Incretin Action in Physiology and Diabetes

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.

Study Overview

• Status: Completed
• Conditions: Insulin Secretion
• Intervention / Treatment: Drug: GIP infusion; Drug: GLP-1 infusion; Drug: Ex-9 infusion

• Study Type: Interventional
• Enrollment (Actual): 39
• 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 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: GIP infusion; after establishing a hyperglycemic clamp (target: 125 mg/dL) GIP will be infused
Experimental: 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.	Drug: GLP-1 infusion; after establishing a hyperglycemic clamp (target: 125 mg/dL) GLP-1 will be infused
Experimental: GIP + 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.	Drug: GIP infusion; after establishing a hyperglycemic clamp (target: 125 mg/dL) GIP will be infused; Drug: GLP-1 infusion; after establishing a hyperglycemic clamp (target: 125 mg/dL) GLP-1 will be infused
Experimental: GIP + 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.	Drug: GIP infusion; after establishing a hyperglycemic clamp (target: 125 mg/dL) GIP will be infused; Drug: Ex-9 infusion; Ex-9 infusion will be initiated at start of hyperglycemic clamp (target: 125 mg/dL)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beta cell sensitivity	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)	30 minute infusion periods

Collaborators and Investigators

• Sponsor: David D'Alessio, M.D.
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2016
• Primary Completion (Actual): April 16, 2021
• Study Completion (Actual): April 16, 2021

Study Registration Dates

• First Submitted: September 3, 2015
• First Submitted That Met QC Criteria: September 14, 2015
• First Posted (Estimated): September 15, 2015

Study Record Updates

• Last Update Posted (Actual): November 18, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: GLP-1; hyperglycemic clamp; Incretins; Glucagon; GIP
• Other Study ID Numbers: Pro00065698; R01DK101991 (U.S. NIH Grant/Contract)