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Schwenk, R.W.* ; Baumeier, C.* ; Finan, B. ; Kluth, O.* ; Brauer, C.* ; Joost, H.G.* ; DiMarchi, R.D.* ; Tschöp, M.H. ; Schürmann, A.*

GLP-1–oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand Obese (NZO) mice.

Diabetologia 58, 604-614 (2015)
Publ. Version/Full Text DOI PMC
Creative Commons Lizenzvertrag
Open Access Green as soon as Postprint is submitted to ZB.
Aims/hypothesis: Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)–oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1–oestrogen during beta cell failure under glucolipotoxic conditions. Methods: Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1–oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1–oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed. Results: In contrast to GLP-1, GLP-1–oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1–oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1–oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells. Conclusions/interpretation: GLP-1–oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Beta Cells ; Glp-1 ; Liver Fat ; Nzo ; Oestrogen ; Pomc; Thioredoxin-interacting Protein; Estrogen-receptor-alpha; Insulin-resistance; Metabolic Syndrome; Glucose-tolerance; Leptin Receptor; Er-alpha; Expression; Gene; Apoptosis
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 58, Issue: 3, Pages: 604-614 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)