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FSTL3-Neutralizing Antibodies Enhance Glucose-Responsive Insulin Secretion in Dysfunctional Male Mouse and Human
Melissa L Brown1, Alexa Lopez2, Nolan Meyer2
1Department of Nutrition and Public Health, University of Saint Joseph, West Hartford, CT 06117, USA.
Abstract:
Diabetes is caused by insufficient insulin production from pancreatic beta cells or insufficient insulin action, leading to an inability to control blood glucose. While a wide range of treatments exist to alleviate the symptoms of diabetes, therapies addressing the root cause of diabetes through replacing lost beta cells with functional cells remain an object of active pursuit. We previously demonstrated that genetic deletion of Fstl3, a critical regulator of activin activity, enhanced beta cell number and glucose-responsive insulin production. These observations suggested the hypothesis that FSTL3 neutralization could be used to therapeutically enhance beta cell number and function in humans. To pursue this possibility, we developed an FSTL3-neutralizing antibody, FP-101, and characterized its ability to prevent or disrupt FSTL3 from complexing with activin or related ligands. This antibody was selective for FSTL3 relative to the closely related follistatin, thereby reducing the chance for off-target effects. In vitro assays with FP-101 and activin revealed that FP-101-mediated neutralization of FSTL3 can enhance both insulin secretion and glucose responsiveness to nonfunctional mouse and human islets under conditions that model diabetes. Thus, FSTL3 neutralization may provide a novel therapeutic strategy for treating diabetes through repairing dysfunctional beta cells.
Insights
Neutralizing FSTL3 with antibody FP-101 enhances pancreatic beta cell function and insulin secretion. This approach may offer a novel therapeutic strategy for treating diabetes by repairing dysfunctional beta cells.
Area of Science:
- Endocrinology
- Immunology
- Regenerative Medicine
Background:
- Diabetes mellitus results from impaired insulin production or action, leading to hyperglycemia.
- Current treatments manage symptoms, but therapies targeting the root cause, such as beta cell regeneration, are actively sought.
- Follistatin-like 3 (FSTL3) regulates activin activity and its genetic deletion enhances beta cell function.
Purpose of the Study:
- To investigate the therapeutic potential of neutralizing FSTL3 for enhancing beta cell number and function in diabetes.
- To develop and characterize an FSTL3-neutralizing antibody, FP-101, for potential diabetes treatment.
Main Methods:
- Development of a selective antibody, FP-101, targeting FSTL3 and its interaction with activin.
- In vitro assays using FP-101 to assess its effect on insulin secretion and glucose responsiveness in mouse and human islets under diabetic conditions.
Main Results:
- FP-101 selectively neutralizes FSTL3, minimizing off-target effects compared to follistatin.
- In vitro studies demonstrated that FP-101 enhances insulin secretion and glucose responsiveness in nonfunctional islets.
- FSTL3 neutralization improved both insulin secretion and glucose sensitivity in models of diabetes.
Conclusions:
- FSTL3 neutralization via antibody FP-101 shows promise for enhancing beta cell function.
- This strategy represents a potential novel therapeutic approach for treating diabetes by restoring beta cell function.
- Targeting FSTL3 offers a pathway for regenerative therapy in diabetes management.
