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

ConditionDiabetes (DM)
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18-60
SponsorDavid D'Alessio, M.D.

About this trial

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.

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

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

Disqualifiers

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

Trial design

Design model

Parallel

Treatments tested in this trial

  • 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.

  • Dexamethasone

    Drug

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

  • Dextrose 20% solution

    Drug

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

  • Dextrose 20% solution

    Drug

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

Treatment groups

30 Participants
are divided into 7 treatment groups

7

Treatment groups

See each treatment group below.

Group A: 2A [revised 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockadeExperimental treatment 3 interventions
Group B: Aim 2A [revised 8/2026]: Sequential glucose-stimulated insulin secretionExperimental treatment 1 intervention
Group C: 2A [discont'd 8/2026]: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockadeExperimental treatment 2 interventions
Group D: 2A: Glucose-stimulated insulin secretion with/without GLP-1 receptor blockade and insulin resistanceExperimental treatment 2 interventions
Group E: 2B: Glucose-stimulated insulin secretion and insulin sensitivityExperimental treatment 1 intervention
Group F: 2B: Glucose-stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivityExperimental treatment 2 interventions
Group G: Aim 2A sub-study [discont'd 8/2026]: Sequential glucose-stimulated insulin secretionExperimental treatment 1 intervention

Trial outcomes

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.

Time frame
4-8 weeks

Secondary outcomes

1

Insulin sensitivity: Aim 2B

Insulin sensitivity will be measured directly in subjects in Aim 2B during the hyperinsulinemic, euglycemic clamp. The glucose infusion rate necessary to maintain blood glucose at 6 mM divided by steady-state plasma insulin will be used as the index of insulin sensitivity.

Time frame
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.

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

David D'Alessio, M.D.

Lead sponsor

Duke University

Sponsor institution

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Source ClinicalTrials.gov
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