Splanchnic Blood Redistribution After Incretin Hormone Infusion and Obesity Surgery (GIP-PET)

The Effects of Glucose-dependent Insulinotrophic Peptide (GIP) and Glucagon-like Peptide 1 (GLP-1) on Splanchnic Redistribution of Blood Flow at Postprandial State and After Roux-en-Y Gastric Bypass and Sleeve

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: Procedure: Roux-en-Y; Drug: GIP-infusion; Drug: MMS; Drug: GLP-1; Procedure: Sleeve gastrectomy

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland, 20540
    • Turku univercity hospital, PET center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. BMI > 35 kg/m2
2. Type 2 diabetes mellitus (fasting glucose more than 7 mmol/l)
3. Age: 18-60 years
4. Previous, carefully planned, conservative treatments for obesity have failed

Exclusion Criteria:

1. BMI over 60 kg/m2
2. Weight more than 170 kg
3. Waist circumference > 150 cm
4. Insulin treatment requiring type 2 diabetes mellitus
5. Mental disorder or poor compliance
6. Eating disorder or excessive use of alcohol
7. Active ulcus-disease
8. Pregnancy
9. Past dose of radiation
10. Presence of any ferromagnetic objects that would make MR imaging contraindicated
11. Any other condition that in the opinion of the investigator could create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results

Inclusion criteria for the control group

1. BMI 18-27 kg/m2
2. Age 18-60 years
3. Fasting plasma glucose less than 6.1 mmol/l
4. Normal glucose tolerance test (OGTT)

Exclusion criteria for the control group

1. Blood pressure > 140/90 mmHg
2. Any chronic disease
3. Mental disorder or poor compliance
4. Any chronic medical defect or injury which hinder/interfere everyday life
5. Eating disorder or excessive use of alcohol
6. Pregnancy
7. Past dose of radiation
8. Any other condition that in the opinion of the investigator could create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results
9. Presence of any ferromagnetic objects that would make MR imaging contraindicated
10. Smoking

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Royx-en-Y surgery; Mixed meal test (MMS) with flow studies before and 2 months after the operation	Procedure: Roux-en-Y; 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.; Drug: GIP-infusion; Blood flow and volume during infusion; Drug: MMS; Blood flow and volume after meal solution
Active Comparator: Control; Healthy volunteer group, GIP, GLP-1 and MMS studies	Drug: GIP-infusion; Blood flow and volume during infusion; Drug: MMS; Blood flow and volume after meal solution; Drug: GLP-1; Blood flow and volume during infusion
Experimental: Sleeve gastrectomy; Mixed meal test (MMS) with flow studies before and 2 months after the operation	Drug: GIP-infusion; Blood flow and volume during infusion; Drug: MMS; Blood flow and volume after meal solution; Procedure: Sleeve gastrectomy; as in RYGS group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Splanchnic blood flow	Flow is measured using radiowater H2O and PET	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GIP and GLP-1 blood concetrations	Blood concentrations are measured from samples	24 months

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Collaborators: Lund University
• Investigators: Principal Investigator: Pirjo Nuutila, Prof, PET centre, Turku

Publications and helpful links

General Publications

• Saari T, Koffert J, Honka H, Kauhanen S, U-Din M, Wierup N, Lindqvist A, Groop L, Virtanen KA, Nuutila P. Obesity-associated Blunted Subcutaneous Adipose Tissue Blood Flow After Meal Improves After Bariatric Surgery. J Clin Endocrinol Metab. 2022 Jun 16;107(7):1930-1938. doi: 10.1210/clinem/dgac191.
• Honka H, Koffert J, Kauhanen S, Teuho J, Hurme S, Mari A, Lindqvist A, Wierup N, Groop L, Nuutila P. Bariatric Surgery Enhances Splanchnic Vascular Responses in Patients With Type 2 Diabetes. Diabetes. 2017 Apr;66(4):880-885. doi: 10.2337/db16-0762. Epub 2017 Jan 17.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: February 25, 2013
• First Submitted That Met QC Criteria: June 18, 2013
• First Posted (Estimate): June 19, 2013

Study Record Updates

• Last Update Posted (Actual): October 20, 2021
• Last Update Submitted That Met QC Criteria: October 12, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: GLP-1; obesity; type 2 diabetes; GIP; incretin hormones; splanchnic blood flow
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Diabetes Mellitus, Type 2; Obesity
• Other Study ID Numbers: 2012-002689-10

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No