Document Detail


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.
MedLine Citation:
PMID:  23188390     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Z F Kang; Y Deng; Y Zhou; R R Fan; J C N Chan; D R Laybutt; J Luzuriaga; G Xu
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-28
Journal Detail:
Title:  Diabetologia     Volume:  56     ISSN:  1432-0428     ISO Abbreviation:  Diabetologia     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-06-12     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  423-33     Citation Subset:  IM    
Affiliation:
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital Shatin, Hong Kong, SAR, People's Republic of China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Diabetes Mellitus, Type 2 / drug therapy*,  metabolism*
Fatty Acids, Nonesterified / metabolism*
Incretins / therapeutic use*
Insulin-Secreting Cells / drug effects*,  metabolism*
Male
Mice
Mice, Inbred C57BL
Receptors, Glucagon / metabolism*
Chemical
Reg. No./Substance:
0/Fatty Acids, Nonesterified; 0/Incretins; 0/Receptors, Glucagon; 0/glucagon-like peptide-1 receptor
Comments/Corrections
Comment In:
Diabetologia. 2013 Feb;56(2):231-3   [PMID:  23188391 ]

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