Gastric Bypass Surgery for Type 2 Diabetes

Recruiting at 1 trial location

Overseen by Marzieh Salehi, MD, MS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

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

Disqualifiers: Heart, lung, liver, kidney disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

RYGB (roux-en-y gastric bypass) has been reported to reverse type 2 diabetes (T2DM) immediately after surgery before any significant weight loss. In addition, a growing number of patients have been recognized with life-threatening hyperinsulinemic hypoglycemia several years following their surgery. While the mechanisms by which RYGB improves glucose metabolism or alters islet cell function in patients after RYGB are not understood, recent studies suggest that increased secretion of GI hormones, primarily glucagon-like peptide 1 (GLP-1), as well as alteration in neural activity may contribute to enhanced insulin secretion in general, and to a greater extent in patients with hypoglycemia. The proposed research is designed to address the role of RYGB on insulin secretion by evaluating the contribution of stimulatory factors (neural and GI hormone) on islet cell function and the islet cell responsiveness to the physiologic stimulatory factors, in RYGB patients with and without hypoglycemia and non-operated controls.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking any medication that might interact with atropine and cannot be stopped, you will be excluded from the study.

What data supports the effectiveness of the drug for treating type 2 diabetes?

Research shows that GLP-1 and GIP, components of the drug, help regulate blood sugar and insulin levels, making them effective for treating type 2 diabetes. Additionally, a study on a similar dual receptor agonist in mice demonstrated improved glucose tolerance and reduced obesity-related issues, suggesting potential benefits for humans. ^{1 2 3 4 5}

How does gastric bypass surgery differ from other treatments for type 2 diabetes?

Gastric bypass surgery is unique because it physically alters the digestive system to help with weight loss and improve blood sugar control, unlike medications that primarily focus on insulin regulation. This surgery can lead to significant and sustained weight loss, which can improve or even resolve type 2 diabetes in some patients. ^{1 4 6 7 8}

Research Team

Marzieh Salehi, MD, MS

Principal Investigator

Marzieh Salehi

Eligibility Criteria

This trial is for individuals who've had gastric bypass surgery and either have low blood sugar episodes or are symptom-free. It's also open to healthy people without diabetes. Participants must be able to visit Cedars-Sinai Medical Center but can't join if they have certain conditions like an enlarged prostate, glaucoma, serious organ diseases, uncontrolled hypertension or cholesterol, significant anemia, or are pregnant.

Inclusion Criteria

I am healthy, have never had surgery, and do not have diabetes.

I can travel to Cedars-Sinai Medical Center for the study.

I have had low blood sugar levels below 50 mg/dl after gastric bypass surgery.

Exclusion Criteria

You have low hemoglobin levels (less than 11g/dL).

I have myasthenia gravis.

I have not developed a serious illness or psychiatric condition recently.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive experimental treatments to evaluate the role of GLP-1 signaling, neural activation, and beta-cell sensitivity to gut hormones

6-8 weeks

Multiple visits for administration of treatments and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Atropine (Other)
• Exendin-(9-39) (Other)
• GLP-1 and GIP (Hormone Therapy)

Trial Overview The study investigates how factors like hormones and nerves affect insulin release after gastric bypass surgery. It involves giving participants drugs such as Exendin-(9-39), Atropine, GLP-1, and GIP to see their effect on insulin secretion in those with and without post-surgery hypoglycemia compared to non-operated controls.

Participant Groups

Group I: atropine Experimental Treatment 1 Intervention

To evaluate the effect of neural activation on insulin secretion and glucose metabolism

Group II: GLP-1 and GIP Experimental Treatment 1 Intervention

to evaluate the beta-cell sensitivity to different doses of exogenous gut hormones

Group III: Exendin-(9-39) Experimental Treatment 1 Intervention

To evaluate the role of GLP-1 signaling in glucose tolerance and insulin secretion

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

Dr. Andrew Masica

The University of Texas Health Science Center at San Antonio

Chief Medical Officer

MD from Indiana University School of Medicine

Dr. Taylor Eighmy

The University of Texas Health Science Center at San Antonio

Acting President

PhD in Civil Engineering from the University of New Hampshire

Findings from Research

GLP-1-based therapies are effective for treating type 2 diabetes (T2D) and have shown a good safety profile, especially with long-acting analogs that can also be used in combination with insulin.

Recent research highlights that GLP-1 secretion increases after bariatric surgery, contributing to weight loss and diabetes remission, while GIP has important effects on bone metabolism but is not suitable for T2D therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 and gastric inhibitory polypeptide: new advances. Gallwitz, B.[2022]

In a study involving 20 critically ill patients, the addition of glucose-dependent insulinotropic polypeptide (GIP) to glucagon-like peptide-1 (GLP-1) did not enhance glucose-lowering effects or insulin responses during nutrient infusion.

While GIP did cause a slight increase in glucagon levels before nutrient delivery, it ultimately did not contribute to improved glucose control in patients experiencing acute hyperglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of exogenous glucose-dependent insulinotropic polypeptide in combination with glucagon-like peptide-1 on glycemia in the critically ill. Lee, MY., Fraser, JD., Chapman, MJ., et al.[2021]

Tirzepatide, approved in 2022, is a novel treatment for type 2 diabetes that acts on both GLP-1 and GIP pathways, showing significant efficacy in lowering blood sugar levels and promoting weight loss in various patient groups.

Clinical trials, including the SURPASS and SURMOUNT studies, indicate that tirzepatide has a safety profile similar to traditional GLP-1 receptor agonists, with common gastrointestinal side effects, making it a promising option for patients needing better glycemic and weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: Clinical review of the "twincretin" injectable. Krauss, Z., Hintz, A., Fisk, R.[2023]

GIP1-39, a newly identified form of gastric inhibitory polypeptide, is more effective than the previously known GIP1-42 in stimulating insulin secretion from rat pancreatic islets, indicating its potential as a stronger insulinotropic agent.

At a concentration of 100 nM, GIP1-39 significantly increases intracellular calcium levels in pancreatic beta cells and enhances insulin exocytosis, suggesting a promising mechanism for its action in promoting insulin release.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GIP1-39, a novel insulinotropic peptide form and aspects on its mechanism of action. Xie, L., Lu, J., Ostenson, CG., et al.[2018]

The hybrid peptide 19W, which activates both GLP-1 and GIP receptors, showed improved stability and effectiveness in stimulating insulin secretion and glucose tolerance in mice, indicating its potential as a treatment for diabesity.

In a 28-day study with high fat-fed mice, 19W significantly reduced food intake, body weight, and fasting blood glucose levels, while also improving liver health, suggesting it could be a promising oral therapy for obesity and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An oral GLP-1 and GIP dual receptor agonist improves metabolic disorders in high fat-fed mice. Ma, T., Lu, W., Wang, Y., et al.[2022]

In a study involving eight fasting students, the infusion of porcine gastric inhibitory polypeptide (GIP) and glucose led to significant increases in serum insulin levels, demonstrating that insulin release is not affected by atropine.

The infusion of GIP also resulted in a significant rise in plasma pancreatic polypeptide (PP) levels when atropine was not administered, indicating that GIP may play a role in stimulating PP release during the intestinal phase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of atropine on GIP-induced insulin and pancreatic polypeptide release in man. Amland, PF., Jorde, R., Burhol, PG., et al.[2019]

In a study involving 17 healthy volunteers, GIP significantly reduced gastric emptying time and improved postprandial glucose and insulin levels, but did not affect appetite or satiety.

GLP-1, on the other hand, markedly increased gastric emptying time, reduced hunger and desire to eat, and also improved glucose regulation, suggesting it may be more beneficial for weight loss in type 2 diabetes treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. Edholm, T., Degerblad, M., Grybäck, P., et al.[2022]

Initial concerns about glucose-dependent insulinotropic polypeptide (GIP) as a treatment for obesity and type 2 diabetes were based on its reduced effectiveness in insulin secretion and potential to increase glucagon and fat storage in non-diabetic individuals.

Recent studies suggest that GIP can be beneficial when glycemia is normalized, leading to the development of new GIP receptor agonists and polyagonist peptides that target GIP, GLP-1, and glucagon receptors, showing promise for improving blood sugar control and aiding weight loss in obese type 2 diabetes patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GIP analogues and the treatment of obesity-diabetes. Bailey, CJ.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 and gastric inhibitory polypeptide: new advances. [2022]

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

The effect of exogenous glucose-dependent insulinotropic polypeptide in combination with glucagon-like peptide-1 on glycemia in the critically ill. [2021]

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

Tirzepatide: Clinical review of the "twincretin" injectable. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

GIP1-39, a novel insulinotropic peptide form and aspects on its mechanism of action. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

An oral GLP-1 and GIP dual receptor agonist improves metabolic disorders in high fat-fed mice. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Effects of atropine on GIP-induced insulin and pancreatic polypeptide release in man. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. [2022]

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

GIP analogues and the treatment of obesity-diabetes. [2021]