TY  - JOUR
TI  - Estrogen improves islet morphology and gut hormone distribution to enhance glucose control in ob/ob mice
AU  - Sridhar, Ananyaa
AU  - Iyer, Vishnu NH
AU  - McGuigan, Orla
AU  - Flatt, Peter R
AU  - Moffett, Charlotte R
AU  - Khan, Dawood
PY  - 2026
JO  - Exploration of Endocrine and Metabolic Diseases
VL  - 3
SP  - 101475
DO  - 10.37349/eemd.2026.101475
UR  - https://www.explorationpub.com/Journals/eemd/Article/101475
AB  - Aim: Estrogens regulate energy balance and glucose homeostasis, but whether they coordinate endocrine changes across the gut–pancreas axis in obesity remains unclear. This study examined whether ethinyl estradiol (EE2) improves metabolic control in obese diabetic mice through combined effects on pancreatic islets and intestinal enteroendocrine cells. Methods: Female ob/ob mice received EE2 (4,000 ng/mL) or vehicle in drinking water for 21 days. Body weight, food intake, glucose levels, glucose tolerance, pancreatic islet composition, and ileal enteroendocrine cell populations were assessed using biochemical assays and immunohistochemistry. Results: EE2 significantly reduced body weight and energy intake and produced sustained lowering of blood glucose with markedly improved glucose tolerance and reduced terminal insulin levels. EE2 increased islet density and beta-cell proliferation and shifted islet size distribution toward larger islets, consistent with enhanced islet growth. Alpha-cell area was significantly reduced, indicating improved insulin–glucagon balance. Peptide YY (PYY)-positive cells within pancreatic islets were markedly increased, whereas somatostatin (SST)-positive cells were unchanged. In the ileum, EE2 significantly reduced crypt depth and increased the number of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-positive enteroendocrine cells, particularly within crypt regions, indicating enhanced incretin cell abundance. These coordinated changes across the gut and pancreas were associated with improved glucose control and reduced hyperinsulinaemia. Conclusions: EE2 improves metabolic control in obese diabetic mice through linked changes in pancreatic islet cell composition and intestinal incretin-producing cells. By increasing beta-cell renewal, reducing alpha-cell area, and enhancing GLP-1, GIP, and PYY expression, estrogen establishes a gut–pancreas endocrine environment that supports glucose homeostasis in obesity.
ER  -