Exendin-(9-39) for Post-Bariatric Surgery Glucose Metabolism

(GLP-1 Trial)

Recruiting at 1 trial location

Overseen By Marzieh Salehi, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center at San Antonio

Disqualifiers: Pregnancy, Anemia, Diabetes, GI obstruction

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 2 days

80 Participants Needed

Trial Summary

What is the purpose of this trial?

The overall goal of this project is to understand the mechanisms by which gastric bypass surgery improves glucose metabolism. The central hypothesis guiding this project is that the reconfiguration of intestinal transit with the Roux-en-Y will increase the release of insulinotropic GI hormones, termed incretins that improve insulin secretion and glucose metabolism. The study is divided into three specific aims. 1. To determine the role of incretin hormones on insulin secretion in patients with gastric bypass surgery using intravenous-oral hyperglycemic clamp. 2. To compare incretin effect and glucose tolerance among patient who suffer from hypoglycemia after RYGB and asymptomatic surgical and non-surgical individuals. 3. To quantify the contribution of GLP-1 to incretin effect enhancement following surgery.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug exendin-(9-39) for post-bariatric surgery glucose metabolism?

Research shows that exendin-(9-39) can block the effects of GLP-1, a hormone that lowers blood sugar, which suggests it might help manage blood sugar levels in people with post-bariatric hypoglycemia. Additionally, studies have evaluated its safety and effectiveness in patients with this condition, indicating potential benefits. ^{1 2 3 4 5}

Is exendin-(9-39) safe for humans?

Exendin-(9-39) has been studied for its effects on glucose metabolism and is generally considered safe, with no significant adverse effects reported in the studies reviewed. It does not activate the GLP1 receptor, which may result in fewer side effects compared to similar compounds like exendin-4. ^{1 3 5 6 7}

How does the drug Exendin-(9-39) differ from other treatments for post-bariatric surgery glucose metabolism?

Exendin-(9-39) is unique because it acts as an antagonist to glucagon-like peptide 1 (GLP-1), which means it blocks the effects of GLP-1, a hormone involved in insulin release and glucose regulation. This is different from other treatments that typically enhance GLP-1 activity to lower blood sugar levels. ^{1 2 3 4 8}

Research Team

Marzieh Salehi, MD,MS

Principal Investigator

Marzieh Salehi

Eligibility Criteria

This trial is for adults aged 18-65 who have had gastric bypass surgery and are experiencing recurrent low blood sugar. Healthy individuals without diabetes or active organ disease can also participate. People with significant anemia, current diabetes (unless awaiting bariatric surgery), pregnancy, or GI obstruction cannot join.

Inclusion Criteria

I do not have diabetes or any active organ disease.

I am between 18 and 65 years old.

I have had weight loss surgery.

Exclusion Criteria

You are pregnant.

I have a blockage in my digestive tract.

I have diabetes, but I am pre-op for bariatric surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo hyperglycemic clamp and meal tolerance tests to evaluate the effect of incretin hormones and GLP-1 receptor blockade on glucose metabolism

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• exendin -(9-39)
• exendin-(9-39)

Trial Overview The study aims to understand how gastric bypass improves blood sugar control by focusing on incretin hormones that affect insulin secretion. Participants will undergo tests like the intravenous-oral hyperglycemic clamp to investigate these effects.

Participant Groups

Group I: hyperglycemic clamp-Meal tolerance test Experimental Treatment 1 Intervention

these studies are to evaluate the effect of exendin-9 on insulin secretion before and after meal ingestion in patients after bariatric surgeries compared to non-surgical controls

Group II: Labeled meal tolerance test Experimental Treatment 1 Intervention

The effect of GLP-1 receptor blockade on glucose tolerance and glucose kinetics are evaluated in the group patients with bariatric surgery vs. nonsurgical using exendin-9-39 infusion during one of the the 2-day dual tracer studies of meal tolerance test

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

Findings from Research

In a study of 109 patients with type 2 diabetes, subcutaneous injections of AC2993 significantly reduced HbA(1c) levels by 0.7 to 1.1% compared to placebo, indicating improved blood sugar control.

AC2993 also enhanced beta-cell function, with a 50-100% increase in the beta-cell index, while the most common side effect reported was mild-to-moderate nausea, suggesting it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Fineman, MS., Bicsak, TA., Shen, LZ., et al.[2022]

The GLP-1 antagonist exendin 9-39 effectively blocked the insulin-releasing effects of GLP-1 in both laboratory settings and in healthy volunteers, demonstrating its role in glucose regulation.

Infusion of exendin 9-39 led to higher postprandial glucose levels in subjects, indicating that GLP-1 is crucial for maintaining normal blood sugar levels after meals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Edwards, CM., Todd, JF., Mahmoudi, M., et al.[2022]

Subcutaneous injection of exendin 9-39 (Ex-9) significantly prevented hyperinsulinaemic hypoglycaemia in patients with post-bariatric hypoglycaemia, improving glucose levels and reducing insulin peaks and related symptoms.

The treatment was well tolerated with no adverse events reported, suggesting that Ex-9 is a safe and effective option for managing PBH, warranting further studies on its long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia. Craig, CM., Liu, LF., Nguyen, T., et al.[2018]

In a phase 2 study involving 19 women with post-bariatric hypoglycaemia, subcutaneous avexitide significantly reduced symptoms of hypoglycaemia and improved glucose levels, with both formulations (lyophilized and liquid) showing effectiveness without requiring glycaemic rescue in higher doses.

The liquid formulation of avexitide at 30 mg twice daily resulted in greater and more sustained plasma concentrations compared to the lyophilized version, leading to a 47% increase in glucose nadir and a 67% reduction in peak insulin, indicating its potential as a viable treatment for post-bariatric hypoglycaemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia. Tan, M., Lamendola, C., Luong, R., et al.[2021]

Exendin (9-39) amide (Ex [9-39]) effectively blocks the insulin-releasing action of GLP-1, which is important for managing conditions like alimentary hypoglycaemia.

Importantly, Ex (9-39) does not interfere with insulin secretion triggered by nutrients, suggesting it can be safely used to target GLP-1 without affecting overall insulin control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistance of succinic acid dimethyl ester insulinotropic action to exendin (9-39) amide. Cancelas, J., García-Martínez, JA., Villanueva-Peñacarrillo, ML., et al.[2018]

Exendin-(9,39) was found to decrease insulin action and the disposition index in healthy subjects, indicating it has a unique effect on glucose metabolism that differs from GLP-1-(9,36)amide.

While exendin-(9,39) slightly increased glucose concentrations, it did not significantly affect insulin secretion, suggesting that its role may be more about modulating insulin sensitivity rather than stimulating insulin release.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct effects of exendin-(9,39) and GLP-1-(9,36)amide on insulin action, β-cell function, and glucose metabolism in nondiabetic subjects. Sathananthan, M., Farrugia, LP., Miles, JM., et al.[2021]

Exendin-4, a GLP1 analogue, is effective for imaging pancreatic beta cells but can cause side effects like nausea and hypoglycemia due to receptor activation and internalization.

By conjugating exendin(9-39) with the cell-penetrating peptide penetratin, researchers improved its internalization and tumor retention, making it a promising alternative tracer with fewer side effects for imaging GLP1 receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conjugation to a cell-penetrating peptide drives the tumour accumulation of the GLP1R antagonist exendin(9-39). Collado Camps, E., van Lith, SAM., Kip, A., et al.[2023]

In a study involving subjects after Roux-en-Y gastric bypass (RYGB), the GLP-1 antagonist exendin-9,39 increased postprandial glucose levels and decreased insulin concentrations, indicating that GLP-1 plays a significant role in glucose metabolism after RYGB.

The findings suggest that while GLP-1 influences glucose metabolism and gastrointestinal motility years after RYGB, it is unclear if it accounts for all metabolic changes observed post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. Shah, M., Law, JH., Micheletto, F., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Resistance of succinic acid dimethyl ester insulinotropic action to exendin (9-39) amide. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Direct effects of exendin-(9,39) and GLP-1-(9,36)amide on insulin action, β-cell function, and glucose metabolism in nondiabetic subjects. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Conjugation to a cell-penetrating peptide drives the tumour accumulation of the GLP1R antagonist exendin(9-39). [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. [2021]