Exendin-9 + Dexamethasone for Insulin Resistance

(UPGRADE Trial)

Overseen By Alyssa Sudnick, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: David D'Alessio, M.D.

Must not be taking: Glucocorticoids, Psychotropics, Narcotics, Metoclopramide

Disqualifiers: Diabetes, Pancreatitis, Renal insufficiency, others

Compensation: Varies

Number of Visits: 2

30 Participants Needed

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. ^{1 2 3 4 5}

Why 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. ^{3 6 7 8 9}

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

Aim 2A: Body Mass Index (BMI) < 27.0

Aim 2A: Fasting plasma glucose of ≤ 95 mg/dL or HbA1c value ≤ 5.8% as measured at screening visit

I am between 35 and 60 years old.

Exclusion Criteria

Apparent sensitivity to the study peptide as determined by the skin test

Anemia (hematocrit < 34%) as measured at screening visit

Pregnant females

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

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.

2-3 weeks

Multiple visits (in-person)

Treatment - Aim 2B

Non-diabetic subjects with obesity undergo two 3-hour procedures with hyperglycemic and hyperinsulinemic clamps to measure insulin secretion and sensitivity.

2-3 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

1 visit (in-person)

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?

Group I: Glucose stimulated insulin secretion with or without GLP-1 receptor blockade and insulin resistance Active Control 1 Intervention

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.

Group II: Aim 2B: Glucose stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity Active Control 1 Intervention

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.

Group III: Aim 2A: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade Placebo Group 1 Intervention

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

Group IV: Aim 2B: Glucose stimulated insulin secretion and insulin sensitivity Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

David D'Alessio, M.D.

Lead Sponsor

Trials

3

Recruited

100+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1530891X20415216

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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4578717/

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 ...

3. nature.com nature.com/articles/s41598-025-22312-8

Dexamethasone enhances intestinal glucose absorption ... Our findings suggest that dexamethasone promotes glucose absorption in the intestine, contributing to hyperglycaemia, and modulates expression ...

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1038/oby.2003.90

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 ...

5. mdpi.com mdpi.com/1424-8247/17/6/760

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 ...

6. diabetesjournals.org diabetesjournals.org/diabetes/article/53/7/1790/14361/Single-Dose-Dexamethasone-Induces-Whole-Body

Single-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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6506484/

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.

8. academic.oup.com academic.oup.com/jcem/article/110/7/1846/7825467

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 ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0960076015300807

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.