DPP4 Inhibition & Beta Cell Function

NCT ID: NCT02683187

Last Updated: 2021-05-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-01
• Study Completion Date: 2018-03-16

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Sitagliptin

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.

Group Type: ACTIVE_COMPARATOR

Active Comparator: Sitagliptin

Intervention Type: 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).

Non-Sitagliptin

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

Group Type: PLACEBO_COMPARATOR

Placebo Comparator - No Sitagliptin

Intervention Type: 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).

Interventions

Active Comparator: Sitagliptin

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).

Intervention Type: DRUG

Placebo Comparator - No Sitagliptin

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).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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%

Exclusion Criteria

• 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

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

David D'Alessio, M.D.

OTHER

Sponsor Role: lead

Responsible Party

David D'Alessio, M.D.

Professor, Division Chief of Endocrinology Division

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Leslie Willis

Durham, North Carolina, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35775723 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

Pro00067061

Identifier Type: -

Identifier Source: org_study_id