Xenin-25: Novel Regulator of Insulin Secretion and Beta-cell Function

The Washington University

Status and phase: Completed; Phase 1

Conditions: Type 2 Diabetes Mellitus

Treatments: Drug: Xenin-25; Drug: Glucose-dependent Insulinotropic Polypeptide (GIP); Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00949663

08-0861B

1R01DK088126-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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 meal tolerance test (MTT) on 4 separate occasions. For the MTT, a liquid meal (Boost Plus)will be ingested following an overnight fast. 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 meal is ingested. Blood samples will be collected before and during the MTT for the measurement of glucose, insulin, C-peptide, glucagon, GIP and xenin-25 levels.

Enrollment: 38 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Ages 18-65. No minors will be studied.
• 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 (see below).
• Otherwise healthy volunteers that have impaired glucose tolerance (see below).
• Otherwise healthy volunteers with Diet Controlled T2DM (see below).
• Otherwise healthy volunteers with T2DM that take oral agents only and if the subject's pre-existing oral anti-diabetic agents can be safely discontinued for 48 hours prior to Oral Glucose Tolerance Test.
• Otherwise healthy volunteers with T2DM who do not use insulin for blood glucose control.
• Persons with HbA1c ≤ 9%.
• Women of childbearing potential must be currently taking/using a method of birth control that is acceptable to the investigators. 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 return have 8-10ml of blood drawn 25-30 days after the last Xenin infusion; to check for Xenin peptide antibodies that MAY develop. (All efforts will be made to complete this visit during study participation.

Exclusion criteria

• <18years of age or >65 years of age
• Lacks cognitive ability to sign the consent &/or follow the study directions for themselves
• Women unwilling to comply with using 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 @ home
• Volunteers with a history of Acute Pancreatitis
• 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.
• Volunteers with a history of cancer. Exception: skin cancer.
• Diabetics that have the potential to have a low blood sugar without them being aware that their blood sugar is low (hypoglycemia unawareness).
• Known heart, kidney. liver or pancreatic disease requiring medications.
• Subjects unwilling to allow the use of their own blood or the human albumin in the preparation of the peptides.
• Unwillingness to allow blood glucose level adjustment (if needed) with IV insulin.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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38 participants in 3 patient groups

Normal Glucose Tolerance

Experimental group

Description:

Healthy individuals exhibiting plasma glucose levels less than 140mg/dl two hours after ingestion of 75-g of glucose.

Treatment:

Drug: Placebo

Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25

Drug: Xenin-25

Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)

Impaired Glucose Tolerance

Experimental group

Description:

Healthy individuals exhibiting plasma glucose levels between 140 and 199 mg/dl two hours after ingestion of 75-g of glucose.

Treatment:

Drug: Placebo

Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25

Drug: Xenin-25

Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)

Type 2 Diabetes Mellitus

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Glucose-dependent Insulinotropic Polypeptide plus Xenin-25

Drug: Xenin-25

Drug: Glucose-dependent Insulinotropic Polypeptide (GIP)