Study of the Effects of Xenin-25 in Humans With and Without Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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An intestinal hormone called Glucose-dependent Insulinotropic Polypeptide (GIP) is released into the blood immediately after ingestion of a meal and plays an important role in regulating blood sugar levels. However, GIP is not active in persons with type 2 diabetes mellitus (T2DM) which is also known as adult onset or non-insulin-dependent diabetes. This study is being conducted to determine whether a hormone called xenin-25 can restore the activity of GIP in persons with T2DM.

Detailed Description
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Each eligible participant will be administered an oral glucose tolerance test so he/she can be assigned to the group with normal glucose tolerance, impaired glucose tolerance (between normal and diabetic), or type 2 diabetes mellitus. Each study subject will then be administered a graded glucose infusion (GGI) on 4 separate occasions. For the GGI, an intravenous glucose infusion will be started at a rate of 1 mg x kg-1 x min-1 for 40 min, followed by 2, 3, 4, 6, and 8 mg x kg-1 x min-1 (40 min for each step). A primed-continuous infusion of vehicle alone, GIP alone, xenin-25 alone, or the combination of GIP plus xenin-25 (each peptide at a dose of 4 pmoles x kg-1 x min-1) will be initiated at the same time the glucose infusion is started. Blood samples will be collected before and during the GGI for the measurement of glucose, insulin, C-peptide, glucagon, GIP and xenin-25 levels.

Official Title
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Restoration of the GIP-mediated Incretin Effect in Persons With Type 2 Diabetes Mellitus

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Placebo
* Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)
* Drug: Xenin-25
* Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals must be able to consent for their own participation (no mental impairment affecting cognition or willingness to follow study instructions). Healthy volunteers with no clinical evidence of T2DM. Otherwise healthy volunteers that have impaired glucose tolerance. Otherwise healthy volunteers with diet controlled T2DM. Otherwise healthy volunteers with T2DM that take oral agents only if the subject's pre-existing oral anti-diabetic agents can be safely discontinued for 48-hours. Persons with HbA1c less than 9%. Women of childbearing potential must be currently taking/using an acceptable method of birth control. A pregnancy test will be done at the beginning of each visit. Any woman with a positive pregnancy test will be removed from the study. Willingness to complete all required visits. Exclusion Criteria: Lacks cognitive ability to sign the consent or follow the study directions. Women unwilling to use an acceptable method of contraception during the course of the study, or who are currently breast-feeding. Any subject whose screening HbA1c is >9.0%. Type 2 diabetes requiring the use of supplemental insulin at home. Volunteers with a history of Acute Pancreatitis. Volunteers with a history of cancer (except for skin cancer). Volunteer with a history of Chronic Pancreatitis and/or risk factors for chronic pancreatitis including hypertriglyceridemia (triglycerides >400mg/ml) hypercalcemia (blood calcium level >11.md/dl) and/or the presence of gallstones. Volunteers with a history of gastrointestinal disorders, particularly related to gastric motility/emptying such as gastric bypass, documented gastro-paresis in diabetic volunteers. Subjects taking medications known to affect glucose tolerance. Hematocrit from the lab is below 33% (or if the finger stick hemoglobin measured with the HemoCue 201+ is <11.2% mg/dlL). Diabetics that have the potential to have a low blood sugar without them being aware that their blood sugar is low (hypoglycemia unawareness). Significant systemic illness including heart, kidney, inflammatory, liver, or malignant disease requiring medications. Subjects will be excluded if their liver or kidney function is outside the upper limits of normal by > 3%. Total Bilirubin levels should be <2. Subjects unwilling to allow the use of human albumin in the preparation of the peptides. Unwillingness to allow blood glucose level adjustment (if needed) with IV insulin

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Glucose Tolerance<br>Healthy individuals exhibiting plasma glucose levels less than 140mg/dl two hours after ingestion of 75-g of glucose. | Drug: Placebo<br>* Intravenous infusion of 1% human albumin in normal saline<br>* Other names: Vehicle alone;Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)<br>* Intravenous infusion of GIP (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: GIP;Drug: Xenin-25<br>* Intravenous infusion of xenin-25 (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: Xenin;Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25<br>* Intravenous infusion of GIP plus xenin-25 (4 pmoles each x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: GIP plus Xenin;|
| Experimental: Impaired Glucose Tolerance<br>Healthy individuals exhibiting plasma glucose levels between 140 and 199 mg/dl two hours after ingestion of 75-g of glucose. | Drug: Placebo<br>* Intravenous infusion of 1% human albumin in normal saline<br>* Other names: Vehicle alone;Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)<br>* Intravenous infusion of GIP (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: GIP;Drug: Xenin-25<br>* Intravenous infusion of xenin-25 (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: Xenin;Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25<br>* Intravenous infusion of GIP plus xenin-25 (4 pmoles each x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: GIP plus Xenin;|
| Experimental: Type 2 diabetes mellitus<br>Healthy individuals exhibiting plasma glucose levels greater than 150 mg/dL under fasting conditions OR greater than 199 mg/dl two hours after ingestion of 75-g of glucose. | Drug: Placebo<br>* Intravenous infusion of 1% human albumin in normal saline<br>* Other names: Vehicle alone;Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)<br>* Intravenous infusion of GIP (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: GIP;Drug: Xenin-25<br>* Intravenous infusion of xenin-25 (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: Xenin;Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25<br>* Intravenous infusion of GIP plus xenin-25 (4 pmoles each x kg-1 x min-1) in 1% human albumin in normal saline<br>* Other names: GIP plus Xenin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effects of GIP, xenin-25, or a combination of GIP plus xenin-25 on insulin secretion and blood glucose levels |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effects of xenin-25 on GIP action in persons with type 2 diabetes |  | 5yrs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Blood Sugar, Xenin-25, GIP, Insulin