Article ; Online: Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes.
2012 Volume 56, Issue 2, Page(s) 423–433
Abstract: Aims/hypothesis: Type 2 diabetes mellitus is associated with reduced incretin effects. Although previous studies have shown that hyperglycaemia contributes to impaired incretin responses in beta cells, it is largely unknown how hyperlipidaemia, another ... ...
Abstract | Aims/hypothesis: Type 2 diabetes mellitus is associated with reduced incretin effects. Although previous studies have shown that hyperglycaemia contributes to impaired incretin responses in beta cells, it is largely unknown how hyperlipidaemia, another feature of type 2 diabetes, contributes to impaired glucagon-like peptide 1 (GLP-1) response. Here, we investigated the effects of NEFA on incretin receptor signalling and examined the glucose-lowering efficacy of incretin-based drugs in combination with the lipid-lowering agent bezafibrate. Methods: We used db/db mice to examine the in vivo efficacy of the treatment. Beta cell lines and mouse islets were used to examine GLP-1 and glucose-dependent insulinotropic peptide receptor signalling. Results: Palmitate treatment decreased Glp1r expression in rodent insulinoma cell lines and isolated islets. This was associated with impairment of the following: GLP-1-stimulated cAMP production, phosphorylation of cAMP-responsive elements binding protein (CREB) and insulin secretion. In insulinoma cell lines, the expression of exogenous Glp1r restored cAMP production and the phosphorylation of CREB. Treatment with bezafibrate in combination with des-fluoro-sitagliptin or exendin-4 led to more robust glycaemic control, associated with improved islet morphology and beta cell mass in db/db mice. Conclusions/interpretation: Elevated NEFA contributes to impaired responsiveness to GLP-1, partially through downregulation of GLP-1 receptor signalling. Improvements in lipid control in mouse models of obesity and diabetes increase the efficacy of incretin-based therapy. |
---|---|
MeSH term(s) | Animals ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Fatty Acids, Nonesterified/metabolism ; Glucagon-Like Peptide-1 Receptor ; Incretins/therapeutic use ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Glucagon/metabolism |
Chemical Substances | Fatty Acids, Nonesterified ; Glp1r protein, mouse ; Glucagon-Like Peptide-1 Receptor ; Incretins ; Receptors, Glucagon |
Language | English |
Publishing date | 2012-11-28 |
Publishing country | Germany |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 1694-9 |
ISSN | 1432-0428 ; 0012-186X |
ISSN (online) | 1432-0428 |
ISSN | 0012-186X |
DOI | 10.1007/s00125-012-2776-x |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Zs.A 279: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.