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.

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.

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.

Inclusion Criteria: BMI > 35 kg/m2 Type 2 diabetes mellitus (fasting glucose more than 7 mmol/l) Age: 18-60 years Previous, carefully planned, conservative treatments for obesity have failed Exclusion Criteria: BMI over 60 kg/m2 Weight more than 170 kg Waist circumference > 150 cm Insulin treatment requiring type 2 diabetes mellitus Mental disorder or poor compliance Eating disorder or excessive use of alcohol Active ulcus-disease Pregnancy Past dose of radiation Presence of any ferromagnetic objects that would make MR imaging contraindicated 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 BMI 18-27 kg/m2 Age 18-60 years Fasting plasma glucose less than 6.1 mmol/l Normal glucose tolerance test (OGTT) Exclusion criteria for the control group Blood pressure > 140/90 mmHg Any chronic disease Mental disorder or poor compliance Any chronic medical defect or injury which hinder/interfere everyday life Eating disorder or excessive use of alcohol Pregnancy Past dose of radiation 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 Presence of any ferromagnetic objects that would make MR imaging contraindicated Smoking

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.