Splanchnic Blood Redistribution After Incretin Hormone Infusion and Obesity Surgery
Condition: Type 2 Diabetes; Obesity
MeSH terms: Obesity; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 1

Summary: 
      Obesity is a worldwide problem and leads to multiple metabolic and endocrinological problems.

      Bariatric surgeries are a growing field as a treatment choice for morbid obesity (BMI > 35
      kg/m2). Clinical and research evidence shows that shortly after RYGB, T2DM resolves with
      improving glucose tolerance. Foregut hypothesis behind bariatric surgeries postulate, that
      bypassed portions of intestine contain a substance, that acts as an anti-incretin, ie. to
      counteract metabolically favourable incretins. In view of the recent studies, it may be that
      GIP is really the anti-incretin behind this hypothesis.

      The current study is conducted to investigate the vasoactive roles of the GIP. The
      investigators aim to show that GIP is the major contributor to the blood flow and tissue
      blood volume observed in postprandial state.
    

Detailed description: 
      Obesity is a worldwide problem and leads to multiple metabolic and endocrinological problems,
      including type 2 diabetes mellitus (T2DM). In T2DM, body is unable to response to circulating
      insulin levels, which ultimately destroys pancreatic β-cells, leading to chronic
      hyperglycaemia with ensuing consequences

      Intestine is able to produce endocrinologically active substances, which affect to body's
      intermediary metabolism. One of these substances in glucose-dependent insulinotrophic
      polypeptide (GIP, part of the incretin family), which potentiates the release of insulin
      postprandially. However, recent evidence suggests, that GIP may have more harmful than
      beneficial role in the pathogenesis: it has been shown that GIP participates in the
      development of insulin resistance, the key defect in the process of metabolic dysfunction.
      GIP may also regulate postprandial redistribution of splanchnic blood flow which might act in
      the body's nutrition handling [8].

      Bariatric surgeries are a growing field as a treatment choice for morbid obesity (BMI > 35
      kg/m2). Most established of these procedures is a Roux-en-Y gastric bypass (RYGB), where
      duodenum and proximal jejunum is bypassed. Clinical and research evidence shows that shortly
      (before any significant weight loss) after RYGB, T2DM resolves with improving glucose
      tolerance. Foregut hypothesis behind bariatric surgeries postulate, that bypassed portions of
      intestine contain a substance, that acts as an anti-incretin¬, ie. to counteract
      metabolically favourable incretins. In view of the recent studies, it may be that GIP is
      really the anti-incretin behind this hypothesis.

      Positron emission tomography (PET) is a modern imaging technique, which can be used to study
      perfusion and metabolism of different organs non-invasively. When radiowater measurement is
      combined with [15O]CO, both tissues specific perfusion and blood volume can be measured,
      respectively. When coupled with magnetic imaging (ie. PET-MRI), the volumes-of-interests can
      be accurately drawn to the desired organs.

      The current study is conducted to investigate the vasoactive roles of the GIP. We aim to show
      that GIP is the major contributor to the blood flow and tissue blood volume observed in
      postprandial state. Moreover, we hypothesize that the elimination of GIP-effect has a central
      role in the improved intermediary metabolism observed after bariatric surgery procedures, and
      that part this change is mediated by changes in splanchnic circulation. Furthermore, we
      investigate the effect of GLP-1 (glucagon-like peptide 1, another member of incretin family)
      on splanchnic circulation.

      In the present study intestinal, hepatic and pancreatic blood flow and volume are measured
      using [15O]H2O- and [15O]CO radiotracers and PET-MRI imaging in healthy normal weight
      volunteers (n = 20, BMI ≤ 27 kg/m2) and in morbidly obese T2DM patients (n = 30, BMI ≤ 35
      kg/m2) before and after the bariatric surgery operation. The PET imaging will be performed at
      fasting state but also separately either during 1) mixed meal solution (MMS), 2) GIP-, or 3)
      GLP-1-infusion. Also abdominal subcutaneous and visceral adipose tissue, intestinal and
      hepatic tissue samples will be collected.
    

Intervention name(s): Roux-en-Y; GIP-infusion; GLP-1; MMS; Sleeve gastrectomy
Intervention type(s): Procedure; Drug; Drug; Drug; Procedure
Intervention description(s): Subjects in the intervention group will be divided into two consecutive surgical groups, RYGB or SG. After the surgery, subjects are controlled in hospital ward for approximately three days.; Blood flow and volume during infusion; Blood flow and volume during infusion; Blood flow and volume after meal solution; as in RYGS group
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: GIP; GLP-1; type 2 diabetes; obesity; splanchnic blood flow; incretin hormones