Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis

• Published in: Scientific reports Vol. 5; no. 1; p. 10211
• Main Authors: Tiano, Joseph P, Tate, Chandra R, Yang, Bin S, DiMarchi, Richard, Mauvais-Jarvis, Franck
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.05.2015
• Subjects: 17β-Estradiol; Animals; Blood glucose; Body Composition - drug effects; Cancer; Cell Culture Techniques; Diabetes; Diabetes mellitus; Drug Carriers; Drug Delivery Systems; Estrogen receptors; Estrogens; Estrogens - administration & dosage; Fasting; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - metabolism; Glucose; Glucose - metabolism; Homeostasis; Homeostasis - drug effects; Humans; Insulin; Insulin - metabolism; Insulin Resistance; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Laboratory testing; Male; Mice; Middle Aged; Pancreas; Receptor mechanisms; Rodents; Secretion
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep10211

The female estrogen 17β-estradiol (E2) enhances pancreatic β-cell function via estrogen receptors (ERs). However, the risk of hormone dependent cancer precludes the use of general estrogen therapy as a chronic treatment for diabetes. To target E2 to β-cells without the undesirable effects of general estrogen therapy, we created fusion peptides combining active or inactive glucagon-like peptide-1 (GLP-1) and E2 in a single molecule (aGLP1-E2 and iGLP1-E2 respectively). By combining the activities of GLP-1 and E2, we envisioned synergistic insulinotropic activities of these molecules on β-cells. In cultured human islets and in C57BL/6 mice, both aGLP1 and aGLP1-E2 enhanced glucose-stimulated insulin secretion (GSIS) compared to vehicle and iGLP1-E2 without superior efficacy of aGLP1-E2 compared to GLP-1 alone. However, aGLP1-E2 decreased fasting and fed blood glucose to a greater extent than aGLP1 and iGLP1-E2 alone. Further, aGLP1-E2 exhibited improved insulin sensitivity compared to aGLP1 and iGLP1-E2 alone (HOMA-IR and insulin tolerance test). In conclusion, targeted estrogen delivery to non-diabetic islets in the presence of GLP-1 does not enhance GSIS. However, combining GLP-1 to estrogen delivers additional efficacy relative to GLP-1 alone on insulin sensitivity and glucose homeostasis in non-diabetic mice.