The Effect of the Interaction of Glucagon and Insulin on Endogenous Glucose Production in Humans

The purpose of this research is to help understand the relative importance of changes in insulin secretion (which lowers glucose) and changes in glucagon (which raises glucose) to regulate metabolism and the body's ability to make glucose.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: 0.4mU Insulin followed by withdrawal period followed by 0.8mU study; Drug: 0.8mU Insulin followed by withdrawal period followed by 0.4mU study

Detailed Description

Study A (Insulin 0.4mU/Kg/min): Subjects will be admitted to the CRTU at approximately 1700 on the day prior to study. They will then consume a standard 10kcal/kg meal (55% carbohydrate, 30% fat, 15% protein, caffeine free) and fast overnight. Blood will then be sampled for baseline enrichment and 2H20 (1.67g/kg of body water) will be given in 3 divided doses at 2200, 2400 and 0200. The following morning (approximately 0530), a forearm vein will be cannulated to allow infusions to be performed. In addition, a cannula will be inserted retrogradely into a vein of the contra-lateral dorsum of the hand. This will be placed in a heated Plexiglas box maintained at around 120oF to allow sampling of arterialized venous blood. At approximately 0600 (-180 min), a primed, (10microCi prime, 0.1microCi/min continuous) infusion containing trace amounts of glucose labeled with [3-3H] glucose will be started and continued till 0900 (0 min).

At 0900 (0 min), the infusion will be varied so as to mimic the anticipated pattern of fall of EGP. In addition, glucose also labeled with [3-3H] glucose will be infused so as to maintain glucose concentrations at ~ 95mg/dL. Peripheral venous glucose concentrations will be measured every 10 minutes to allow the infusion rate of glucose to be adjusted as necessary.

Simultaneously, an infusion of somatostatin (60ng/kg/min) will be started at time 0 to inhibit endogenous islet secretion and therefore ensure identical portal insulin concentrations on the two study days. Insulin will be infused at a constant rate known to produce ~ 50% suppression of EGP (0.4mU/Kg/min).

From 0900 (0 min) to 1030 (90 min) no glucagon will be infused. Subsequently, a glucagon infusion will commence (91 - 180 min) at 0.35 ng/Kg/min and then increase to 0.70 ng/Kg/min (181- 270 min), a rate which will be maintained till the end of the study (1330).

Study B (0.8mU/Kg/min): Approximately 1-2 weeks after the first study visit, subjects will be asked to return to the CRTU. This study visit will be similar to Study A. However, insulin will be infused at 0.8mU/Kg/min 0 to 270 minutes.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• We will recruit 15 otherwise healthy subjects using intramural and local extramural advertising after approval from the Mayo Clinic Institutional Review Board. Individuals who express interest in participating will be invited for a screening visit. Individuals with a BMI < 19 or > 28 kg/m2 will be excluded from the study to avoid potential confounding effects that may result from extreme leanness or from obesity. Subjects will have no known systemic illness, taking any medication that could affect glucose metabolism and no history of upper gastrointestinal surgery.

Exclusion Criteria:

• Subjects < 18 years of age or > 40 years of age will not be studied to minimize the potential confounding effects of age on glucagon and insulin action. The subjects will not be taking medications that affect glucose metabolism (to be determined by PI) and have no history of chronic illness or upper gastrointestinal surgery. We are seeking to recruit subjects who do not have diabetes (fasting glucose <100mg/dL).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 0.4mU Insulin; During the euglycemic clamp insulin will be infused at 0.4mU/Kg/Min	Drug: 0.4mU Insulin followed by withdrawal period followed by 0.8mU study; Clamp study with insulin infused at 0.4 mU/Kg/min, followed by a 2 week withdrawal period followed by a clamp study with insulin infused at 0.8 mU/Kg/min; Other Names: 0.4 then 0.8; Drug: 0.8mU Insulin followed by withdrawal period followed by 0.4mU study; Clamp study with insulin infused at 0.8 mU/Kg/min, followed by a 2 week withdrawal period followed by a clamp study with insulin infused at 0.4 mU/Kg/min; Other Names: 0.8 then 0.4
Other: 0.8mU Insulin; During the euglycemic clamp insulin will be infused at 0.8mU/Kg/Min	Drug: 0.4mU Insulin followed by withdrawal period followed by 0.8mU study; Clamp study with insulin infused at 0.4 mU/Kg/min, followed by a 2 week withdrawal period followed by a clamp study with insulin infused at 0.8 mU/Kg/min; Other Names: 0.4 then 0.8; Drug: 0.8mU Insulin followed by withdrawal period followed by 0.4mU study; Clamp study with insulin infused at 0.8 mU/Kg/min, followed by a 2 week withdrawal period followed by a clamp study with insulin infused at 0.4 mU/Kg/min; Other Names: 0.8 then 0.4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Glucose Production (EGP)	is calculated by tracer-based measurement and expressed per kg lean body mass	It will be quantified at 90, 180 and 270 minutes for the study with 0.4mU insulin infusion and compared to values obtained for the study with 0.8mU insulin infusion at the same timepoints

Collaborators and Investigators

• Sponsor: Adrian Vella
• Investigators: Principal Investigator: Adrian Vella, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2020
• Primary Completion (Actual): July 30, 2021
• Study Completion (Actual): January 6, 2022

Study Registration Dates

• First Submitted: June 30, 2020
• First Submitted That Met QC Criteria: July 1, 2020
• First Posted (Actual): July 8, 2020

Study Record Updates

• Last Update Posted (Actual): June 21, 2022
• Last Update Submitted That Met QC Criteria: May 25, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: 20-001570

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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