A Game-Changing Solution for Obesity and Diabetes: Optimizing Endogenous GLP-1 to Reduce Weekly Injections

Understanding GLP-1 and Its Physiological Importance

Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by intestinal L-cells specifically in the colon and ileum through the post-translational processing of proglucagon. Upon nutrient intake, GLP-1 is secreted into the bloodstream, stimulating glucose-dependent insulin release from pancreatic β-cells, suppressing glucagon from α-cells, slowing gastric emptying, and signaling satiety to the brain. L-cells use a variety of GPCRs and transporters that control GLP-1 secretion to sense nutrients via amino acids, sugars, and fatty acids

However, native GLP-1 has a very short half-life in circulation due to rapid degradation by dipeptidyl peptidase-4 (DPP-4). Several serious metabolic disorders can occur when GLP-1 secretion or responsiveness is compromised:

1. Type 2 Diabetes Mellitus (T2DM) is due to inadequate GLP-1, which leads to uncontrolled glucagon secretion and insufficient insulin release, resulting in poor glycemic control.
2. Dysregulated appetite and obesity occur because weight gain and increased food intake are caused by a weakened satiety response driven by blunted GLP-1 signaling.
3. Metabolic Dysregulation (e.g., Dyslipidemia, NAFLD) because GLP-1 also acts on hepatic metabolism and lipid regulation.

Clinical Challenges in Current GLP-1 Therapy

Presently, many patients are treated with systemic GLP-1 receptor agonists (e.g., semaglutide, liraglutide) by weekly injections. These treatments work well to reduce blood sugar, increase insulin production, and cause weight loss. However, they also present important limitations:

1. Adherence issues arise because frequent injections are still difficult for patients over a long period of time.
2. Side effects can occur because of the high systemic levels and can result in gastrointestinal distress, nausea, and other negative effects.
3. Durability is also limited, as stopping treatment often results in metabolic rebound, including weight regain and loss of glycemic control due to GLP-1 production being inhibited.

These limitations emphasize the need for a more robust, physiological GLP-1 treatment. Gene-based strategies are being pioneered by biotechnology companies RenBio and Fractyl Health to facilitate sustained GLP-1 production.

A Revolutionary Treatment for GLP-1 Delivery

Using its MYO Technology, RenBio transforms target tissues or muscle into long-term GLP-1 producers by introducing plasmid DNA encoding a GLP-1 receptor agonist. In preclinical studies presented at ASGCT, MYO-based GLP-1 delivery demonstrated long-term circulating GLP-1 levels and durable weight control in an animal obesity model.

On the other side, Fractyl Health uses an AAV-based gene therapy (RJVA-001) that targets pancreatic β-cells using a glucose-responsive promoter designed to ensure that GLP-1 is secreted only in nutrient-regulated physiological conditions. In db/db mice (T2DM model), a single administration of RJVA-001 resulted in a glucose reduction of up to ~50% and a body weight loss of ~11%, outperforming chronic semaglutide. In diet-induced obese mice, sustained weight maintenance was shown over 13 weeks post-dose. In Yucatan pig models, low-dose AAV delivery to the pancreas via endoscopically guided catheter achieved therapeutically relevant GLP-1 expression with no observed adverse safety signals.

These innovations allow single-dose treatment without multiple injections. They are mimicking the natural process of the body to release GLP-1 in response to glucose. Additionally, they enhance safety by reducing vector doses and systemic GLP-1 exposure, potentially lowering the risk of side effects and immune-related issues.

These therapies represent a promising breakthrough for obesity and type 2 diabetes by reducing the need for weekly injections and enabling the body to serve as a sustained source of GLP-1.

However, these therapies remain in preclinical or IND/CTA-enabling stages. Comprehensive analyses are still required, including immune response, transgene expression control, and long-term safety. To ensure product purity, stability, and safety, plasmid DNA-based or AAV-based products must be produced under strict GMP guidelines. Contamination-free and exact environmental control are critical to this process. Specialized lab equipment is necessary to support every phase of development.

Essential Laboratory Equipment for Reliable GLP-1 Therapeutic Development

Labs utilize two essential tools to meet these requirements: a biosafety cabinet, which enables the sterile handling of plasmid DNA and viral vectors, and a CO₂ incubator, which ensures ideal conditions for mammalian cell growth during AAV production. Key components that support reliable and GMP-aligned workflows are highlighted in the following equipment features.

Esco G4 Biological Safety Cabinet

• Centurion 7" Capacitive touchscreen LCD. Easy-to-use, smartphone-like user interface
• Energy efficient DC-ECM Blower that provides stable airflow and reduce operating cost
• ULPA filter, 10x safer than HEPA, provides cleaner ISO Class 3 work zone
• Large performance envelope with the widest margin of operator and product protection
• Anti-microbial coating with silver ions to reduce bio-burden and lab contamination
• Easy to clean with curved wall corners, dished tray, tray support rods, and angled drain pan

CelCulture® Touch CO₂ Incubator

• Centurion Touchscreen Controller with 7-inch HD display. Intuitive and easy to use
• Heat-resistant CO2 IR sensor features drift-free and stays in place during decontamination
• Direct heat and air jacket system ensures rapid temperature recovery and uniform heating.
• Fast CO2 recovery after door opening
• ULPA filter to reduce contamination risk.
• The rounded chamber design for hassle-free, tool-free cleaning

References

Baggio, L. L., & Drucker, D. J. (2007). Biology of incretins: GLP-1 and GIP. Gastroenterology, 132(6), 2131–2157. https://doi.org/10.1053/j.gastro.2007.03.054

Centers for Disease Control and Prevention. (2024). Prevalence of diagnosed diabetes—United States. https://www.cdc.gov/diabetes/

Drucker, D. J. (2018). Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metabolism, 27(4), 740–756. https://doi.org/10.1016/j.cmet.2018.03.001

Ehmsen, S., et al. (2022). A single injection of AAV-GLP1 improves glucose regulation and reduces body weight in obese mice. Molecular Therapy, 30(5), 1921–1934. https://doi.org/10.1016/j.ymthe.2022.02.019

Fractyl Health. (2024). Rejuva® gene therapy platform overview. https://www.fractyl.com/

Haberman, N. (2024). Gene therapy to induce long-acting GLP-1 for obesity and diabetes: Preclinical advances. Nature Medicine News. https://www.nature.com/

RenBio. (2024). RBIO-101: DNA-based, single-dose GLP-1 therapy. https://www.renbio.com/

Rowlands, J., et al. (2018). GLP-1 action in the brain: From cellular physiology to neurobiology of disease. British Journal of Pharmacology, 175(21), 3977–3987. https://doi.org/10.1111/bph.14489

Xu, G., et al. (2023). Advances in GLP-1–based therapeutics: Pharmacology, efficacy, and limitations. Diabetes, Obesity and Metabolism, 25(1), 67–82. https://doi.org/10.1111/dom.14932