Glucagon

Research Reagent · Laboratory Use Only

What are the research findings on glucagon's role in glucose regulation and metabolic function?

Glucagon is a 29-amino acid peptide hormone secreted by pancreatic alpha cells that counteracts insulin by stimulating hepatic glycogenolysis and gluconeogenesis. Research published in Diabetes (PMID: 28223344) highlights its critical role in glucose homeostasis. Studies also explore glucagon receptor antagonism as a therapeutic target in type 2 diabetes and obesity research.

Scientific AbstractPMID 42029657 · 2026

Background & Aims

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors individually benefit patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the effect of GLP-1 receptor agonist-SGLT-2 inhibitor combination on the risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and type 2 diabetes (T2D).

Methods

This is a target trial emulation study using data from U.S. Marketscan Databases. Propensity score-matched cohorts were built to compare (1) 4606 patients who received GLP-1 receptor agonist-SGLT-2 inhibitor combination with 18424 who received only GLP-1 receptor agonist, and (2) 5368 patients who received this combination with 21472 who received only SGLT-2 inhibitor. Cox regression models were conducted in on-treatment designs.

Results

Compared with GLP-1 receptor agonists, GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 39% lower risk of major adverse liver outcomes (HR 0.61 [95%CI 0.49 to 0.77]) and a 35% lower risk of major adverse cardiovascular events (HR 0.65 [0.60 to 0.70]) during a median follow-up of 6.3 months. Compared with SGLT-2 inhibitors, the combination was associated with a 43% lower risk of major adverse liver outcomes (HR 0.57 [0.46 to 0.69]) and a 20% lower risk of major adverse cardiovascular events (HR 0.80 [0.75 to 0.86]) during a median follow-up of 6.0 months.

Conclusion

In this study, GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and T2D.

Mechanistic Research SummaryCurated from PubMed

This data is for laboratory research purposes only. Not for human or animal consumption.

What is Glucagon and GLP-1 Receptor Agonist-SGLT2 Inhibitor Combination Therapy?

Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin-based therapeutics that enhance insulin secretion and promote weight loss, while sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce renal glucose reabsorption. Combined therapy represents a dual-mechanism approach for managing metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D).

Mechanism of Action

GLP-1 receptor agonists activate GLP-1 receptors on pancreatic beta cells and peripheral tissues, enhancing insulin secretion, improving glucose homeostasis, and reducing hepatic fat accumulation through weight-dependent and weight-independent pathways. SGLT-2 inhibitors block the sodium-glucose cotransporter-2 in renal proximal tubules, promoting urinary glucose excretion and reducing systemic glucose burden while improving hepatic lipid metabolism and myocardial energy utilization. The combination synergistically targets hepatic steatosis, systemic inflammation, and cardiovascular dysfunction.

Observed Laboratory Results

  • 39% reduction in major adverse liver outcomes (HR 0.61 [95% CI 0.49–0.77]) versus GLP-1 receptor agonist monotherapy over 6.3-month median follow-up
  • 35% reduction in major adverse cardiovascular events (HR 0.65 [0.60–0.70]) with combination therapy compared to GLP-1 receptor agonist alone
  • 43% reduction in major adverse liver outcomes (HR 0.57 [0.46–0.69]) versus SGLT-2 inhibitor monotherapy, with 20% cardiovascular risk reduction (HR 0.80 [0.75–0.86]) over 6.0-month median follow-up
Clinical Research Parameters
10 trials4 human studies

The following data represents formally registered clinical research studies and peer-reviewed human subject research indexed in public registries. All dose ranges, endpoints, and observations below reflect published study parameters — not recommendations. For research reference only.

ClinicalTrials.gov ↗
NCT03665350
TERMINATEDPhase IIn=10

Insulin Treatment in Diabetic Older People With Heart Failure.

Cardiac failure (HF) and type 2 diabetes mellitus (T2DM) are two clinical conditions with a significant impact on public health worldwide. In the elderly population the prevalence of T2DM is constantly increasing as well as its incidence in all Western countries including Italy. The combination of HF and T2DM is frequent and leads to an increased risk of death and of non-fatal adverse cardiovascul

Study Interventions
Insulin
Primary Endpoints
Change in blood glucose variability
Study Period
2018-11-08 → 2019-09-18
NCT07366710
ACTIVE NOT RECRUITINGN/An=36

Measuring Amino Acid and Glucose Metabolism in Healthy Volunteers and NAFLD Patients Using Total-body PET

This observational study aims to quantify whole-body amino acid and glucose metabolism in healthy adults and in patients with non-alcoholic fatty liver disease (NAFLD) using total-body PET/CT. The study investigates how orally and intravenously administered PET tracers (18F-FDG and 18F-FET) are absorbed in the gastrointestinal tract, distributed across major organs, and metabolized in different ph

Study Interventions
18F-FDG (oral), 18F-FDG (intravenous), 18F-FET (oral)
Primary Endpoints
Whole-body tracer uptake (SUVmean) assessed using total-body PET/CT
Study Period
2024-11-05 → 2027-10
NCT02036710
COMPLETEDN/An=12

Location of GLP-1 Release

Background: Physicians do not have a unified, scientifically tested theory of causation for obesity and its comorbidities, nor do they have explanations for the mechanics of the metabolic/bariatric surgery procedures. Integral to proffered hypotheses are the actions of the hormones glucagon-like peptide (GLP-1), peptide YY (PYY), and leptin. Study objective: To obtain blood levels of GLP-1, PYY,

Primary Endpoints
GLP-1; peptide YY (PYY)
Study Period
2011-11 → 2013-10
NCT04372550
UNKNOWNN/An=90

Effects of Early Exercise Rehabilitation in Severe Burns

BACKGROUND: Postburn changes in glucose and protein metabolism are at their peak during the acute phase of severe burns. The resulting metabolic derangements lead to substantial muscle wasting, insulin resistance, which ultimately hampers full recovery and reintegration into society. PURPOSE: This randomized controlled trial was initiated to investigate the effects of exercise-based rehabilitat

Study Interventions
Exercise, Standard of Care
Primary Endpoints
Change in quadriceps muscle layer thickness (QMLT); Change in rectus femoris cross sectional area (RF-CSA)
Study Period
2019-11-25 → 2021-10
NCT01337440
UNKNOWNPhase IVn=20

Efficacy and Safety of Ursodeoxycholic Acid (UDCA) Added to the DPP-4 Inhibitor in People With Type 2 Diabetes and Chronic Liver Diseases

1\. Objectives 1. To test whether Ursodeoxycholic Acid (UDCA) increases Glucagon-like peptide-1 (GLP-1) response to nutrients and improves glycemic control in people with type 2 diabetes. 2. To test whether sitagliptin enhances UDCA-induced beneficial effect in GLP-1 levels and glycemic control. 3. To test safety of combination therapy of sitagliptin and UDCA in people with type 2 diabetes. 2\.

Study Interventions
UDCA, Sitagliptin
Primary Endpoints
the difference of haemoglobin A1c (HbA1c) and glycoalbumin (GA)
Study Period
2010-04 → 2013-03
NCT03235050
COMPLETEDPhase IIn=834

A Study to Evaluate the Efficacy and Safety of MEDI0382 in the Treatment of Overweight and Obese Subjects With Type 2 Diabetes

This study is designed to evaluate the dose range for MEDI0382 with respect to blood glucose control and weight loss effects, as well as to further explore the safety profile of MEDI0382

Study Interventions
MEDI0382 low dose, MEDI0382 mid dose, MEDI0382 high dose
Primary Endpoints
Change in HbA1c; Percent Change in Body Weight
Study Period
2017-08-02 → 2019-06-14
NCT03713190
COMPLETEDPhase IIn=25

Effects of Empagliflozin on Endogenous Glucose Production in End Stage Renal Disease(ESRD).

A study of the effects of empagliflozin, a SGLT-2 inhibitor, on endogenous glucose production and plasma glucagon levels in patients with end-stage renal disease (ESRD)

Study Interventions
Empagliflozin, Placebo
Primary Endpoints
Changes in plasma Glucose level
Study Period
2018-09-10 → 2020-03-15
NCT07268508
RECRUITINGN/An=60

Impact of a Pro-diversity Gut Microbiota Diet After a Bariatric Surgery on Gut Microbiota, Eating Behaviour and Sensory Function

Bariatric surgery is the most effective treatment for long-term weight loss and reducing obesity-related health risks. It alters the gastrointestinal tract as well as metabolic and hormonal functions, influencing eating behaviour. However, weight loss outcomes and long-term maintenance vary between patients, likely due to changes in the gut microbiota. Dietary recommendations aimed at improving mi

Study Interventions
Nutritional counseling
Primary Endpoints
Microbiota diversity 12 months after surgery
Study Period
2025-11-05 → 2029-04-05
NCT02811276
COMPLETEDN/An=20

The Impact of a High Protein Diet on Substrate Oxidation and Energy Metabolism

In the 19th century, researchers found out that the differences in the energy content of macronutrients (protein, carbohydrate and fat) can elicit different responses in the amount of calories individuals burn per day. It was demonstrated that protein has a metabolic advantage when compared to the other macronutrients (carbohydrate and fat). Since these findings, researchers all over the world sta

Study Interventions
Diet
Primary Endpoints
Difference in fat balance assessed by indirect calorimetry during 32 hours of a high-protein (HP) total diet replacement compared to 32hours of a control (CON) diet.
Study Period
2016-10 → 2018-03
NCT02001363
UNKNOWNN/An=90

Efficacy Study of Glucagonlike Peptide-1 to Treat Reperfusion Injury

The investigators planned to research the cardioprotective effects of intravenous liraglutide on reperfusion injury.

Study Interventions
liraglutide (Novo Nordisk, Bagsværd, Denmark), liraglutide placebo (Novo Nordisk)
Primary Endpoints
the salvage index measured by cardiac magnetic resonance
Study Period
2013-11 → 2016-03

All data presented on this page is for laboratory research purposes only. Glucagon is referenced here as a research reagent. This page does not constitute medical advice, clinical guidance, or endorsement of any compound for human or animal use. All referenced studies are available via PubMed (PMID: 42029657) and the DOI-linked journal publication. Researchers must consult applicable institutional and regulatory frameworks before conducting any protocols.