xenin-25: novel regulator of insulin secretion and beta-cell function

Conditions: Type 2 Diabetes Mellitus

Summary: 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.

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.

Eligibility criteria:
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: * \ 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.

Keywords: diabetes blood sugar xenin-25 gip insulin