- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01729299
Ghrelin Effect on Beta Cell Function in Health and Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
We plan to study 20 healthy subjects on 4 occasions where they will receive ghrelin, ghrelin+Ex-9, Ex-9 or saline infusion after an overnight fast in a randomized order; Ex-9 will be used to block GLP-1 action. A 240-minute meal tolerance test (MTT) using a dual glucose tracer method will serve as the foundation of each study visit. One tracer, [6,6-2H2]glucose will be infused intravenously before and during the test meal to quantify fasting endogenous glucose production (EGP), and glucose disappearance during the meal. A second tracer, [U-13C]glucose, will be included in the meal to trace the appearance of oral glucose. The systemic appearance rates of both ingested tracer and total (i.e., ingested and endogenously produced) glucose will be calculated. Using this protocol, we will be able to evaluate a) insulin secretion in response to mixed-meal ingestion, b) glucose appearance and glucose disappearance during meal ingestion, c) the ghrelin effect on these parameters without GLP-1, and d) the effect of GLP-1 in the response based on the effects with and without Ex-9.
This dual-tracer method has been used to assess the ability of an individual to dispose of an oral glucose load, and accurately fractionates the appearance of ingested glucose in plasma (Ra meal), EGP, and peripheral glucose disposal (Rd) in this setting 41-42. The [6,6-2H2]glucose and [U-13C]glucose are stable-isotope tracers and are different from radioactive-isotope tracers in that they do not emit radiation.
All procedures will be performed at the CTRC at the Cincinnati Children's Hospital Medical Center (CCHMC).
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Jenny Tong, MD, MPH
- Phone Number: 513-558-4446
- Email: jenny.tong@uc.edu
Study Locations
-
-
Ohio
-
Cincinnati, Ohio, United States, 45267
- Recruiting
- University of Cincinnati
-
Contact:
- Jenny Tong, MD, MPH
- Phone Number: 513-558-4446
- Email: jenny.tong@uc.edu
-
Contact:
- Ahrar Haque, MD
- Phone Number: 513-558-3923
- Email: haqueau@uc.edu
-
Principal Investigator:
- Jenny Tong, MD, MPH
-
Cincinnati, Ohio, United States
- Recruiting
- Cincinnati Children's Hospital and Medical Center
-
Contact:
- Ahrar Haque, MD
- Phone Number: 513-558-3923
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Healthy men and women
- Ages between 18 and 45 years
- BMI between 18 and 29 kg/m2
Exclusion Criteria:
- History or clinical evidence of impaired fasting glucose or diabetes mellitus, myocardial infarction within the past year, history or symptoms of congestive heart failure, uncontrolled hypertension, history or active liver or renal disease (AST or ALT >2x upper limits of normal, calculated glomerular filtration rate [GFR] <60).
- History of pituitary or adrenal disorders or neuroendocrine tumor.
- Anemia defined as hematocrit <33%.
- Use of medications that alter glucose metabolism
- Pregnancy or lactation.
- Abnormal Electrocardiogram (ECG): evidence of ischemia or arrhythmia.
- Women who have a positive pregnancy test at any time during the study period.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: saline
Saline: 0.9% saline solution
|
|
Experimental: ghrelin and exendin (9-39)
Ghrelin+Ex-9: Combination of ghrelin and Ex-9,
|
|
Experimental: Exendin (9-39)
Exendin (9-39) (25 µg/kg) bolus over 1 min followed by a continuous infusion of 2.5 µg/kg/min
|
|
Experimental: ghrelin
synthetic human Acyl Ghrelin (0.28 μg/kg) bolus over 1 min followed by 2 μg/kg/h continuous infusion,
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
post-prandial insulin secretion
Time Frame: 1 year
|
Postprandial insulin secretion (ISR-meal) will be derived from plasma C-peptide concentrations during MTT using deconvolution with population estimates of C-peptide clearance.
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
endogenous GLP-1 contribution to postprandial insulin secretion
Time Frame: 1 year
|
The endogenous GLP-1 contribution to postprandial insulin secretion (GLP-1 effect) will be calculated as the difference in ISR-meal with and without Ex-9.
|
1 year
|
β-cell response to glucose
Time Frame: 1 year
|
An index of β-cell response to glucose will be calculated as the incremental insulin/glucose (I/G) AUC (ΔAUCI/G).
|
1 year
|
insulin sensitivity
Time Frame: 1 year
|
Whole body insulin sensitivity will be estimated using the Matsuda Index that has been well validated in large cohort studies and has demonstrated a good correlation with IVGTT or hyperinsulinemic-euglycemic clamp derived measures of insulin sensitivity.
β-cell function (DI-meal) will be calculated as ΔAUCI/G x Matsuda Index
|
1 year
|
fasting EGP
Time Frame: 1 year
|
Fasting EGP will be calculated as the ratio of 6,6-[2H2]glucose infusion rate to plasma tracer enrichment (tracer-to-tracee ratio [TTR]6,6 from measurements obtained in the last 20 min of the basal tracer equilibration period, when plasma glucose concentration and 6,6-[2H2]glucose enrichment are stable).
|
1 year
|
glucose appearance
Time Frame: 1 year
|
Total rates of glucose appearance after meal ingestion (total Ra) will be calculated by modeling 6,6-[2H2] enrichment ([TTR]6,6) using both a two-compartment model and Steele's equation42.
Meal glucose appearance will be determined from the analysis of [U-13C]-glucose fluxes.
The meal will be labeled to 2.66% with U-13C]-glucose (TTRmeal).
From the measurement of plasma [TTR]13C, we will calculate the exogenous (meal) glucose concentrations, [Gmeal] , from total glucose concentrations, [Gtot] , using the formula [Gmeal] = [Gtot] x [TTR]13C / TTRmeal as previously described 42,45.
Endogenous glucose concentration [Gend] will be calculated as [Gend] = [Gtot] - [Gmeal].
|
1 year
|
EGP during MTT
Time Frame: 1 year
|
EGP during MTT will be calculated using model analysis of TTR of endogenous glucose ([TTR]end) and calculated as [TTR]end = [TTR]6,6 x [Gtot] / [Gend]
|
1 year
|
exogenous glucose rate of appearance
Time Frame: 1 year
|
Exogenous glucose rate of appearance, Ra meal, will be calculated by subtracting EGP during meal from total Ra (Ra meal = total Ra - EGP).
|
1 year
|
metabolic glucose clearance
Time Frame: 1 year
|
As for indexes of peripheral insulin sensitivity, we will calculate metabolic glucose clearance during MTT using peripheral glucose disposal (Rd) divided by glucose concentration (expressed as ml/min/kg) where Rd is calculated by subtracting the rate of change of plasma glucose mass from total Ra.
|
1 year
|
area under the curve
Time Frame: 1 year
|
AUC for glucagon, GLP-1, GIP, and free fatty acids (FFA), a measure of lipolysis.
|
1 year
|
ghrelin measures
Time Frame: 1 year
|
AG and total ghrelin levels will be measured during clamp-MTT.
|
1 year
|
gastric emptying
Time Frame: 1 year
|
Gastric emptying estimated by the gastric half-emptying time calculated from the emptying curve as the time when 50% of the total cumulated dose of acetaminophen has been eliminated46.
|
1 year
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Jenny Tong, MD, MPH, University of Cincinnati
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- 12070904
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