Studies of Insulin and Glucagon Action in the Liver

NCT07300982 | Not Yet Recruiting Phase 1 FDA Drug

• 2 other identifiers: Pro00117291R01DK141090
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study examines how glucagon works to regulate glucose metabolism, based on new findings that suggest glucagon signaling in the liver has more than one role, and that these multiple roles can be opposing in nature. Understanding this biology provides an opportunity to develop new generations of glucagon-based drugs that target specific pathways, making them more effective at controlling blood glucose. Participants will complete paired, 5-hour hyperinsulinemic glucose clamp visits in which they receive either glucagon or saline infusions while blood glucose is maintained and frequent blood samples are collected. The primary focus is whether coordinated glucagon and insulin signaling enhances hepatic insulin sensitivity.

Conditions

Diabetes (DM)

Keywords

Glucose metabolism; Hepatic insulin sensitivity; Glucagon; Insulin; hepatic glucose production

Outcome Measures

Primary Outcomes (3)

• Glucose appearance (Ra)

  Glucose appearance will be determined using steady state computations, unless a stable tracer:tracee ratio is not maintained

  In these experiments outcomes will be based on measurements made in the final 90 minutes of the hyperinsulinemic glucose clamp.

• Glucose disappearance (Rd)

  Glucose disappearance (Rd) will be determined using steady state computations, unless a stable tracer:tracee ratio is not maintained

  In the experiments described here glucose turnover (Ra and Rd) will be determined in the final 90 minutes of the hyperinsulinemic glucose clamp.

• Hepatic insulin sensitivity

  Hepatic insulin sensitivity will be calculated as EGP divided by insulin concentration

  Basal period (time -30-0 min), after the insulin infusion alone (60-90 min), and during the glucagon/saline infusions (120-180 min)

Study Arms (2)

Glucagon infusion during hyperinsulinemic clamp

EXPERIMENTAL

Glucagon infusion either graded (0.2→0.4→0.6 ng/kg/min) or continuous (0.4 ng/kg/min) during the final 90 minutes of a hyperinsulinemic glucose clamp. The graded or continuous glucagon infusions are given as a component of 2 separate protocols.

Drug: Glucagon

Saline infusion during hyperinsulinemic clamp

PLACEBO COMPARATOR

Saline infusion during the final 90 minutes of an otherwise identical clamp procedure.

Drug: Saline (placebo)

Interventions

Glucagon DRUG

Glucagon infusion either graded (0.2→0.4→0.6 ng/kg/min) or continuous (0.4 ng/kg/min) during the final 90 minutes of a hyperinsulinemic glucose clamp. The graded or continuous glucagon infusions are given as a component of 2 separate protocols. Glucagon prepared per pharmacy/bedside protocol.

Glucagon infusion during hyperinsulinemic clamp

Saline (placebo) DRUG

IV saline infusion during clamp for 90 minutes as control.

Saline infusion during hyperinsulinemic clamp

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults age 18-45 years
• Body Mass Index (BMI) \< 27.0 kg/m²
• Fasting plasma glucose ≤ 95 mg/dL or HbA1c ≤ 5.8% as measured at screening visit

You may not qualify if:

• Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders
• No personal history of diabetes or pancreatitis
• No personal history of cardiac, gastrointestinal, renal or liver disease
• No history of diabetes among any first-degree family members
• Renal insufficiency (eGFR \< 60 mL/kg/min)
• Anemia (hematocrit \< 34%) as measured at screening visit
• Pregnant females
• Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)

Sponsors & Collaborators

• Duke University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Duke Center for Living

Durham, North Carolina, 27705, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus; Insulin Resistance

Interventions

Glucagon; Sodium Chloride

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Proglucagon; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• David D'Alessio, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Johanna Johnson, MS

CONTACT

919-660-6766; johanna.johnson@duke.edu

Alyssa Sudnick, MS

CONTACT

919-660-6769; alyssa.sudnick@duke.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The studies proposed here will focus on the hepatic interactions of insulin and glucagon using physiological concentrations of these two islet peptides. A group of healthy subjects will be studied on two occasions over 2 weeks in counterbalanced order (with and without glucagon) during a glucose clamp with a fixed dose of insulin. Hepatic glucoses production and glucose metabolism will be measured with stably labeled glucose tracers.

Study Record Dates

• First Submitted: December 22, 2025
• First Posted: December 24, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: December 24, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)