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

Abstract

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.

• Authors: Joseph P Tiano, Chandra R Tate, Bin S Yang, Richard DiMarchi, Franck Mauvais-Jarvis
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 10211 (May 13 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 25970118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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