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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a specific treatment, exendin-(9-39), affects insulin and glucose levels in individuals who have undergone gastric bypass surgery. The researchers aim to understand how the surgery alters hormone release and improves glucose metabolism, particularly in those experiencing frequent low blood sugar post-surgery. Participants will join different groups to compare effects before and after meals and between those with and without surgery. Ideal candidates for this trial are individuals who have had bariatric surgery and frequently experience low blood sugar afterward. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the chance to contribute to groundbreaking insights.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that exendin-(9-39), a substance that blocks certain receptors, has been used safely in various studies. It helps manage blood sugar levels by reducing insulin release, particularly when blood sugar is low. One study focused on children and found that it could raise blood sugar levels without major problems.

Another study tested exendin-(9-39) on mice with low blood sugar and found it worked well without causing significant harm. However, since this trial remains in its early stages, researchers are closely monitoring the treatment's safety. While initial results are promising, more information is needed to fully understand its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about exendin-(9-39) because it offers a new approach to managing glucose metabolism after bariatric surgery. Unlike standard treatments that primarily focus on improving insulin sensitivity or supplementing insulin, exendin-(9-39) specifically targets the GLP-1 receptor. This receptor plays a crucial role in insulin secretion, and blocking it can help researchers understand and potentially control the unpredictable blood sugar levels seen in some post-bariatric surgery patients. This unique mechanism could lead to more personalized and effective management of glucose levels in these individuals.

What evidence suggests that this trial's treatments could be effective for improving glucose metabolism after bariatric surgery?

This trial will evaluate the effects of exendin-(9-39) on glucose metabolism in patients who have undergone bariatric surgery. Research suggests that exendin-(9-39) might help control blood sugar levels after weight-loss surgery. Studies have shown that it can prevent hyperinsulinemic hypoglycemia, a condition where blood sugar drops too low after eating. This treatment blocks certain signals that trigger insulin release, helping to stabilize blood sugar. Evidence also indicates it affects the rate of stomach emptying, which can aid in blood sugar control. Although more research is needed, these findings suggest that exendin-(9-39) could help manage blood sugar in patients after surgery. ^{1 6 7 8 9}

Who Is on the Research Team?

Marzieh Salehi, MD,MS

Principal Investigator

Marzieh Salehi

Are You a Good Fit for This Trial?

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 have had weight loss surgery.

I have had low blood sugar episodes after gastric bypass 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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) 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28776922/

Efficacy and pharmacokinetics of subcutaneous exendin (9 ... Results: Although an exposure-response relationship was observed, all doses effectively prevented hyperinsulinaemic hypoglycaemia and improved associated ...

2. dom-pubs.onlinelibrary.wiley.com dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.14507

Exendin(9-39)NH 2 : Recommendations for clinical use based ... We systematically searched the literature on exendin(9-39)NH2 and included for review 44 clinical studies reporting use of exendin(9-39)NH2 in ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3717878/

Direct Effects of Exendin-(9,39) and GLP-1-(9,36)amide on ... Although it is presumed that exendin-(9,39) has no direct effects on glucose metabolism, it alters gastric emptying and capacitance through vagal mechanisms, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02771574

Study Details | NCT02771574 | Efficacy, Tolerability and ... This study is designed to evaluate the efficacy, safety and pharmacokinetics of subcutaneous exendin (9-39) in subjects with post-bariatric hypoglycemia.

5. diabetesjournals.org diabetesjournals.org/diabetes/article/72/3/336/148061/The-Importance-of-Endogenously-Secreted-GLP-1-and

The Importance of Endogenously Secreted GLP-1 and GIP for ... Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3447900/

GLP-1 Receptor Antagonist Exendin-(9-39) Elevates ... We showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1 −/− mice.

7. diabetesjournals.org diabetesjournals.org/care/article/45/6/1381/144984/Exendin-9-39-Effects-on-Glucose-and-Insulin-in

Exendin-(9-39) Effects on Glucose and Insulin in Children ... The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in ...

8. jci.org jci.org/articles/view/1349/citations

Citations to Exendin(9-39)amide is an antagonist of ... Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it? EP Smith, G Polanco, A Yaqub, M Salehi, Metabolism, 2017. The role of ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03373435

NCT03373435 | Safety and Efficacy of Exendin 9-39 in ... This clinical study will evaluate whether taking an investigational drug called exendin 9-39 is safe, well-tolerated, and helps to prevent low blood sugar in ...