Glucagon Response Study for Non-alcoholic Fatty Liver Disease

Overseen by Adrian Vella

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Adrian Vella

Disqualifiers: Abdominal surgery, Systemic illness, Vascular disease, MRI contraindications, Alcohol, others

No Placebo Group

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Whether impaired postprandial glucagon suppression in prediabetes and T2DM is an attempt to overcome resistance to glucagon's actions on hepatic AA catabolism, a defect in α-cell function, or a combination of both are important, unanswered questions. NAFLD is associated with T2DM risk and impaired insulin action. Unfortunately, it is unclear if glucagon resistance is caused by obesity, hepatic steatosis or both. The experiments outlined will determine if glucagon's actions on hepatic amino acid catabolism and EGP interact with hepatic lipid metabolism in lean and obese subjects with and without T2DM (and with varying degrees of hepatic steatosis).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

How does this drug differ from other treatments for non-alcoholic fatty liver disease?

This drug is unique because it uses glucagon-like peptide-1 (GLP-1) receptor agonists, which are typically used for diabetes and obesity, to help reduce liver fat and inflammation in non-alcoholic fatty liver disease. Unlike other treatments, it specifically targets the hormone glucagon to potentially improve liver health. ^{1 2 3 4 5}

Research Team

Adrian Vella

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults with obesity, Type 2 Diabetes, or Non-alcoholic Fatty Liver Disease who can consent to participate. It's not suitable for those with a history of certain abdominal surgeries, MRI contraindications like metal implants or claustrophobia, severe anemia (low hematocrit), abnormal thyroid levels (TSH), active illness/malignancy, significant vascular disease symptoms, or high alcohol consumption.

Inclusion Criteria

Willing to participate

Able to give consent

Exclusion Criteria

TSH less than 0.4 or greater than 5.5

I have another active illness or cancer.

I have had surgery in my upper stomach area before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a hyperglycemic clamp with 2 doses of glucagon to study hepatic metabolism

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Glucagon (Hormone Therapy)

Trial Overview The study investigates how glucagon—a hormone that affects blood sugar—interacts with liver metabolism in people who are lean and obese and may have Type 2 Diabetes. The focus is on understanding glucagon's role in breaking down amino acids and its relationship with liver fat content.

Participant Groups

Group I: Obese Adults Experimental Treatment 1 Intervention

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Group II: Healthy Adults Experimental Treatment 1 Intervention

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Group III: Adults with Type 2 Diabetes Experimental Treatment 1 Intervention

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Who Is Running the Clinical Trial?

Adrian Vella

Lead Sponsor

Trials

9

Recruited

210+

Findings from Research

In a study using non-obese mice with nonalcoholic steatohepatitis (NASH), the GLP-1 analogue exendin-4 significantly reduced liver fat accumulation and inflammation after four weeks of treatment, indicating its potential efficacy in managing NASH.

Exendin-4 works by inhibiting the influx of free fatty acids into the liver and reducing oxidative stress, which helps to alleviate the symptoms of hepatic steatosis and inflammation associated with NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. Yamamoto, T., Nakade, Y., Yamauchi, T., et al.[2022]

A systematic review of 11 randomized controlled trials involving 936 middle-aged individuals found that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced liver fat content and serum liver enzyme levels in patients with nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) over a median treatment duration of 26 weeks.

GLP-1 RAs, particularly liraglutide and semaglutide, also showed greater histological resolution of NASH without worsening liver fibrosis, indicating their potential as effective treatments for these liver conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials. Mantovani, A., Petracca, G., Beatrice, G., et al.[2021]

In a study involving 10 non-diabetic patients with non-alcoholic fatty liver disease (NAFLD) and 10 matched controls, GLP-1 infusion effectively suppressed glucagon levels in both groups, indicating that the glucagon-suppressive effect of GLP-1 is preserved in NAFLD patients.

Despite the presence of fasting hyperglucagonaemia in NAFLD patients, GLP-1 did not affect endogenous glucose production, suggesting that while GLP-1 enhances insulin secretion in these patients, it does not alter glucose output from the liver.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease. Junker, AE., Gluud, LL., van Hall, G., et al.[2018]

In a 52-week weight management trial, semaglutide significantly reduced alanine aminotransferase (ALT) levels by 6%-21% in subjects with elevated ALT, indicating its potential effectiveness in treating non-alcoholic fatty liver disease (NAFLD).

Semaglutide also led to significant reductions in high-sensitivity C-reactive protein (hsCRP) levels by 25%-43% compared to placebo, suggesting an anti-inflammatory effect that may benefit individuals at risk for NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Newsome, P., Francque, S., Harrison, S., et al.[2021]

In a study of 4442 patients with type 2 diabetes, liraglutide 1.8 mg significantly reduced liver enzyme levels (ALT) compared to placebo, indicating potential benefits for liver health.

The improvement in liver enzymes was primarily linked to weight loss and better blood sugar control rather than a direct effect of liraglutide on liver injury, suggesting that its efficacy may be mediated through these mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Armstrong, MJ., Houlihan, DD., Rowe, IA., et al.[2022]

References

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

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease. [2018]

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

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. [2022]