DPP4 Inhibition & Beta Cell Function

Role of Alpha-cell GLP-1 in the Beta-cell Response to DPP-4 Inhibition

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Active Comparator: Sitagliptin; Drug: Placebo Comparator - No Sitagliptin

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27707
      • Leslie Willis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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).
Placebo Comparator: 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	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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: David D'Alessio, M.D.
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): March 16, 2018
• Study Completion (Actual): March 16, 2018

Study Registration Dates

• First Submitted: February 11, 2016
• First Submitted That Met QC Criteria: February 16, 2016
• First Posted (Estimate): February 17, 2016

Study Record Updates

• Last Update Posted (Actual): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 6, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: GLP-1; insulin secretion; Glucagon-Like Peptide 1; alpha cell; paracrine effect
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: Pro00067061

Drug and device information, study documents

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