Endogenous GLP-1 Secretion on Islet Function in People With and Without Type 2 Diabetes

Study Overview
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Brief Summary
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GLP-1 is a hormone made by the body that promotes the production of insulin in response to GLP-1 is produced within the islets expressing prohormone convertase 1/3eating. However, there is increasing evidence that this hormone might help support the body's ability to produce insulin when diabetes develops. The purpose of this study is to determine the effect of endogenous GLP-1 secretion on insulin secretion in people with and without type 2 diabetes.

Detailed Description
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Accumulating evidence suggests that in rodents and humans GLP-1 is synthesized within islets and may act locally in a paracrine fashion. Indeed, mice with genetic loss of intra-islet GLP-1 exhibit decreased insulin secretion and impaired response to metabolic stressors. 'Pancreatic' GLP-1 may contribute to the effects of DPP-4 inhibitors in rodents and humans. Antagonism of GLP1R with exendin-9,39 during fasting impairs the islet cell response to an I.V. glucose challenge. Islet GLP-1 content is increased in T2DM and in islets from non-diabetic humans exposed to hyperglycemia and Free Fatty Acids. These observations imply that paracrine GLP-1 secretion supports islet function in the presence of glucolipotoxicity. In this experiment we will examine the role of endogenous GLP-1 secretion in people with and without T2DM and during β-cell stress induced by FFA elevation.

Official Title
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To Determine the Effect of Endogenous GLP-1 Secretion on Islet Function in People With and Without Type 2 Diabetes

Conditions
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Healthy, Type 2 Diabetes

Intervention / Treatment
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* Biological: Saline
* Biological: Exendin-9,39
* Biological: Saline + Intralipid/Heparin
* Biological: Exendin-9,39 + Intralipid/Heparin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria - non-diabetic subjects: Weight-stable, non-diabetic subjects Exclusion Criteria - non-diabetic subjects: Age < 25 or > 65 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose). HbA1c ≥ 6.5% Use of glucose-lowering agents. For female subjects: positive pregnancy test at the time of enrollment or study History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy. Active systemic illness or malignancy. Symptomatic macrovascular or microvascular disease. Inclusion criteria - diabetic subjects: Weight-stable, diabetic subjects treated with diet and lifestyle alone or with metformin monotherapy Exclusion Criteria - diabetic subjects: Age < 25 or > 65 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose). Use of any glucose-lowering agent other than metformin. 2 or more fasting glucose values > 250mg/dl on medication or after medication withdrawal. Unwillingness or inability to withdraw medication for three weeks prior to, and for the duration of the study. For female subjects: positive pregnancy test at the time of enrollment or study History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy. Active systemic illness or malignancy. Symptomatic macrovascular or microvascular disease.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Saline<br>Saline infusion | Biological: Saline<br>* Saline infused during the study<br>|
| Active Comparator: Exendin-9,39<br>Exendin-9,39 infusion | Biological: Exendin-9,39<br>* Exendin-9,39 infused during the study<br>|
| Active Comparator: Saline + Intralipid/Heparin<br>Induction of acute insulin resistance during Saline infusion | Biological: Saline + Intralipid/Heparin<br>* Saline infused during acute insulin resistance<br>|
| Active Comparator: Exendin-9,39 + Intralipid/Heparin<br>Induction of acute insulin resistance during Exendin-9,39 infusion | Biological: Exendin-9,39 + Intralipid/Heparin<br>* Exendin-9,39 infused during acute insulin resistance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 | Concentrations of glucagon Measured by immunoassay over the -30 to 0 minutes of study. On one study day subjects received saline, on the other exendin-9,39. The infusion commenced at -120 minutes. | Average concentration over the -30 to 0 minutes of study |