Recruiting

Phase 1

Glucagon PeptidesRole of Alpha-to-beta Cell Communication to Adapt Insulin Secretion to Insulin Resistance.

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

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

Feb, 2026

Completion date

Dec, 2027

Anticipated

Primary completion date

Dec, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 18 - 60

Healthy Volunteers: Accepted

Aim 2A: 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

Randomized

Intervention Model

Crossover

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

placebo comparator: Aim 2A: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade

Aim 2A: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Blood glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained stable at a level of 2.5-3.0 mM above fasting glucose 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; the orders will be assigned randomly.

Intervention: The interventions here are the experimental hyperglycemia with and without exendin-9

active comparator: Glucose stimulated insulin secretion with or 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.

placebo comparator: Aim 2B: Glucose stimulated insulin secretion and insulin sensitivity

Aim 2B: Each subject will have a 3-hour experiment with a 90-minute hyperglycemic clamp at a level of 2.5-3.0 mM above fasting glucose followed by a 60 minute hyperinsulinemic (80 units/meter2 Body Surface Area/minute), euglycemic clamp.

active comparator: Aim 2B: Glucose stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity

Aim 2B: Subjects will have an identical hyperglycemic clamp but with infusion of exendin-9 (600 pmol/kg/min). Exendin-9 infusion will be stopped before the following hyperinsulinemic clamp that will be conducted identically to the control arm. Allocation of subjects in Aim 2B to the study with and without exendin-9 will be randomized.

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

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 both experimental days and dexamethasone for one week before their second experimental day.

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

Dexamethasone

Dexamethasone 6 mg daily

Primary outcome measure

Insulin secretion [ Time Frame: Insulin secretion rates will be measured on both days of study in subjects participating in Aims 2A and 2B. Studies will be completed over a period of 4-5 weeks ]
Insulin secretion with and without exendin-9: Aims 2A and 2B [ Time Frame: 4-5 weeks ]

Central Contacts and Locations

Central contacts

Johanna Johnson, MS

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

Alyssa Sudnick, MS

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

Locations

Duke Center for Living

Recruiting

Durham, North Carolina, United States, 27705

Contacts

Johanna Johnson, MS

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

Alyssa Sudnick, MS

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

Principal Investigator:

David D'Alessio, MD

More Information

Sponsor

David D'Alessio, M.D.

Last update posted

Feb 5, 2026

Last verified

Feb, 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 2026-09-09. This information was provided to ClinicalTrials.gov by David D'Alessio, M.D. on 2026-02-05.