Effect of RYGB on Alpha- and Beta Cell Function and Sensitivity to Incretins in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The aim of the study is to investigate the effect of Roux-en-Y gastric bypass (RYGB) on pancreatic alpha and beta-cell function and for the sensitivity of incretin hormones in patients with pre-operative type 2 diabetes. Primary hypotheses: After RYGB, the sensitivity to GLP-1 and GIP is improved (improved insulinotropic effect). After RYGB, the insulin secretion improves during an oral glucose tolerance test within 3 months postoperatively. After RYGB, the insulin secretion during intraveneous stimulation with glucose or non-glucose (arginin) is unchanged.

Detailed Description
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Design: 12 patients with type 2 diabetes will be recruited. All subjects will undergo 11 study visits: four visits before, three visits at 1 week after surgery and four visits at 3 months postoperatively: Oral glucose tolerance tests (OGTTs) with measurement of GLP-1 and GIP secretion will be performed before and 3 months post-surgery. Hyperglycemic clamps with co-infusion of saline, GLP-1 or GIP will be performed in a randomised order at three separate study visits in randomized order before, 1 week and 3 months after surgery.

Official Title
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Effect of RYGB on Alpha- and Beta Cell Function and Sensitivity to Incretins in Patients With Type 2 Diabetes

Conditions
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Type2 Diabetes, Obesity, Morbid

Intervention / Treatment
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* Diagnostic Test: Oral Glucose Tolerance Test
* Diagnostic Test: Hyperglycemic clamp with infusion of saline, GLP-1 or GIP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for RYGB in Denmark (ie. BMI > 35 in the presence of obesity related co-morbidities as type 2 diabetes) Type 2 diabetes Pre-operative: Fasting plasma glucose ≥7,0 mmol/L or 2 hour plasma glucose ≥ 11,1 mmol/L (after pausing antidiabetic medication for a minimum of 3 days) Written informed consent. Exclusion Criteria: Exclusion criteria for RYGB (psychiatric illness, obesity triggered by medical treatment for psychiatric illness, mental retardation, alcohol or drug abuse, severe heart-lung disease despite optimal medical treatment, previous serious problems with universal anesthesia, previous peritonitis, large hiatus hernia, diseases of the ventricle / previously complicated upper abdominal surgery, recurrent esophagitis, poor compliance). Type 2 diabetes where antidiabetic medication cannot be paused for 3 days. Pregnancy and breast-feeding. Hemoglobin <7.0 mmol/L

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective evaluation of gastric bypass patients, who will be examined before, 1 week and 3 months after the gastric bypass operation.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral glucose tolerance test<br>Oral glucose tolerance test with ingestion of 75 g glucose and blood sampling. This test will be performed before and 3 months after RYGB. | Diagnostic Test: Oral Glucose Tolerance Test<br>* Standard test of glucose tolerance with ingestion of 75 g glucose followed by blood sampling.<br>|
| Active Comparator: Hyperglycemic clamp with saline infusion combined with arginine test<br>Hyperglycemic clamp with blood glucose kept at 15 mmol/L by adjustable infusions of intraveneous glucose for 120 min with co-infusion of saline. After 120 min an arginine test with infusion of 50 g Arginine is performed. This test will be performed before, 1 week and 3 months after RYGB. | Diagnostic Test: Hyperglycemic clamp with infusion of saline, GLP-1 or GIP<br>* Blood glucose kept at 15 mmol/L via iv 20% glucose infusions. Primed co-infusion of either: Saline GLP-1 (Prime dose 6 pmol/kg, infusion 1 pmol/kg/min) GIP (Prime dose 3 pmol/kg, infusion 1.5 pmol/kg/min).<br>|
| Active Comparator: Hyperglycemic clamp with GLP-1 infusion<br>Hyperglycemic clamp with blood glucose kept at 15 mmol/L by adjustable infusion of intraveneous glucose for 90 min with co-infusion of GLP-1. This test will be performed before, 1 week and 3 months after RYGB. | Diagnostic Test: Hyperglycemic clamp with infusion of saline, GLP-1 or GIP<br>* Blood glucose kept at 15 mmol/L via iv 20% glucose infusions. Primed co-infusion of either: Saline GLP-1 (Prime dose 6 pmol/kg, infusion 1 pmol/kg/min) GIP (Prime dose 3 pmol/kg, infusion 1.5 pmol/kg/min).<br>|
| Active Comparator: Hyperglycemic clamp with GIP infusion<br>Hyperglycemic clamp with blood glucose kept at 15 mmol/L by adjustable infusions of intraveneous glucose for 90 minutes with co-infusion of GIP. This test will be performed before, 1 week and 3 months after RYGB. | Diagnostic Test: Hyperglycemic clamp with infusion of saline, GLP-1 or GIP<br>* Blood glucose kept at 15 mmol/L via iv 20% glucose infusions. Primed co-infusion of either: Saline GLP-1 (Prime dose 6 pmol/kg, infusion 1 pmol/kg/min) GIP (Prime dose 3 pmol/kg, infusion 1.5 pmol/kg/min).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulinotropic effects of GLP-1 and GIP | Insulin secretion during steady state of all hyperglycemic clamps | Change from before to 1 week and 3 months after RYGB | 
| Insulin secretion during oral stimulation | AUC of C-peptide during oral glucose tolerance test | Change from before to 3 month after RYGB | 
| Insulin secretion during iv stimulation | Insulin secretion during hyperglycemic clamp with saline infusion and during argininine iv stimulation test | Change from before to 1 week and 3 months after RYGB | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alpha cell function | Glucagon secretion during hyperglycemic clamps | Change from before to after 1 week and 3 months after RYGB |