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

Abstract

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.

• Authors: Robert W Schwenk, Christian Baumeier, Brian Finan, Oliver Kluth, Christine Brauer, Hans-Georg Joost, Richard D DiMarchi, Matthias H Tschöp, Annette Schürmann
• Journal: Diabetologia (Diabetologia) Vol. 58 Issue 3 Pg. 604-14 (Mar 2015) ISSN: 1432-0428 [Electronic] Germany
• PMID: 25527001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogens
• Glucagon-Like Peptide 1

Topics

• Animals
• Estrogens (therapeutic use)
• Glucagon-Like Peptide 1 (therapeutic use)
• Hyperphagia (drug therapy, metabolism)
• Insulin-Secreting Cells (drug effects, metabolism)
• Islets of Langerhans (drug effects, metabolism)
• Male
• Mice
• Mice, Obese
• New Zealand