Diabetes (DM)Phase 1UPGRADENCT07224334
Role of Alpha-to-beta Cell Communication to Adapt Insulin Secretion to Insulin Resistance.
A Phase 1 study testing 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 and Dextrose 20% solution in people with Diabetes (DM), run by David D'Alessio, M.D. at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes (DM)
- What is being tested?
- 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 and Dextrose 20% solution
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 30 Dec 2025to Dec 2027
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
None listed.
Who cannot join
- 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
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- 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
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Duke Center for Living
Durham, North Carolina, 27705
Johanna Johnson, MS, 919-660-6766, johanna.johnson@duke.edu
Alyssa Sudnick, MS, 919-660-6769, alyssa.sudnick@duke.edu
About this study
Official title: Alpha to Beta Cell Communication in Health and Disease
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.
Read the detailed description
Subjects will undergo screening for medical history, medication usage, and blood work; those who qualify will be offered participation. Study participation will last approximately 4-8 weeks depending on the study protocol enrolled and appointment availability.
Aim 2A (Aim 1 of the protocol): Each participant will have two 5-hour hyperglycemic clamp procedures to test the effect of fasting glucagon-like peptide 1 (GLP-1) action before and after experimental insulin resistance. The effect of endogenous proglucagon peptides (glucagon and GLP-1) to stimulate insulin secretion will be determined by blockade of the GLP-1 receptor with the antagonist exendin-9 (Ex-9) during glucose infusions. Insulin secretion experiments will be repeated before and after induction of insulin resistance. To induce insulin resistance, subjects will take dexamethasone, a synthetic glucocorticoid that has been shown in published studies and in a pilot study by our group to reduce insulin sensitivity by ~30%.
Effective following a protocol revision in August 2026, participants in Aim 2A will also complete a third study visit that consists of two identical, sequential hyperglycemic clamps to evaluate time-of-day effects on insulin response independent of Ex-9. This protocol revision is a result of observations from the Aim 2A sub-study.
Aim 2A sub-study (Aim 1a of the protocol): Implemented in July 2026, a small subset of participants completed a single study visit to undergo two identical, sequential hyperglycemic clamps to examine potential time-of-day effects on glucose-stimulated insulin secretion.
Aim 2B (Aim 2 of the protocol): This study will recruit non-diabetic subjects with obesity. They will be studied on two occasions using a 4.5-hour procedure with a hyperglycemic clamp to measure insulin secretion, followed by a hyperinsulinemic, euglycemic clamp to measure insulin sensitivity. This procedure will be done 2 times, once with saline infused during hyperglycemia as a control, and once with exendin-9 given during hyperglycemia to determine the role of GLP-1 receptor action.
- Conditions
- Diabetes (DM)
- Being tested
- 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
- Keywords
- insulin secretion, insulin sensitivity, GLP-1, alpha- to beta-cell communication
- Medical subject headings
- Diabetes Mellitus, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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/minDrug
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.
DexamethasoneDrug
Dexamethasone 6 mg daily; administered for 7 days leading up to the second exendin-9 experiment in Aim 2A
Dextrose 20% solutionDrug
Administered intravenously to maintain a stable blood glucose level of basal + 2.5 mM
Dextrose 20% solutionDrug
Administered intravenously to maintain a stable blood glucose level of 6.0 mM
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Dextrose 20% solution |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2025
- Study start30 Dec 2025
- Primary completionDec 2027 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Diabetes (DM)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- David D'Alessio, M.D.
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, David D'Alessio, M.D., Duke University
- Investigators
- David D'Alessio, MD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07224334
- Sponsor's protocol ID
- Pro00116631
- Other IDs
- R01DK142423
- Acronym
- UPGRADE
- Status last verified
- Sep 2026
- First submitted
- 29 Oct 2025
- Last updated
- 1 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 11457805Jensen 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.
PubMed 22286551Salehi 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.
PubMed 18827000Gray 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.
PubMed 38015721Schirra 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.
PubMed 9525985Salehi 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.
PubMed 20215429