title: 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: OBJECTIVE
  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
  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.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.
authors.forename: Z F
authors.initials: ZF
authors.lastname: Kang
authors.forename: Y
authors.initials: Y
authors.lastname: Deng
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: R R
authors.initials: RR
authors.lastname: Fan
authors.forename: J C N
authors.initials: JC
authors.lastname: Chan
authors.forename: D R
authors.initials: DR
authors.lastname: Laybutt
authors.forename: J
authors.initials: J
authors.lastname: Luzuriaga
authors.forename: G
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018027:Receptors, Glucagon / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D018027:Receptors, Glucagon