GLP-1 Follicular Extracellular Vesicles: β-Cell Regenerative Therapy in Type 2 Diabetes Mellitus and PMOS Dysfunction
DOI:
https://doi.org/10.18192/osurj.v5i2.7982Abstract
Type 2 Diabetes Mellitus (T2DM) is characterized by β-cell dysfunction and loss of insulin-producing mass in the pancreas (1). Current glucose-lowering therapies slow disease progression but fail to reverse β-cell decline (2). Polyendocrine Metabolic Ovarian Syndrome (PMOS) and T2DM share underlying metabolic dysfunction, including insulin resistance and chronic inflammatory signaling. Restoring β-cell health may represent a promising strategy to improve metabolic regulation, improve glycemic management, and potentially alleviate PMOS-related infertility (3).
This study proposes engineering ovarian follicular-fluid-derived extracellular vesicles (FF-EVs) to support pancreatic β-cell regeneration. FF-EVs are intended to enhance β-cell mass, improve glucose-stimulated insulin secretion, and reduce T2DM-linked reproductive dysfunction like PMOS (4).
Follicular fluid from hormonally stimulated female C57BL/6 mice will be used to isolate EVs enriched in reproductive microRNAs and insulin-like growth factors (5). These are engineered to display glucagon-like-peptide-1 (GLP-1) on their membrane surface through fusion with EV-anchoring Lysosome-Associated Membrane Protein 2B (LAMP2B), enabling selective pancreatic β-cell uptake through GLP-1 receptor binding. The engineered EVs will be loaded with pro-regenerative cargo proteins (harmine and mRNAs encoding PDX1, NGN3, and MAFA), promoting β-cell proliferation and β-cell mass restoration (6)
Optimal EV formulations will be tested in C57BL/6 mice (no-STZ, STZ-induced). β-cell viability, diabetic markers (Glut2, Glut4, INSR, IRS1/2) were assessed in vitro through glucose-stimulated insulin secretion, then in vivo evaluation of pancreatic β-cell proliferation (7).
Translational evaluation will use human β-cell lines and in vitro human organoids (pancreas-ovarian follicles) to validate β-cell recovery and improvements of metabolic-reproductive parameters.
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