Studies of Insulin and Glucagon Action in the Liver (SIGNAL)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes (DM)
• Intervention / Treatment: Drug: Glucagon; Drug: Saline (placebo)

Detailed Description

Volunteers will undergo screening for medical history, medication usage, and blood work; those who qualify will be offered participation. Study participation will last approximately 5-12 weeks depending on appointment availability and the number of infusions planned. This protocol involves two sets of paired procedures. Approximately 15 participants will complete each set of paired visits. Participants can opt to complete one set of paired visits or both sets of paired visits.

Set 1: Each participant will complete two 5-hour hyperinsulinemic clamp procedures to examine the effects of glucagon on glucose metabolism while measuring systemic glucose turnover and related blood markers. The procedures will be identical, except for the final phase of the procedure when either saline or a stepwise glucagon infusion will be administered.

Set 2: Each participant will complete two 5-hour hyperinsulinemic clamp procedures to examine the effects of insulin on glucose metabolism while measuring systemic glucose turnover and related blood markers. The procedures will be identical, except for the final phase of the procedure when either saline or a steady glucagon infusion will be administered.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Johanna Johnson, MS; Phone Number: 919-660-6766; Email: johanna.johnson@duke.edu
• Study Contact Backup: Name: Alyssa Sudnick, MS; Phone Number: 919-660-6769; Email: alyssa.sudnick@duke.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Center for Living
      • Contact: Johanna Johnson, MS; Phone Number: 919-660-6766; Email: johanna.johnson@duke.edu
      • Principal Investigator: David D'Alessio, MD
      • Contact: Alyssa Sudnick, MS; Phone Number: 919-660-6769; Email: alyssa.sudnick@duke.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glucagon infusion during hyperinsulinemic clamp; 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; 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.
Placebo Comparator: Saline infusion during hyperinsulinemic clamp; Saline infusion during the final 90 minutes of an otherwise identical clamp procedure.	Drug: Saline (placebo); IV saline infusion during clamp for 90 minutes as control.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: David D'Alessio, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: December 22, 2025
• First Submitted That Met QC Criteria: December 22, 2025
• First Posted (Actual): December 24, 2025

Study Record Updates

• Last Update Posted (Actual): December 24, 2025
• Last Update Submitted That Met QC Criteria: December 22, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Insulin; Glucagon; Glucose metabolism; Hepatic insulin sensitivity; hepatic glucose production
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes Mellitus; Insulin Resistance; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Inorganic Chemicals; Chlorine Compounds; Pancreatic Hormones; Sodium Compounds; Proglucagon; Chlorides; Hydrochloric Acid; Glucagon; Sodium Chloride
• Other Study ID Numbers: Pro00117291; R01DK141090 (U.S. NIH Grant/Contract)

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
• product manufactured in and exported from the U.S.: No