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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

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.

Type Journal
ISBN 1432-0428 (Electronic) 0012-186X (Linking)
Authors Kang, Z. F.; Deng, Y.; Zhou, Y.; Fan, R. R.; Chan, J. C.; Laybutt, D. R.; Luzuriaga, J.; Xu, G.;
Garvan Authors A/Prof Ross Laybutt
Publisher Name DIABETOLOGIA
Published Date 2013-01-01 00:00:00
Published Volume 56
Published Issue 2
Published Pages 423-33
URL http://www.ncbi.nlm.nih.gov/pubmed/23188390
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?11705_12169/13_Kang_Diabetologica_.pdf