Clinical trial NCT00798915: Study of the Effects of Xenin-25 in Humans With and Without Type 2 Diabetes Mellitus
Official title: Restoration of the GIP-mediated Incretin Effect in Persons With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes
Keywords: Diabetes
Blood Sugar
Xenin-25
GIP
Insulin
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2008-11-26
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Detailed 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 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.

Eligibility criteria: 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

Primary outcomes:
measure: The effects of GIP, xenin-25, or a combination of GIP plus xenin-25 on insulin secretion and blood glucose levels
timeFrame: 5 years
Secondary outcomes:
measure: The effects of xenin-25 on GIP action in persons with type 2 diabetes
timeFrame: 5yrs
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Dominic Reeds, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Burton Wice, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chowdhury S, Wang S, Patterson BW, Reeds DN, Wice BM. The combination of GIP plus xenin-25 indirectly increases pancreatic polypeptide release in humans with and without type 2 diabetes mellitus. Regul Pept. 2013 Nov 10;187:42-50. doi: 10.1016/j.regpep.2013.10.003. Epub 2013 Oct 29.
citation: Wice BM, Reeds DN, Tran HD, Crimmins DL, Patterson BW, Dunai J, Wallendorf MJ, Ladenson JH, Villareal DT, Polonsky KS. Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. Diabetes. 2012 Jul;61(7):1793-800. doi: 10.2337/db11-1451. Epub 2012 Apr 20.