Ghrelin Effect on Beta Cell Function in Health and Disease

Ghrelin Effect on Beta Cell Function in Health and Disease

Sponsors

Lead Sponsor: David Dalessio

Collaborator: National Institutes of Health (NIH)

Source University of Cincinnati
Brief Summary

To determine the role of nutrient status on ghrelin regulation of insulin secretion. We hypothesize that ghrelin and glucagon-like peptide-1 (GLP-1)(both are hormones made in the gut,) have differential effects on β-cell function in the fed state. We will compare insulin secretion and glucose turnover during meal ingestion using a dual glucose tracer and mixed meal protocol in subjects receiving ghrelin or saline. We will also determine the role of ghrelin-stimulated GLP-1 levels in this process using the GLP-1 receptor (GLP-1R) antagonist Exendin(9-39) (Ex-9).

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).

Overall Status Unknown status
Start Date April 2013
Completion Date April 2014
Primary Completion Date April 2014
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
post-prandial insulin secretion 1 year
Secondary Outcome
Measure Time Frame
endogenous GLP-1 contribution to postprandial insulin secretion 1 year
β-cell response to glucose 1 year
insulin sensitivity 1 year
fasting EGP 1 year
glucose appearance 1 year
EGP during MTT 1 year
exogenous glucose rate of appearance 1 year
metabolic glucose clearance 1 year
area under the curve 1 year
ghrelin measures 1 year
gastric emptying 1 year
Enrollment 30
Condition
Intervention

Intervention Type: Drug

Intervention Name: Exendin (9-39)

Intervention Type: Drug

Intervention Name: acyl ghrelin

Intervention Type: Drug

Intervention Name: saline

Arm Group Label: saline

Eligibility

Criteria:

Inclusion Criteria:

1. Healthy men and women

2. Ages between 18 and 45 years

3. BMI between 18 and 29 kg/m2

Exclusion Criteria:

1. 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).

2. History of pituitary or adrenal disorders or neuroendocrine tumor.

3. Anemia defined as hematocrit <33%.

4. Use of medications that alter glucose metabolism

5. Pregnancy or lactation.

6. Abnormal Electrocardiogram (ECG): evidence of ischemia or arrhythmia.

7. Women who have a positive pregnancy test at any time during the study period.

Gender: All

Minimum Age: 18 Years

Maximum Age: 45 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Jenny Tong, MD, MPH Principal Investigator University of Cincinnati
Overall Contact

Last Name: Jenny Tong, MD, MPH

Phone: 513-558-4446

Email: [email protected]

Location
Facility: Status: Contact: Contact Backup: Investigator:
University of Cincinnati | Cincinnati, Ohio, 45267, United States Recruiting Jenny Tong, MD, MPH 513-558-4446 [email protected] Jenny Tong, MD, MPH Principal Investigator
Cincinnati Children's Hospital and Medical Center | Cincinnati, Ohio, United States Recruiting Ahrar Haque, MD 513-558-3923
Location Countries

United States

Verification Date

April 2013

Responsible Party

Type: Sponsor-Investigator

Investigator Affiliation: University of Cincinnati

Investigator Full Name: David Dalessio

Investigator Title: Professor

Keywords
Has Expanded Access No
Number Of Arms 4
Arm Group

Label: saline

Type: Placebo Comparator

Description: Saline: 0.9% saline solution

Label: ghrelin and exendin (9-39)

Type: Experimental

Description: Ghrelin+Ex-9: Combination of ghrelin and Ex-9,

Label: Exendin (9-39)

Type: Experimental

Description: Exendin (9-39) (25 µg/kg) bolus over 1 min followed by a continuous infusion of 2.5 µg/kg/min

Label: ghrelin

Type: Experimental

Description: synthetic human Acyl Ghrelin (0.28 μg/kg) bolus over 1 min followed by 2 μg/kg/h continuous infusion,

Study Design Info

Allocation: Randomized

Intervention Model: Crossover Assignment

Primary Purpose: Basic Science

Masking: Single (Participant)

Source: ClinicalTrials.gov