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

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.

• Placebo (Drug), also known as Vehicle Alone: Intravenous infusion of 1% human albumin in normal saline
• Glucose-dependent Insulinotropic Polypeptide (GIP) (Drug), also known as GIP: Intravenous infusion of GIP (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline
• Xenin-25 (Drug), also known as Xenin: Intravenous infusion of xenin-25 (4 pmoles x kg-1 x min-1) in 1% human albumin in normal saline
• Glucose-dependent Insulinotropic Polypeptide plus Xenin-25 (Drug), also known as GIP plus Xenin: Intravenous infusion of GIP plus xenin-25 (4 pmoles each x kg-1 x min-1) in 1% human albumin in normal saline

Primary outcomes

• The effects of GIP, xenin-25, or a combination of GIP plus xenin-25 on insulin secretion and blood glucose levels [3 years]

Secondary outcomes

• We will develop an assay to measure the normal fasting and postprandial concentrations of endogenous xenin-25 and determine whether they are altered in T2DM. [3 years]

Sex: All, ages: 18 Years to 65 Years, 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.

• Results publication: Chowdhury S, Reeds DN, Crimmins DL, Patterson BW, Laciny E, Wang S, Tran HD, Griest TA, Rometo DA, Dunai J, Wallendorf MJ, Ladenson JH, Polonsky KS, Wice BM. Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes. Am J Physiol Gastrointest Liver Physiol. 2014 Feb 15;306(4):G301-9. doi: 10.1152/ajpgi.00383.2013. Epub 2013 Dec 19. PMID 24356886

• Burton Wice, PhD, Principal investigator, Washington University School of Medicine
• Dominic Reeds, MD, Principal investigator, Washington University School of Medicine

NIH grants: R01DK088126