Hyperglycemia and the Extra-pancreatic Effect of Incretins

Study Overview
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Brief Summary
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Incretin hormones (GLP-1 and GIP) released from the intestine in response to meal ingestion augment insulin secretion from the pancreas to help maintain glycemic control. Studies in vitro and in vivo have shown that these incretin hormones also have functional effects in other tissues independent of the insulin secretory response. Both GLP-1 and GIP stimulate insulin secretion in a glucose-dependent manner, however the glucose-dependency of their extra-pancreatic effects has not been examined in vivo. By using pancreatic clamp methodology during euglycemic and hyperglycemic conditions we will test the hypothesis that extra-pancreatic effects of GLP-1 and GIP are glucose-dependent.

Official Title
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Determining the Extra-pancreatic Effects of Incretin Hormones During Euglycemic and Hyperglycemic Pancreatic Clamps

Conditions
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Extra-pancreatic Incretin Effect, Glucose Effectiveness

Intervention / Treatment
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* Biological: Saline
* Biological: GIP
* Biological: GLP-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18-60 years BMI 18-30 kg/m2 Male Normal glycemic control (fasting glucose <5.6 mM) Exclusion Criteria: Evidence of chronic disease Smoking Active weight loss (>2 kg in previous 6 months) Treatment with drugs known to affect our outcome varaibles

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control<br>Saline will be coninfused during the pancreatic clamp | Biological: Saline<br> <br> |
| Experimental: GIP<br>GIP will be infused intravenously during the pancreatic clamp at 1.5 pmol/kg/min | Biological: GIP<br> <br> |
| Experimental: GLP-1<br>GLP-1 will be infused intravenously during the pancreatic clamp at 0.5 pmol/kg/min | Biological: GLP-1<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose metabolism | Pancreatic clamp will be performed including infusion of somatostatin and replacement of basal insulin, glucagon, and growth hormone. During pancreatic clamps, euglycemia (5 mM) will be maintained via exogenous glucose infusion for the first 2-hours, followed by hyperglycemia (+5 mM) for the final 2-hours. An infusion of the stable isotope [U13C]glucose will be performed to assess glucose kinetics. Expired air will be collected for the analysis of [U13C]glucose into 13CO2. | up to 4 hours | 
| Lipid metabolism | An infusion of the stable isotope [D5]glycerol will be performed to assess glycerol kinetics. | up to 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial function | Ultrasound Doppler will be used to examine lower and upper limb blood flow and flow-mediated dilation | Baseline, 2 hours, and 4 hours | 
| Signaling | Skeletal muscle (vastus lateralis) and subcutaneous abdominal adipose biopsies will be obtained under local anaesthetic by the Bergstrom needle technique. Intracellular signalling related to glucose and lipid metabolism will be measured. | Baseline, 2 hours, and 4 hours |