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

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.

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