Ghrelin Effect on Beta Cell Function in Health and Disease

Diabetes Clinical Trial

Official title:

Ghrelin Effect on Beta Cell Function in Health and Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01729299
• Other study ID #: 12070904
• Status: Recruiting
• Phase: N/A
• First received: November 13, 2012
• Last updated: April 2, 2013
• Start date: April 2013
• Est. completion date: April 2014

Study information

• Verified date: April 2013
• Source: University of Cincinnati
• Contact: Jenny Tong, MD, MPH
• Phone: 513-558-4446
• Email: jenny.tong[@]uc.edu
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

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.

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Diabetes

Intervention

Drug:
• Exendin (9-39)

• acyl ghrelin

• saline

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital and Medical Center	Cincinnati	Ohio
United States	University of Cincinnati	Cincinnati	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
David Dalessio	National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	post-prandial insulin secretion	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	No
Secondary	endogenous GLP-1 contribution to postprandial insulin secretion	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	No
Secondary	ß-cell response to glucose	An index of ß-cell response to glucose will be calculated as the incremental insulin/glucose (I/G) AUC (?AUCI/G).	1 year	No
Secondary	insulin sensitivity	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. ß-cell function (DI-meal) will be calculated as ?AUCI/G x Matsuda Index	1 year	No
Secondary	fasting EGP	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	No
Secondary	glucose appearance	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	No
Secondary	EGP during MTT	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	No
Secondary	exogenous glucose rate of appearance	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	No
Secondary	metabolic glucose clearance	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	No
Secondary	area under the curve	AUC for glucagon, GLP-1, GIP, and free fatty acids (FFA), a measure of lipolysis.	1 year	No
Secondary	ghrelin measures	AG and total ghrelin levels will be measured during clamp-MTT.	1 year	No
Secondary	gastric emptying	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	No