title: 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.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine, Chicago, IL 60611.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Tiano
authors.affiliation: Division of Endocrinology &Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112.
authors.forename: Chandra R
authors.initials: CR
authors.lastname: Tate
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, 47405.
authors.forename: Bin S
authors.initials: BS
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, 47405.
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.affiliation: 1] Division of Endocrinology &Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112 [2] Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine, Chicago, IL 60611.
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D018929:Cell Culture Techniques; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004967:Estrogens / Q000008:administration & dosage*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged
chemical_list: D004337:Drug Carriers; D004967:Estrogens; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose