Clinical Trial: Intestinal Metabolic Reprogramming as a Key Mechanism of Gastric Bypass in Humans

Study Status: Enrolling by invitation
Recruit Status: Enrolling by invitation
Study Type: Observational

Official Title: Intestinal Metabolic Reprogramming as a Key Mechanism of Gastric Bypass in Humans

Brief Summary: 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.

Detailed Summary:

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 variabi
Sponsor: University of Pittsburgh

Current Primary Outcome:

  • Description of intestinal morphology. [ Time Frame: Baseline, at time of operation ]
    Histology and electron microscopy will be used to assess cellular architecture, brush border, cytoskeleton and junctions, and the size and shape of organelles.
  • Description of intestinal morphology. [ Time Frame: 1 month after surgery. ]
    Histology and electron microscopy will be used to assess cellular architecture, brush border, cytoskeleton and junctions, and the size and shape of organelles.
  • Description of intestinal morphology. [ Time Frame: 6 months after surgery. ]
    Histology and electron microscopy will be used to assess cellular architecture, brush border, cytoskeleton and junctions, and the size and shape of organelles.
  • Description of intestinal morphology. [ Time Frame: 12 months after surgery. ]
    Histology and electron microscopy will be used to assess cellular architecture, brush border, cytoskeleton and junctions, and the size and shape of organelles.
  • Characterization of gene and protein expression of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways. [ Time Frame: Baseline, at time of operation. ]
    Gene expression (RT-PCR) and protein expression (western blotting) for about 100 markers of cellular proliferation (e.g., cyclins, MKi67, PCNA), cytoskeletal remodeling (e.g., brush border enzymes and proteins), cellular machinery of glucose and cholesterol

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Comparison of intestinal morphology signature between patients with and without diabetes. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
    • Comparison of gene and protein expression profiles and levels of expression of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways between patients with and without diabetes. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
    • Comparison of metabolite profile between patients with and without diabetes. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
    • Correlation of intestinal morphology signature with eating behaviors. Assessed by specific questionnaire. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Morphology as described in Primary Measures 1 - 4 correlated with eating behaviors as obtained and described by the Eating and Weight History Form (EWH).
    • Correlation of eating behaviors with gene and protein expression of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways. Assessed by specific questionnaire. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Gene and protein expression of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways as described in Primary Measures 5 - 8 correlated with eating behaviors as obtained and described by the Eating and Weight History Form (EWH).
    • Correlation of metabolite profile with eating behaviors. Assessed by specific questionnaire. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Intestinal and serum/plasma metabolite profiling as described in primary outcomes 9 - 12 correlated with eating behaviors as obtained and described by the Eating and Weight History Form (EWH).
    • Correlation of intestinal morphology signature with quality of life assessed by SF-36 Instrument. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Morphology as described in Primary Measures 1 - 4 correlated with quality of life as measured by the SF-36 Instrument (total and subscales).
    • Correlation of quality of life assessed by SF-36 Instrument with gene and protein expression for markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Gene and protein expression of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways as described in Primary Measures 5 - 8 correlated with quality of life as measured by the SF-36 Instrument (total and subscales).
    • Correlation of metabolite profile with quality of life assessed by SF-36 Instrument. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Intestinal and serum/plasma metabolite profiling as described in primary outcomes 9 - 12 correlated with quality of life as measured by the SF-36 Instrument (total and subscales).
    • Correlation of intestinal morphology signature with adverse symptomatology (e.g., Dumping syndrome, Hypoglycemia). Assessed by specific questionnaires. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Morphology as described in Primary Measures 1 - 4 correlated with dumping syndrome characteristics as defined on the Sigstad Clinical Diagnostic Index and the Gastrointestinal and Neurological Symptom Form and hypoglycemic symptoms as described on the Glycemic Symptom Form.
    • Correlation of adverse symptomatology (Dumping syndrome, Hypoglycemia) with gene/protein expression of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Gene and protein expression levels of markers of cellular proliferation, cytoskeletal remodeling, and cellular machinery of glucose and cholesterol metabolic pathways as described in Primary Measures 5 - 8 correlated with dumping syndrome characteristics as defined on the Sigstad Clinical Diagnostic Index and the Gastrointestinal and Neurological Symptom Form and hypoglycemic symptoms as described on the Glycemic Symptom Form.
    • Correlation of metabolite profile with adverse symptomatology (e.g., Dumping syndrome, Hypoglycemia). Assessed by specific questionnaires. [ Time Frame: Baseline (0 months) and 1 month, 6 months and 12 months post-surgery. ]
      Intestinal and serum/plasma metabolite profiling as described in primary outcomes 9

      Original Secondary Outcome: Same as current

      Information By: University of Pittsburgh

      Dates:
      Date Received: February 5, 2016
      Date Started: February 2016
      Date Completion: September 2020
      Last Updated: May 4, 2017
      Last Verified: May 2017