Ghrelin and Beta Cell Function in Diabetes

Ghrelin Effect on Beta Cell Function in Health and Disease #2

Ghrelin is a hormone naturally produced in the stomach and the gut. The purpose of this research study is to determine the role of this gut hormone in the regulation of insulin secretion from the pancreas and glucose disposal after we eat. The investigators hypothesize that ghrelin has an effect on the pancreas and on how our body handles glucose after we eat. The investigators will compare insulin secretion and glucose changes during meal ingestion while either acyl ghrelin (AG) or saline (salt solution) is being infused through your vein on separate study days. AG is a form of the ghrelin hormone that has a small modification to it that allows it to bind to a specific receptor. The investigators hypothesize that AG has an effect on how the body handles glucose after a meal. AG has been approved by the U.S. Food and Drug Administration (FDA) for human research only. This study will also involve the use of a medicine called arginine, which is a naturally occurring product and found in many nutritional supplements. Its use in this study is investigational. The use of arginine helps maximize insulin release from the pancreas so the investigators can better examine whether AG affects insulin secretion.

Study Overview

• Status: Withdrawn
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Synthetic human AG; Drug: Arginine; Drug: 0.9% saline solution

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Center For Living

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

T2DM study subjects to be considered for the study must meet the following inclusion criteria:

1. Established T2DM with good to moderate glycemic control
2. HbA1c < 8.5%
3. Diabetes treatment with metformin, sulfonylurea, thiazolidinediones or combination of these medications; with no use of insulin during the study period
4. BMI ≤ 45.0 kg/m2

Control study subjects will be matched for age- (± 2 years), BMI (± 1.5 kg/m2) and gender and must meet the following inclusion criteria:

1. HbA1c ≤ 5.7%
2. Fasting plasma glucose ≤ 95 mg/dL
3. BMI ≤ 45.0 kg/m2

Exclusion Criteria:

All subjects will be excluded for the following reasons:

1. History of myocardial infarction or arrhythmia within the past year, abnormal electrocardiogram (ECG) with evidence of ischemia or arrhythmia, history or symptoms of congestive heart failure
2. Uncontrolled hypertension
3. History or active liver or renal disease (AST or ALT >2x upper limits of normal, calculated glomerular filtration rate [eGFR] <60 at screening)
4. History of pituitary or adrenal disorders or neuroendocrine tumor
5. Anemia defined as hematocrit <33% at screening
6. Active cancer diagnosis or currently undergoing cancer treatment
7. History of anorexia nervosa or previous gastrointestinal tract surgery
8. Pregnancy or lactation

Control subjects will be excluded for the following reasons:

1. History or clinical evidence of impaired fasting glucose or impaired glucose tolerance on a 75 g OGTT, established diabetes mellitus, or taking medications prescribed for diabetes
2. Use of medications that alter insulin sensitivity (i.e. niacin, glucocorticoids, metformin)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Study Group: Type 2 Diabetes Mellitus (T2DM); Subjects with Type 2 Diabetes Mellitus (T2DM). Subjects will receive AG and saline infusions, but the order of which they receive will be random and they will not be told which one they are receiving on each given visit. Arginine will be used at both study visits.	Drug: Synthetic human AG; Synthetic human AG (0.28 μg/kg) bolus over 1 minute followed by 2 μg/kg/hr continuous infusion for 4.5 hours.; Drug: Arginine; Arginine hydrochloride (5 g) intravenously over 45 seconds.; Drug: 0.9% saline solution; A continuous infusion of 0.9% saline solution (control) for 4.5 hours.
Active Comparator: Control Group; Control group of healthy subjects. Subjects will receive AG and saline, but the order of which they receive will be random and they will not be told which one they are receiving on each given visit. Arginine will be used at both study visits.	Drug: Synthetic human AG; Synthetic human AG (0.28 μg/kg) bolus over 1 minute followed by 2 μg/kg/hr continuous infusion for 4.5 hours.; Drug: Arginine; Arginine hydrochloride (5 g) intravenously over 45 seconds.; Drug: 0.9% saline solution; A continuous infusion of 0.9% saline solution (control) for 4.5 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postprandial insulin secretion (ISR-meal)	Postprandial insulin secretion (ISR-meal) will be derived from plasma C-peptide concentrations during MTT (0-240 min) using deconvolution with population estimates of C-peptide clearance.	approximately 8 weeks
Index of β-cell sensitivity to glucose	Index of β-cell sensitivity to glucose will be calculated as incremental insulin/glucose (I/G) AUC (ΔAUCI/G).	approximately 8 weeks
Whole body insulin sensitivity using the Matsuda Index	The Matsuda Index is a well-known index of insulin sensitivity derived from several glucose and insulin values obtained during a mixed meal	approximately 8 weeks
β-cell function (DI-meal)	β-cell function (DI-meal) will be calculated as ΔAUCI/G x Matsuda Index	approximately 8 weeks

Collaborators and Investigators

• Sponsor: Jenny Tong, MD, MPH
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Jenny Tong, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2018
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): June 1, 2019

Study Registration Dates

• First Submitted: May 7, 2015
• First Submitted That Met QC Criteria: May 8, 2015
• First Posted (Estimate): May 12, 2015

Study Record Updates

• Last Update Posted (Actual): April 2, 2018
• Last Update Submitted That Met QC Criteria: March 29, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Ghrelin; age, BMI, and gender matched controls
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: Pro00060865; R01DK097550 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No