Caloric Restriction for Type 2 Diabetes

Overseen By Jeanette Laugen

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Adrian Vella

Disqualifiers: Abdominal surgery, Systemic illness, Vascular disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 1 day

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if eating fewer calories can help people with type 2 diabetes improve blood sugar control and liver function. The study employs a special diet and glucagon treatment (a hormone therapy) to test these effects. Participants must have type 2 diabetes managed by diet or pills and must not have undergone certain types of stomach surgeries. Those with stable weight and a BMI of 28 or more might be suitable for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to important diabetes research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that diabetes should be managed by diet alone or with oral medications, so you might be able to continue your current oral diabetes medications.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that glucagon treatments are usually well-tolerated, but some side effects can occur. Common issues include nausea, vomiting, and swelling at the injection site. Changes in blood sugar levels, such as hypoglycemia or hyperglycemia, may also occur, along with headaches and stomach pain.

While these side effects might seem concerning, glucagon is already used safely for other conditions. This trial is in the early stages, so researchers are still gathering detailed safety information. However, glucagon's previous use in other treatments provides some confidence in its safety. Always consult a healthcare provider about any concerns before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Glucagon is unique because it targets blood sugar regulation by increasing glucose production in the liver, a mechanism not commonly emphasized in existing Type 2 diabetes treatments. Most current treatments, like metformin and insulin, focus on reducing blood sugar levels either by improving insulin sensitivity or by increasing insulin in the body. Researchers are excited about glucagon's potential to work alongside these treatments by offering a new way to manage blood sugar levels, especially in cases where traditional approaches have limited effectiveness.

What evidence suggests that caloric restriction could be an effective treatment for type 2 diabetes?

This trial will examine the effects of combining glucagon with a calorie-restricted diet on insulin function and fasting blood sugar in people with type 2 diabetes. Studies have shown that glucagon, a hormone that regulates sugar and energy in the body, can improve these outcomes. Additionally, research has indicated that reducing calorie intake can lower body weight and blood sugar levels. Together, glucagon and a calorie-restricted diet may enhance blood sugar management and liver function, offering promising effects for better controlling type 2 diabetes. ^{6 7 8 9 10}

Who Is on the Research Team?

Adrian Vella

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with type 2 diabetes managed by diet or oral medications, having a BMI of at least 28. Participants should be weight-stable without active illnesses, significant past surgeries, severe vascular disease, abnormal thyroid levels, contraindications to MRI scans like metal implants or claustrophobia, low hematocrit levels, or high alcohol consumption.

Inclusion Criteria

I have type 2 diabetes and my weight has been stable.

You weigh more than what's considered healthy for your height.

My diabetes is controlled by diet or oral medications.

Exclusion Criteria

You drink more than 2 alcoholic drinks a day or more than 14 drinks a week, or you have a positive AUDIT questionnaire.

Your hematocrit level is less than 35%.

I have an active illness or another cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Caloric Restriction

Participants follow a caloric restriction diet of 900 kcal daily for 6 weeks, monitored by weekly meetings with a dietician

6 weeks

6 visits (virtual or in-person)

Treatment

Participants undergo a hyperglycemic clamp with 2 doses of glucagon infused

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Glucagon

Trial Overview The study examines how caloric restriction affects liver metabolism in people with type 2 diabetes. It will compare the body's response to glucagon—a hormone that raises blood sugar—before and after participants restrict their calorie intake.

How Is the Trial Designed?

Group I: Adults with type 2 diabetes Experimental Treatment 2 Interventions

20 subjects will be studied on one occasion, following 6 weeks of caloric restriction. They will be instructed to consume a diet of 900 kcal daily using meals derived from "Nutritional Guidelines after Bariatric Surgery". Compliance will be monitored by weekly meetings with the dietician using an electronic record of food intake. After this subjects will undergo a hyperglycemic clamp with 2 doses of glucagon infused.

Glucagon is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as GlucaGen for:

• Hypoglycemia
• Diagnostic aid

Approved in United States as Glucagon for:

• Severe hypoglycemia
• Diagnostic aid

Approved in Canada as Glucagon Novo Nordisk for:

• Hypoglycemia
• Diagnostic aid

Approved in Japan as Glucagon Lilly for:

• Hypoglycemia
• Diagnostic aid

Who Is Running the Clinical Trial?

Adrian Vella

Lead Sponsor

Trials

9

Recruited

210+

Published Research Related to This Trial

The study developed two radioligands, [(18)F]FBEM-[Cys(40)]-exendin-4 and [(18)F]FBEM-[Cys(0)]-exendin-4, which both show high affinity for the GLP-1 receptor (GLP-1R) and can be used for imaging pancreatic tumors, specifically insulinoma.

Among the two, [(18)F]FBEM-[Cys(40)]-exendin-4 demonstrated superior tumor uptake and binding affinity in an INS-1 xenograft model, making it a more effective tracer for GLP-1R imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Kiesewetter, DO., Gao, H., Ma, Y., et al.[2022]

GLP-1 is a crucial hormone that enhances insulin secretion and lowers glucagon levels, making it a key player in managing Type 2 diabetes by counteracting several diabetic symptoms such as insulin resistance and overeating.

Exogenous GLP-1 administration can normalize fasting hyperglycemia in Type 2 diabetic patients, but its short half-life necessitates the development of longer-lasting GLP-1 analogues or strategies to boost its natural release from the intestines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for type 2-diabetes. Nauck, MA., Holst, JJ., Willms, B., et al.[2018]

GLP-1 analogues effectively lower HbA1c levels by about 1% in patients with type 2 diabetes who are not achieving satisfactory control with oral medications, based on a systematic review of 28 randomized controlled trials.

These medications also promote significant weight loss (between 2.3 to 5.5 kg) compared to other treatments, with a low incidence of hypoglycemia, making them a safe and effective option for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis. Shyangdan, DS., Royle, PL., Clar, C., et al.[2022]

GLP-1 is a hormone that enhances insulin secretion and lowers blood sugar levels in type 2 diabetes, showing significant efficacy in normalizing fasting hyperglycemia and reducing postprandial glucose spikes when administered at elevated levels.

Current research is focused on developing GLP-1 analogues with longer-lasting effects and exploring ways to increase the body's own GLP-1 production, as the natural hormone has a very short half-life and is quickly broken down.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective. Nauck, MA.[2019]

GLP-1 receptor analogues (GLP-1RAs) are effective treatments for type 2 diabetes, improving blood sugar control and weight management while having a low risk of hypoglycemia.

These medications work by increasing insulin secretion and reducing glucagon release in a glucose-dependent manner, and they are generally well tolerated, with gastrointestinal issues being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Analogues in Type 2 Diabetes: Their Use and Differential Features. Lyseng-Williamson, KA.[2022]

GLP-1 analogues, such as exenatide and liraglutide, significantly improve glycemic control in type 2 diabetes patients, reducing HbA1c levels by about 1% compared to placebo, based on a review of 17 trials with 6899 participants.

These medications also promote weight loss and improve beta-cell function, although gastrointestinal side effects like nausea are common, particularly at the start of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide analogues for type 2 diabetes mellitus. Shyangdan, DS., Royle, P., Clar, C., et al.[2023]

Glucagon and glucagon-like peptides (GLPs) play crucial roles in regulating blood glucose levels, with glucagon increasing glucose production in the liver and GLP-1 enhancing insulin secretion while inhibiting glucagon release, making them important for glucose homeostasis.

A pilot study on GLP-2 showed promising results in improving energy absorption and bone density in patients with short bowel syndrome, indicating potential therapeutic benefits for various diseases, including diabetes and intestinal disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Glucagon-like peptides--synthesis, biological actions and some clinical implications]. Otto Buczkowska, E., Dworzecki, T.[2006]

Incretins, specifically GLP-1, play a crucial role in insulin secretion and can normalize blood glucose levels in type 2 diabetes, despite reduced responsiveness of pancreatic B-cells in these patients.

GLP-1 has multiple antidiabetic effects, including inhibiting glucagon secretion and delaying gastric emptying, but its short half-life limits its use, leading to the development of longer-lasting GLP-1 analogues and DPP-IV inhibitors as potential treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The entero-insular axis in type 2 diabetes--incretins as therapeutic agents. Creutzfeldt, W.[2006]

GLP-1 plays a crucial role in regulating blood glucose levels by influencing insulin secretion and appetite control, making it a potential treatment for diabetes.

GLP-2 supports nutrient absorption and intestinal health by promoting the growth of intestinal cells and reducing cell death, suggesting its therapeutic use in patients with intestinal injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis, secretion and biological actions of the glucagon-like peptides. Lovshin, J., Drucker, DJ.[2004]

In a phase 3 trial involving 599 patients with uncontrolled type 2 diabetes, once-weekly dulaglutide was found to be non-inferior to once-daily liraglutide in reducing HbA1c levels, with a mean reduction of -1.42% for dulaglutide compared to -1.36% for liraglutide.

Both treatments had similar safety profiles, with common gastrointestinal side effects like nausea and diarrhea, and no severe hypoglycemia reported, indicating that dulaglutide is a safe and effective alternative to liraglutide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Dungan, KM., Povedano, ST., Forst, T., et al.[2022]

GLP-1-based therapies for type 2 diabetes, including GLP-1 receptor agonists and DPP-4 inhibitors, effectively lower HbA1c levels by approximately 0.8-1.1% over 12 weeks, demonstrating their efficacy as both monotherapy and in combination with other diabetes medications.

These therapies not only improve glycemic control but also have a low risk of adverse events, including hypoglycemia, making them a safe treatment option, particularly beneficial when combined with metformin for patients not adequately controlled by metformin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLP-1 for type 2 diabetes. Ahrén, B.[2015]

GLP-1 is a gut hormone that enhances insulin secretion and promotes pancreatic B-cell growth, making it a promising treatment for Type 2 diabetes, especially since its insulinotropic action remains effective in diabetic patients.

DPP-IV resistant analogues like exenatide and selective DPP-IV inhibitors have shown significant efficacy in improving glycemic control and reducing body weight in Type 2 diabetes, and they are well tolerated compared to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incretins and other peptides in the treatment of diabetes. Todd, JF., Bloom, SR.[2018]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0002916525002400

Nutritional priorities to support GLP-1 therapy for obesity Individuals using GLP-1s to treat obesity experience significant reductions in appetite and energy intake, with observed caloric reductions of 16%–39% [56].

2. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT01560676

https://clinicaltrials.gov/ct2/show/NCT01560676 No information is available for this page.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11402415/

GLP-1 single, dual, and triple receptor agonists for treating ... In a phase 2 clinical trial, retatrutide reduced HbA1c to −2.02%, compared to −1.41% for dulaglutide 1.5 mg and −0.01% for placebo (Table 1).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5685032/

Efficacy and safety of the glucagon-like peptide-1 receptor ... Lixisenatide, however, resulted in significantly greater reductions in body weight and postprandial plasma glucose excursions than sitagliptin.

5. link.springer.com link.springer.com/article/10.1007/s11357-025-01899-w

Glucagon receptor signaling is indispensable for the ... Caloric restriction fails to further improve glucose homeostasis in Gcgr KO mice. We previously showed that lifelong 15% CR improves glucose ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7666610/

Glucagon Therapy: A Comparison of Current and Novel ... The most common adverse reactions for adults include nausea, vomiting, and injection site edema; hypoglycemia, headache, abdominal pain, hyperglycemia, ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/98/020918s000_Glucagen_Medr.pdf

GlucaGen (Glucagon (rDNA)) This is a standard test to distinguish type 1 from type. 2 diabetes. Patients were randomized to an initial test with' either GlucaGen or ...

8. hhs.texas.gov hhs.texas.gov/sites/default/files/documents/jan-2024-durb-agenda-item5l.pdf

Glucagon Agents Summary The safety and efficacy of intranasal glucagon (Baqsimi) in treating severe hypoglycemia have been established in pediatric patients ≥ 4 years of age. The ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT01994746

NCT01994746 | Efficacy and Safety of Nasal Glucagon for ... ... 2 years or type 2 diabetes receiving multiple daily insulin doses for at least 2 years; At least 18.0 years of age and less than 65.0 years; Body mass index ...

10. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2805054

Efficacy and Safety of Oral Small Molecule Glucagon-Like ... This randomized clinical trial investigates the efficacy, safety, and tolerability of danuglipron treatment for 16 weeks in adults with type ...