A Phase 1 interventional study of Graded Glucose Infusion with Placebo and Graded Glucose Infusion with GIP Alone in Does the Vagus Nerve Mediate the Effects of Xenin-25, sponsored by Washington University School of Medicine. Withdrawn at 1 site in United States. Open to participants aged 18 Years to 70 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-04-26.
Sponsored by Washington University School of Medicine · Phase 1, Interventional, and Treatment
Glucose-dependent Insulinotropic Polypeptide (GIP) and xenin-25 are peptide hormones produced/released from your intestines and help regulate blood sugar levels after you eat. We have previously performed studies in humans that measured the effects of xenin-25 and GIP (alone and together) on blood sugar levels. One study was conducted with an intravenous infusion of glucose but without ingestion of a meal. In this study, xenin-25 increased the effects of GIP on insulin secretion- but only in humans without type 2 diabetes mellitus (T2DM). A second study was conducted in conjunction with ingestion of a meal. In this study, xenin-25 reduced blood glucose levels by delaying gastric emptying and this effect was similar in humans with and without T2DM. A variety of studies that we have performed suggest that xenin-25 works by activating nerves. A specific nerve called the vagus nerve plays an important role in regulating insulin secretion. This study will determine if the vagus nerve (which was disrupted if you had a vagotomy) is needed for the effects of xenin-25 on insulin secretion and/or gastric emptying.
Two groups of subjects, both without T2DM, will be studied. One group will consist of people who previously received a complete truncal vagotomy as part of a surgical treatment unrelated to this research project. The other group will be subjects who have not had a truncal vagotomy.
Initially, each potential participant will be administered an oral glucose tolerance test at the screening visit to make sure that they do not have type 2 diabetes. They will also have a sham feeding test to check for the completeness (or absence) of the vagotomy. As outlined below, each subject will then receive 4 graded glucose infusions (GGI) and 2 meal tolerance tests (MTT)- each on a separate occasion following an overnight fast.
For each GGI, the subject will be given an intravenous infusion of glucose such that blood glucose levels slowly increase over a 4 hour period. On separate occasions, the participant will also receive a primed-continuous infusion of GIP alone, xenin-25 alone, GIP plus xenin-25, or placebo (constant dose of 4 pmoles x kg-1 x min-1). Blood samples will be collected before and during the GGI for the measurement of glucose, insulin, C-peptide, glucagon, pancreatic polypeptide, GIP and xenin-25 levels. Insulin secretion rates will also be calculated. By comparing results for the two groups, we will learn if the vagus nerve mediates the effects of GIP, xenin-25, or the combination of GIP plus xenin-25 on insulin secretion in humans and thus, if this signaling circuit is impaired in humans with T2DM.
For the MTTs, the participant will ingest a liquid meal (Boost Plus) plus acetaminophen (Tylenol). On separate occasions, a primed-continuous infusion of vehicle alone or xenin-25 alone (constant dose of 12 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 acetaminophen, glucose, insulin, C-peptide, glucagon, GIP and xenin-25 levels. Insulin secretion rates will also be calculated. The rate of acetaminophen appearance in the blood is an indirect measure of the rate of gastric emptying. By comparing results for the two groups, we will learn if the vagus nerve mediates the effects of xenin-25 on gastric emptying in humans.
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Exclusion Criteria:
Healthy participants without diabetes who have undergone a complete truncal vagotomy
Drug: Graded Glucose Infusion with Placebo · Drug: Graded Glucose Infusion with GIP Alone · Drug: Graded Glucose Infusion with xenin-25 alone · Drug: Graded Glucose Infusion with GIP plus xenin-25 · Drug: Meal Tolerance Test with Placebo · Drug: Meal Tolerance Test with xenin-25
Healthy participants without diabetes who have not had a complete truncal vagotomy
Drug: Graded Glucose Infusion with Placebo · Drug: Graded Glucose Infusion with GIP Alone · Drug: Graded Glucose Infusion with xenin-25 alone · Drug: Graded Glucose Infusion with GIP plus xenin-25 · Drug: Meal Tolerance Test with Placebo · Drug: Meal Tolerance Test with xenin-25
Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.
Also known as: GGI with Albumin Alone
Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of GIP in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.
Also known as: GGI with GIP
Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of xenin-25 in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.
Also known as: GGI with Xenin
Starting at 0 minutes, glucose infusion rates will be increased to 1, 2, 3, 4, 6, and 8 mg/kg/min every 40 minutes. Starting at 0 minutes, a primed-continuous intravenous infusion of GIP plus xenin-25 in saline containing 1% human albumin will continue for 240 minutes. The study is finished at 240 minutes.
Also known as: GGI with GIP plus Xenin
At 0 minutes, a liquid mixed meal (Boost Plus) plus acetaminophen will be ingested. Starting at 0 minutes, a primed-continuous intravenous infusion of saline containing 1% human albumin will continue for 300 minutes. The study is finished at 300 minutes.
Also known as: MTT with Albumin Alone
At 0 minutes, a liquid mixed meal (Boost Plus) plus acetaminophen will be ingested. Starting at 0 minutes, a primed-continuous intravenous infusion of xenin-25 in saline containing 1% human albumin will continue for 300 minutes. The study is finished at 300 minutes.
Also known as: MTT with xenin
Insulin secretion rates will be measured during the GGI and MTTs
Time frame: 3 years
Plasma acetaminophen levels will be measured during MTTs
Time frame: 3 years
Plasma glucose levels will be measured during the GGIs and MTTs.
Time frame: 3 years
Plasma glucagon levels will be measured during the GGIs and MTTs.
Time frame: 3 years
Plasma insulin levels will be measured during the GGIs and MTTs.
Time frame: 3 years
Plasma C-peptide levels will be measured during the GGIs and MTTs.
Time frame: 3 years
Plasma pancreatic polypeptide levels will be measured during the GGIs and MTTs.
Time frame: 3 years
Plasma GIP levels will be measured during the GGIs and MTTs.
Time frame: 3 years
Plasma xenin-25 levels will be measured during the GGIs and MTTs.
Time frame: 3 years
This study is withdrawn, as verified in Apr 2018. You cannot join it, but the record below documents what was studied.
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Washington University School of Medicine