Incretin Action in Physiology and Diabetes

Phase 1

Completed

• Conditions: Insulin Secretion
• Interventions: Drug: GLP-1 infusion; Drug: GIP infusion; Drug: Ex-9 infusion

• Registration Number: NCT02550548
• Lead Sponsor: David D'Alessio, M.D.

Brief Summary

This project is designed to advance understanding of the incretin effect in health and disease. This system of gut-islet linkage is essential for normal glucose tolerance, impaired in T2DM, and amenable to therapeutic intervention. However, there are important gaps in understanding incretin function that limit application of this system; this project will address several of these. A secondary, but critical aspect of this research is focus on inter-individual variation in the physiology of the incretin system. This is a novel direction for research in this field and is critical to advancing the concept of individualized medical care in diabetes by establishing whether there is a physiologic basis for predicting the existence of responders and non-responders to incretin therapies.

Currently, we have described only Aim 1 from this grant in this protocol registration. While Aim 2 and 3 are described in the grant, Aim 1 will be conducted first and the results from this Aim and / or the publication of other results in the field may affect the approach to Aims 2 and 3.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-09-03
• Study First Submitted QC: 2015-09-14
• Study First Posted: 2015-09-15
• Study Start: 2016-04-21
• Primary Completion: 2021-04-16
• Study Completion: 2021-04-16
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-16
• Last Update Posted: 2023-11-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 39

Inclusion Criteria

• healthy adult volunteers
• fasting plasma glucose value ≤ 95 mg/dL, measured at screening visit
• HbA1c ≤ 5.9%, measured at screening visit

Exclusion Criteria

• history of diabetes diagnosis, including gestational diabetes
• presence of Type II diabetes mellitus among any first degree family members
• 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
• pregnancy
• uncontrolled hypertension
• consumption of daily medications that alter glucose metabolism or GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GLP-1 infusion	GLP-1 infusion	During a 240 minute hyperglycemic clamp, subjects will have (after 90 minutes of the clamp) GLP-1 infused at 4 incremental dosages, (initial dose will be 1.0 ng/kg/min, followed by 2.0, 3.0, and 4.0 ng/kg/min). Each dose will be infused continuously for 30 minutes, followed immediately by the next higher dose. The total time of this procedure is 240 minutes.
GIP + GLP-1 infusion	GIP infusion	During a 240 minute hyperglycemic clamp, subjects will have (after 90 minutes of the clamp) GIP + GLP-1 infused simultaneously at 4 incremental dosages (doses will be half the amounts described above). These doses will be infused continuously for 30 minutes, followed immediately by the next higher doses. The total time of this procedure is 240 minutes.
GIP infusion	GIP infusion	During a 240 minute hyperglycemic clamp, subjects will have (after 90 minutes of the clamp) GIP infused at 4 incremental dosages, (initial dose will be 2.0 ng/kg/min, followed by 4.0, 8.0, and 16.0 ng/kg/min). Each dose will be infused continuously for 30 minutes, followed immediately by the next higher dose. The total time of this procedure is 240 minutes.
GIP + GLP-1 infusion	GLP-1 infusion	During a 240 minute hyperglycemic clamp, subjects will have (after 90 minutes of the clamp) GIP + GLP-1 infused simultaneously at 4 incremental dosages (doses will be half the amounts described above). These doses will be infused continuously for 30 minutes, followed immediately by the next higher doses. The total time of this procedure is 240 minutes.
GIP + Ex-9 infusion	GIP infusion	During a 240 minute hyperglycemic clamp, subjects will have (after 90 minutes of the clamp) GIP infused at 4 incremental dosages (as described above) with Ex-9 infused at a steady dose of 2.5 mcg/kg/min starting 90 minutes before the GIP infusion and maintained throughout the clamp experiment. The total time of this procedure is 240 minutes.
GIP + Ex-9 infusion	Ex-9 infusion	During a 240 minute hyperglycemic clamp, subjects will have (after 90 minutes of the clamp) GIP infused at 4 incremental dosages (as described above) with Ex-9 infused at a steady dose of 2.5 mcg/kg/min starting 90 minutes before the GIP infusion and maintained throughout the clamp experiment. The total time of this procedure is 240 minutes.

Primary Outcome Measures

Name	Time	Method
Beta cell sensitivity	30 minute infusion periods	Beta-cell sensitivity for each incretin will equal the slope of the insulin secretion rate divided by the specific incretin level (GLP-1 or GIP)

Trial Locations

Locations (1)

Duke Center for Living; 🇺🇸 Durham, North Carolina, United States