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.

Temozolomide (TMZ) can cross the blood‐brain barrier (BBB) and deliver methyl groups to the purine (guanine) bases of DNA, leading to mispairing during DNA replication and subsequent cell death. However, increased expression of the repair enzyme methyl guanine methyltransferase (MGMT), which removes methyl groups from purine bases, counteracts methylation by TMZ. We evaluated the anticancer potential of thymoquinone (TQ), a hydrophobic flavonoid that inhibits resistance and induces apoptosis in various cancer cells, both in vitro and in vivo. In vitro experiments showed that compared with the Hs683 and M059J cell lines, U251 cells were more sensitive to TMZ. Compared to U251 cells, U251R cells, a TMZ drug‐resistant strain established in this study, are characterized by increased expression of phosphorylated extracellular signal‐regulated kinase (p‐ERK) and MGMT. TQ treatments induced apoptosis in all cell lines. The p38 mitogen‐activated protein kinase signal pathway was mainly activated in U251 and U251R cells; however, p‐ERK and MGMT upregulation could not suppress TQ effects. Furthermore, si‐p38 pretreatment of U251R cells in TQ treatments inhibited cell apoptosis. We speculate that TQ contributed to the phosphorylation and activation of p38, but not of ERK‐induced apoptosis (irrespective of TMZ resistance). In vivo, U251R‐derived tumors subcutaneously inoculated in nude mice exhibited significant tumor volume reduction after TQ or TQ + TMZ cotreatments. High‐performance liquid chromatography assay confirmed the presence of TQ in murine brain tissues. Our findings demonstrate that TQ can effectively cross the BBB and function alone or in combination with TMZ to treat glioblastoma.