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

Sci Rep. 2015 May 13;5:10211. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Composition / drug effects
  • Cell Culture Techniques
  • Drug Carriers
  • Drug Delivery Systems
  • Estrogens / administration & dosage*
  • Glucagon-Like Peptide 1 / administration & dosage*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose / metabolism*
  • Homeostasis / drug effects*
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Middle Aged


  • Drug Carriers
  • Estrogens
  • Insulin
  • Glucagon-Like Peptide 1
  • Glucose