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

NCT07224334 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: Pro00116631R01DK142423
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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)

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Insulin secretion with and without exendin-9: Aims 2A and 2B

  Insulin secretion rates derived from deconvolution of C-peptide concentrations will be the primary outcome for insulin secretion. This measure will be compared within subjects in Aim 2A with the difference between the saline and exendin-9 clamps on each day used as the measure of fasting GLP-1 receptor mediated insulin secretion. Comparison of GLP-1 receptor mediated insulin secretion between the placebo and dexamethasone studies will be used to determine the effect of insulin resistance. Comparison of insulin secretion during the two sequential saline clamps in Aim 2A (revised 8/2026) and Aim 2A sub-study will be used to determine a time-of-day effect of subsequent glucose clamps. Insulin secretion rates will also be compared within subjects in Aim 2B. Here the two different study days, one with saline and one with exendin-9 will be used.

  4-8 weeks

Secondary Outcomes (1)

• Insulin sensitivity: Aim 2B

  Insulin sensitivity will be measured in subjects participating in Aim 2B during the hyperinsulinemic clamp in each of the two days of study. The two experiments will be completed in a 4-6 week period.

Study Arms (7)

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

EXPERIMENTAL

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.

Drug: 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; Drug: Dexamethasone; Drug: Dextrose 20% solution

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

EXPERIMENTAL

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.

Drug: Dextrose 20% solution

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

EXPERIMENTAL

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.

Drug: 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; Drug: Dextrose 20% solution

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

EXPERIMENTAL

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.

Drug: 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; Drug: Dextrose 20% solution

2B: Glucose-stimulated insulin secretion and insulin sensitivity

EXPERIMENTAL

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.

Drug: Dextrose 20% solution

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

EXPERIMENTAL

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.

Drug: 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; Drug: Dextrose 20% solution

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

EXPERIMENTAL

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.

Drug: Dextrose 20% solution

Interventions

Dexamethasone DRUG

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

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

Dextrose 20% solution DRUG

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

2A [discont'd 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade; 2A [revised 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade; 2A: Glucose-stimulated insulin secretion with/without GLP-1 receptor blockade and insulin resistance; 2B: Glucose-stimulated insulin secretion and insulin sensitivity; 2B: Glucose-stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity; Aim 2A [revised 8/2026]: Sequential glucose-stimulated insulin secretion; Aim 2A sub-study [discont'd 8/2026]: Sequential glucose-stimulated insulin secretion

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 DRUG

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.

2A [discont'd 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade; 2A [revised 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade; 2A: Glucose-stimulated insulin secretion with/without GLP-1 receptor blockade and insulin resistance; 2B: Glucose-stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders
• Personal history of diabetes or pancreatitis

Sponsors & Collaborators

• David D'Alessio, M.D.: 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

RECRUITING

Related Publications (6)

• Ryan AS, Muller DC, Elahi D. Sequential hyperglycemic-euglycemic clamp to assess beta-cell and peripheral tissue: studies in female athletes. J Appl Physiol (1985). 2001 Aug;91(2):872-81. doi: 10.1152/jappl.2001.91.2.872.

  PMID: 11457805 BACKGROUND

• Jensen DH, Aaboe K, Henriksen JE, Volund A, Holst JJ, Madsbad S, Krarup T. Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes. Diabetologia. 2012 May;55(5):1406-16. doi: 10.1007/s00125-012-2459-7.

  PMID: 22286551 BACKGROUND

• Salehi M, Vahl TP, D'Alessio DA. Regulation of islet hormone release and gastric emptying by endogenous glucagon-like peptide 1 after glucose ingestion. J Clin Endocrinol Metab. 2008 Dec;93(12):4909-16. doi: 10.1210/jc.2008-0605. Epub 2008 Sep 30.

  PMID: 18827000 BACKGROUND

• Gray SM, Goonatilleke E, Emrick MA, Becker JO, Hoofnagle AN, Stefanovski D, He W, Zhang G, Tong J, Campbell J, D'Alessio DA. High Doses of Exogenous Glucagon Stimulate Insulin Secretion and Reduce Insulin Clearance in Healthy Humans. Diabetes. 2024 Mar 1;73(3):412-425. doi: 10.2337/db23-0201.

  PMID: 38015721 BACKGROUND

• Schirra J, Sturm K, Leicht P, Arnold R, Goke B, Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998 Apr 1;101(7):1421-30. doi: 10.1172/JCI1349.

  PMID: 9525985 BACKGROUND

• Salehi M, Aulinger B, Prigeon RL, D'Alessio DA. Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes. Diabetes. 2010 Jun;59(6):1330-7. doi: 10.2337/db09-1253. Epub 2010 Mar 9.

  PMID: 20215429 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus; Insulin Resistance

Interventions

Dexamethasone; Glucose; Solutions

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Hexoses; Monosaccharides; Sugars; Carbohydrates; Pharmaceutical Preparations

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: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine Duke University, Director Division of Endocrinology

Model Details: Subjects in Aim 2A will have paired, single-day experiments and a single-day control experiment performed within 6-8 weeks. Each subject in Aim 2B will have paired, single-day experiments performed within 4-6 weeks.

Study Record Dates

• First Submitted: October 29, 2025
• First Posted: November 4, 2025
• Study Start: December 30, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: October 1, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)