Exendin-9 + Dexamethasone for Insulin Resistance
(UPGRADE Trial)
What You Need to Know Before You Apply
What is the purpose of this trial?
This trial explores how certain treatments affect insulin resistance and blood sugar levels. It tests two drugs, dexamethasone (a corticosteroid) and exendin-9 (an experimental treatment), to assess their impact on blood sugar regulation. Participants will undergo various tests to understand their bodies' responses to these treatments. Individuals with stable blood sugar levels and no history of diabetes or other major diseases might be suitable candidates for this trial. The goal is to gain insights into how these drugs influence blood sugar control. As a Phase 4 trial, this research aims to understand how these FDA-approved treatments benefit a broader patient population.
Will I have to stop taking my current medications?
Yes, if you are taking daily medications that affect blood sugar or digestive function, like glucocorticoids or psychotropics, you will need to stop them to participate in the trial.
What is the safety track record for these treatments?
Research has shown that dexamethasone is generally safe, though it can cause side effects. It may impair the body's response to insulin, leading to higher blood sugar levels. However, studies have found that even at high doses, it does not always cause diabetes. Some individuals, particularly those with pre-existing diabetes, might experience increased blood sugar.
Exendin-9 has undergone testing in other human trials and has demonstrated potential benefits. It helps prevent low blood sugar in children with a specific condition, suggesting it might be safe and well-tolerated in humans. However, reports on its effects on insulin and eating habits are mixed.
Overall, both treatments have been studied, and while they have some side effects, they are generally considered safe for humans.12345Why are researchers enthusiastic about this study treatment?
Researchers are excited about these treatments for insulin resistance because they explore unique mechanisms of action. Exendin-9 is a GLP-1 receptor blocker that might regulate insulin secretion differently compared to traditional medications that enhance insulin sensitivity, like metformin. Dexamethasone is typically known for its role in inducing insulin resistance, but in this context, it helps to study insulin dynamics under controlled conditions. Together, these treatments could provide new insights into managing insulin resistance, potentially leading to innovative ways to address this condition beyond current options.
What evidence suggests that this trial's treatments could be effective for insulin resistance?
Research has shown that exendin-9, one of the treatments in this trial, can decrease the amount of insulin the body releases, potentially helping to control blood sugar levels. It slightly reduces insulin effectiveness, which could aid in managing insulin resistance. In this trial, some participants will receive exendin-9 during experimental hyperglycemia. Conversely, dexamethasone, another treatment option, is known to cause insulin resistance, making it harder for the body to use insulin effectively. This can lead to higher blood sugar levels and increased insulin production. Participants will receive dexamethasone to induce insulin resistance before repeating the glucose clamp study. Both treatments affect insulin and blood sugar differently, enhancing understanding of blood sugar control.36789
Who Is on the Research Team?
David D'Alessio, MD
Principal Investigator
Duke University
Are You a Good Fit for This Trial?
This trial is for individuals with diabetes or insulin resistance. Participants should be able to receive an intravenous infusion and not have any conditions that would interfere with the study's interventions or objectives.Inclusion Criteria
Exclusion Criteria
Timeline for a Trial Participant
Screening
Participants are screened for eligibility to participate in the trial
Treatment - Aim 2A
Participants undergo two 5-hour hyperglycemic clamp procedures to test the effect of fasting GLP-1 action before and after experimental insulin resistance.
Treatment - Aim 2B
Non-diabetic subjects with obesity undergo two 3-hour procedures with hyperglycemic and hyperinsulinemic clamps to measure insulin secretion and sensitivity.
Follow-up
Participants are monitored for safety and effectiveness after treatment
What Are the Treatments Tested in This Trial?
Interventions
- Dexamethasone
- Exendin-9
Trial Overview
The trial is testing exendin-9, a peptide that blocks GLP-1 receptor activity, administered via IV at a specific rate alongside Dexamethasone. It aims to understand how this affects α-cell secretion of proglucagon peptides and β-cell function related to blood glucose levels.
How Is the Trial Designed?
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Treatment groups
Experimental Treatment
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.
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.
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.
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.
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.
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.
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.
Find a Clinic Near You
Who Is Running the Clinical Trial?
David D'Alessio, M.D.
Lead Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
Citations
Effect of Dexamethasone on Insulin Secretion
Dexamethasone-treated animals had 1.18-fold higher fasting blood glucose concentration and 6.5-fold increase in fasting serum insulin concentration compared ...
Dexamethasone-Induced Insulin Resistance
An insulin-resistant rat model, induced by dexamethasone, was used to evaluate a Michaelis–Menten-based kinetic model using 6-deoxy-6-[18F]fluoro-D-glucose ...
Dexamethasone enhances intestinal glucose absorption ...
Our findings suggest that dexamethasone promotes glucose absorption in the intestine, contributing to hyperglycaemia, and modulates expression ...
Metabolic Adaptations to Dexamethasone‐Induced Insulin ...
Results: In all subjects, dexamethasone induced a decrease in insulin sensitivity and a proportionate increase in first-phase insulin secretion ...
Dexamethasone-Induced Insulin Resistance Attenuation ...
As expected, DEXA reduced the adrenal gland weight, demonstrating the effectiveness of this synthetic glucocorticoid administration (Table 2). The oral ...
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diabetesjournals.org
diabetesjournals.org/diabetes/article/53/7/1790/14361/Single-Dose-Dexamethasone-Induces-Whole-BodySingle-Dose Dexamethasone Induces Whole-Body Insulin ...
These data suggest that in the short term, DEX is capable of inducing insulin resistance and switching cardiac glucose disposal from oxidation ...
Effect of high-dose dexamethasone on patients without ...
The use of high-dose dexamethasone in this cohort of neurosurgical patients did not result in glucocorticoid-induced diabetes.
Effectiveness of Dexamethasone for COVID-19 in Hospitalized ...
Dexamethasone, a potent glucocorticoid used for moderate to severe COVID-19, can worsen hyperglycemia in patients with diabetes, potentially leading to worse ...
Hyperinsulinemia caused by dexamethasone treatment is ...
Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme.
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