Recruiting
Phase 1

Glucagon Peptides

Sponsor:

David D'Alessio, M.D.

Code:

NCT07224334

Conditions

Diabetes (DM)

Eligibility Criteria

Sex: All

Age: 18 - 60

Healthy Volunteers: Accepted

Interventions

Exendin-9 is a 30 amino acid peptide that is an established competitive antagonist of the GLP-1 receptor. Subjects will receive exendin-9 by intravenous infusion at a rate of 600 pmol/kg/min

Dexamethasone

Dextrose 20% solution

Dextrose 20% solution

Study Details

Brief summary:

Glucagon secretion from α-cells has long been viewed as primarily a counterregulatory mechanism - e.g. an agent with a role to prevent blood sugar from decreasing to levels that compromise function. Our group, along with other researchers, have begun to identify a much more complex role for α-cells, raising questions about when and how glucagon may influence blood glucose levels. This proposal looks to detail proglucagon peptide secretion from α-cells and the impact this has on β-cell function and glucose tolerance, in preclinical studies of human islets and translational studies in human subjects. This protocol registration describes Aim 2 from this NIH grant which involves 2 study populations and separate protocols but addresses a common question. Aim 3 in the grant is focused on a separate hypothesis and will be conducted and published separately from Aim 2.

Conditions

Diabetes (DM)

Study ID

NCT07224334

Start date

Dec 30, 2025

Status verified date

Sep, 2026

Completion date

Dec, 2027

Anticipated

Primary completion date

Dec, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 60

Healthy Volunteers: Accepted

Aim 2A and 2A sub-study: Inclusion Criteria:

  • Age 18-45
  • Body Mass Index (BMI) < 27.0
  • Fasting plasma glucose of ≤ 95 mg/dL or HbA1c value ≤ 5.8% as measured at screening visit

Exclusion Criteria:

  • Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders
  • Personal history of diabetes or pancreatitis
  • Personal history of cardiac, gastrointestinal, renal or liver disease
  • Immediate family history of diabetes
  • Renal insufficiency (eGFR < 60 mL/kg/min)
  • Anemia (hematocrit < 34%) as measured at screening visit
  • Pregnant females
  • Poor vein access
  • Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)
  • Apparent sensitivity to the study peptide as determined by the skin test

Aim 2B: Inclusion Criteria:

  • Age 35-60
  • Body Mass Index (BMI) ≥ 27.0
  • Fasting plasma glucose of < 126 mg/dL or HbA1c value < 6.5% as measured at screening visit

Exclusion Criteria:

  • Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders
  • Personal history of diabetes or pancreatitis
  • Personal history of cardiac, gastrointestinal, renal or liver disease
  • Immediate family history of diabetes
  • Renal insufficiency (eGFR < 60 mL/kg/min)
  • AST and/or ALT levels > 3x the upper limit of the normal range
  • Anemia (hematocrit < 34%) as measured at screening visit
  • Pregnant females
  • Poor vein access
  • Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)
  • Apparent sensitivity to the study peptide as determined by the skin test

Study Design

Enrollment

30 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

experimental: 2A [revised 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade

Aim 2A \[revised AUG 2026\]: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Plasma glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained at \~140 mg/dL for 90 minutes. Following the washout, a second, identical hyperglycemic clamp will be performed. Subjects will receive an infuson of saline during the first clamp and receive exendin-9 (600 pmol/kg/min) during the second clamp. Intervention: The interventions here are the experimental hyperglycemia with and without exendin-9.

experimental: Aim 2A [revised 8/2026]: Sequential glucose-stimulated insulin secretion

Aim 2A \[revised AUG 2026\]: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Plasma glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained at \~140 mg/dL for 90 minutes. Following the washout, a second, identical hyperglycemic clamp will be performed. Subjects will receive an infusion of saline during both clamps and the procedure will align with the temporal pattern applied during all procedures in Aim 2A. Experiment: The experiment in this arm is the examination of potential time of day effects on glucose-stimulated insulin secretion.

experimental: 2A [discont'd 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade

Aim 2A \[discontinued AUG 2026\]: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Plasma glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained stable at \~140 mg/dL for 90 minutes. Following the washout, a second, identical hyperglycemic clamp will be performed. Subjects will receive either saline or exendin-9 (600 pmol/kg/min) during the clamps; in 10 subjects the saline/clamp will be first and in 10 subjects the exendin-9/clamp will be first; this will be assigned in alternating order as individuals are enrolled. Intervention: The interventions here are the experimental hyperglycemia with and without exendin-9.

experimental: 2A: Glucose-stimulated insulin secretion with/without GLP-1 receptor blockade and insulin resistance

Aim 2A: Subjects will be treated with 6 mg dexamethasone once daily for 7 days to induce insulin resistance before repeating the 5 hr glucose clamp study. The infusion of glucose with saline and exendin-9 will be performed identically to the first study. Intervention: The intervention in this arm is the induction of insulin resistance with dexamethasone treatment.

experimental: 2B: Glucose-stimulated insulin secretion and insulin sensitivity

Aim 2B: Each subject will have a 4.5 hr experiment with a 90-minute hyperglycemic clamp at a level of 2.5 mM above fasting glucose followed by a 60-minute gradual reduction in glucose infusion that leads to a 90-minute hyperinsulinemic (80 units/meter2 Body Surface Area/minute), euglycemic clamp at a level of 6 mM.

experimental: 2B: Glucose-stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity

Aim 2B: Subjects will receive an infusion of exendin-9 (600 pmol/kg/min) or saline during the 90-minute hyperglycemic clamp period of the procedure. Subjects receiving exendin-9 during their first procedure will receive saline during their second procedure and vice versa; in 10 subjects the saline/clamp will be administered first and in 10 subjects the exendin-9/clamp will be administered first; this will be assigned in alternating order as individuals are enrolled. The hyperinsulinemic, euglycemic clamp during the second portion of the procedure will be conducted identically to the control arm.

Intervention: The intervention in this study is the administration of exendin-9 during experimental hyperglycemia.

experimental: Aim 2A sub-study [discont'd 8/2026]: Sequential glucose-stimulated insulin secretion

Aim 2A control sub-study \[discontinued AUG 2026\]: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Plasma glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained at \~140 mg/dL for 90 minutes. Following the washout, a second, identical hyperglycemic clamp will be performed. Subjects will receive an infusion of saline during both clamps and the procedure will align with the temporal pattern applied during all procedures in Aim 2A. Experiment: The experiment in this arm is the examination of potential time of day effects on glucose-stimulated insulin secretion.

Interventions

Exendin-9 is a 30 amino acid peptide that is an established competitive antagonist of the GLP-1 receptor. Subjects will receive exendin-9 by intravenous infusion at a rate of 600 pmol/kg/min

Subjects in Aim 2A will receive exendin-9 on two experimental days; Subjects in Aim 2B will receive exendin-9 on one of their two experimental days.

Dexamethasone

Dexamethasone 6 mg daily; administered for 7 days leading up to the second exendin-9 experiment in Aim 2A

Dextrose 20% solution

Administered intravenously to maintain a stable blood glucose level of basal + 2.5 mM

Dextrose 20% solution

Administered intravenously to maintain a stable blood glucose level of 6.0 mM

Primary outcome measure

  • Insulin secretion with and without exendin-9: Aims 2A and 2B [ Time Frame: 4-8 weeks ]

Central Contacts and Locations

Central contacts

Johanna Johnson, MS

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

Alyssa Sudnick, MS

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

Locations

Duke Center for Living

Recruiting

Durham, North Carolina, United States, 27705

Contacts

Johanna Johnson, MS

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

Alyssa Sudnick, MS

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

Principal Investigator:

David D'Alessio, MD

More Information

Sponsor

David D'Alessio, M.D.

Last update posted

Oct 1, 2026

Last verified

Sep, 2026

Keywords

  • insulin secretion
  • insulin sensitivity
  • GLP-1
  • alpha- to beta-cell communication

Trial information was received from ClinicalTrials.gov and was last updated on 2026-10-24. This information was provided to ClinicalTrials.gov by David D'Alessio, M.D. on 2026-10-01. Recruitment status is synced daily from ClinicalTrials.gov and may not reflect the sponsor's current status. Confirm during your call.