UPMC is a world-class center for both women's...
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