DPP4 Inhibition & Beta Cell Function

NCT02683187 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: Pro00067061
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being done to determine the role of a hormone, glucagon-like peptide 1 (GLP-1), on insulin secretion and to study how GLP-1 works in in diabetic individuals as compared to non-diabetic individuals, under fasting conditions. GLP-1 is a naturally occurring hormone made in the intestines. It is released into the circulating blood after eating and helps to control the blood glucose levels by increasing insulin secretion by cells in the pancreas. However, the exact method by which GLP-1 causes insulin secretion and how GLP-1 activity is changed in diabetic persons remain unclear. This research is being done to address these questions and better understand the function of GLP-1. In this research, the investigators will use a synthetic form of Exendin-9 to determine the effects of GLP-1 on insulin secretion in diabetic and non-diabetic persons. Exendin-9 acts as a blocker of GLP-1 action, allowing us to study the specific effects of the GLP-1 hormone. Exendin-9 is an investigational compound, which means it is still being tested in research studies and is not approved by the U.S. Food and Drug Administration (FDA). In this study, the investigators will also use the drug Sitagliptin, which is an FDA-approved drug for the treatment of type 2 diabetes mellitus. In this study, use of Sitagliptin is considered investigational since it is not being used for treatment of diabetes but is instead being used to understand how GLP-1 works and to better understand how medications like Sitagliptin work in patients with type 2 diabetes mellitus.

Conditions

Healthy

Keywords

insulin secretion; GLP-1; alpha cell; paracrine effect; Glucagon-Like Peptide 1

Outcome Measures

Primary Outcomes (1)

• Arginine-stimulated Insulin Secretion With and Without GLP-1 Blockade

  The investigators will use the mean increment of insulin secretion rate above baseline in the 30 minutes after Arginine stimulation to integrate insulin secretion, the primary outcome measure, and 2-way ANOVA with and without Sitagliptin and Ex-9/saline at the two factors.

  30 minutes

Study Arms (2)

Sitagliptin

ACTIVE COMPARATOR

The infusion procedures performed during study visits 2 and 3 are identical except that the oral medicine Sitagliptin will only be administered at one of the two visits, with order of Sitagliptin administration determined at random by study staff. In this arm, Sitagliptin will be administered.

Drug: Active Comparator: Sitagliptin

Non-Sitagliptin

PLACEBO COMPARATOR

The infusion procedures performed during study visits 2 and 3 are identical except that the oral medicine Sitagliptin will only be administered at one of the two visits, with order of Sitagliptin administration determined at random by study staff. In this arm, placebo will be administered

Drug: Placebo Comparator - No Sitagliptin

Interventions

Active Comparator: Sitagliptin DRUG

Subjects will receive sitagliptin prior to the start of the experiment involving 1/2 of the subjects receiving Exendin-9 (a GLP-1 receptor blocker) first over 60 minutes ; followed by a bolus arginine (5g) infusion after 30 minutes into the Ex-9 infusion, with blood draws over the next 30 minutes. Followed by a 60 minute washout and the procedure is repeated , this time with saline instead of Ex-9 (these procedures are reversed - saline first then Ex-9 - half of the time).

Sitagliptin

Placebo Comparator - No Sitagliptin DRUG

Subjects will receive Placebo (instead of sitagliptin) prior to the start of the experiment involving 1/2 of the subjects receiving Exendin-9 (a GLP-1 receptor blocker) first over 60 minutes ; followed by a bolus arginine (5g) infusion after 30 minutes into the Ex-9 infusion, with blood draws over the next 30 minutes. Followed by a 60 minute washout and the procedure is repeated , this time with saline instead of Ex-9 (these procedures are reversed - saline first then Ex-9 - half of the time).

Non-Sitagliptin

Eligibility Criteria

• Age: 35 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diabetic cohort: adults age 35-70 years with Type 2 diabetes managed by an oral medication or diet and exercise
• Non-diabetic cohort: healthy adults age 35-70 years
• Male or female
• Ability to speak and understand English
• Diabetic cohort: HbA1c ≤ 8.0%
• Non-diabetic cohort: HbA1c ≤ 6.2%

You may not qualify if:

• Rheumatoid arthritis
• Inflammatory bowel disease
• Unstable angina or uncompensated heart failure
• Pulmonary disorders, including COPD and asthma
• Malabsorptive GI disease, such as celiac disease, or gastric bypass
• Significant hepatic disease
• Renal insufficiency (eGFR \< 60 mL/kg/min)
• Anemia (hematocrit \< 34%) as measured at screening visit
• Uncontrolled hypertension
• Pregnant females
• Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)
• Consumption or injection of insulin
• Apparent sensitivity to any of the study peptides as determined by the skin test

Sponsors & Collaborators

• David D'Alessio, M.D.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Leslie Willis

Durham, North Carolina, 27707, United States

Location

Related Publications (1)

• Gray SM, Hoselton AL, Krishna R, Slentz CA, D'Alessio DA. GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1. J Clin Endocrinol Metab. 2022 Aug 18;107(9):2500-2510. doi: 10.1210/clinem/dgac396.

  PMID: 35775723 DERIVED

Results Point of Contact

• Title: Dr. David D'Alessio
• Organization: Duke University Medical Center

david.d'alessio@duke.edu

919-684-5778

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Division Chief of Endocrinology Division

Study Record Dates

• First Submitted: February 11, 2016
• First Posted: February 17, 2016
• Study Start: March 1, 2017
• Primary Completion: March 16, 2018
• Study Completion: March 16, 2018
• Last Updated: May 3, 2021
• Results First Posted: May 3, 2021

Record last verified: 2021-04

Locations

US (1)