The molecular regulatory mechanisms and the characterization of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in hypoxia were studied in a mouse brain capillary endothelial cell line, MBEC4. Activation of GAPDH gene expression by hypoxia was suppressed by an intracellular Ca(2+) chelator and inhibited by a non-selective cation channel blocker or a Na(+)/Ca(2+) exchanger (NCX) blocker. Sequencing of reverse transcription-PCR products demonstrated that MBEC4 expressed an mRNA encoding NCX3, which functions even under cellular ATP-depleted conditions, in addition to mRNAs encoding NCX1 and NCX2. The inhibition of Ca(2+)/calmodulin-dependent protein kinases or c-Jun/AP-1 activation caused a significant decrease in the activation of GAPDH mRNA by hypoxia. These results suggest that hypoxia stimulates Ca(2+) influx through non-selective cation channels and causes the reverse operation of the three NCX isoforms, and consequently, increased intracellular Ca(2+) up-regulates GAPDH gene expression through an AP-1-dependent pathway. Furthermore, subcellular fractionation experiments showed that hypoxia increased GAPDH proteins not only in the cytosolic fraction, but also in the nuclear and particulate fractions, in which GAPDH should play no roles in glycolysis. However, the GAPDH activity did not rise in proportion to the increase of GAPDH protein by hypoxia even in the cytosolic fraction. These results suggest that not all hypoxia-induced GAPDH molecules contribute to glycolysis.

Impaired early-phase insulin response to glucose was associated with mild glucose intolerance, suggesting the importance of impaired insulin secretion in the development of glucose intolerance in nonobese subjects.

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BackgroundThe 52-week monotherapy with the dipeptidyl peptidase-4 inhibitor sitagliptin and the sulphonylurea glimepiride on early-phase insulin secretion in Japanese patients with type 2 diabetes mellitus (T2DM) is not known.MethodsA randomized, parallel-group, open-label trial was conducted at 18 centers between February, 2011 and March, 2013. 171 outpatients with T2DM were recruited and randomly assigned to glimepiride or sitagliptin by minimization. Doses of glimepiride (0.25–1.0 mg/day) and sitagliptin (25–100 mg/day) were adjusted for hemoglobin A1c (HbA1c) > 6.9 %. Analyses were performed on full analysis set (FAS) of randomized subjects taking medications as allocated, and underwent 75 g oral glucose tolerance test (OGTTs) before and after treatment. The primary outcome was insulinogenic index to quantify early-phase insulin secretion after treatment, which was evaluated by analysis of covariance (ANCOVA).ResultsOf 171 enrolled subjects, 68 in the sitagliptin group and 65 in the glimepiride group were included in the FAS (mean age, 64 years; baseline (HbA1c), 7.4 %). The primary outcome revealed a significantly higher insulinogenic index in the sitagliptin group than that in the glimepiride group (p = 0.036). Sitagliptin also reduced plasma glucose levels at 60 and 120 min during OGTT compared with glimepiride, while achieving a similar improvement in HbA1c during treatment. Body weight did not change in either of the two groups, and one case of hypoglycemia was observed in the glimepiride group.ConclusionsSitagliptin shows better effects on insulinogenic index after 52-week treatment compared with glimepiride in Japanese patients with T2DM.Trial registration University hospital Medical Information Network (UMIN) Clinical Trials Registry, No.00004791.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-016-0131-y) contains supplementary material, which is available to authorized users.