Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study).

The aim of this study was to evaluate the effect of gemigliptin vs sitagliptin or glimepiride as initial combination therapy with metformin on glycaemic variability and to assess the correlation between glycaemic variability reduction and the dipeptidyl peptidase-4 (DPP-4) inhibition in patients with type 2 diabetes. This multicentre, randomized, active-controlled, open-label exploratory study included 69 patients with HbA1c > 7.5%. Subjects were randomized to receive gemigliptin 50 mg (n = 24), sitagliptin 100 mg (n = 23) or glimepiride 2 mg (n = 22) for 12 weeks. After 12 weeks, the change in mean amplitude of glycaemic excursion (MAGE) compared with baseline was significantly lower in the DPP-4 inhibitor groups compared with that in patients who received glimepiride. Furthermore, the standard deviation (SD) of glucose was significantly lower in patients who received gemigliptin than that in patients who received sitagliptin or glimepiride. The DPP-4 inhibition was significantly correlated with changes in MAGE and SD of glucose. In conclusion, gemigliptin and sitagliptin were more effective than glimepiride in reducing glycaemic variability as initial combination therapy with metformin in patients with type 2 diabetes, and the DPP-4 inhibition was associated with a reduction in glycaemic variability.

A search for synthetic peptides that inhibit soluble N-ethylmaleimide sensitive-factor attachment receptor-mediated membrane fusion.

Soluble N-ethylmaleimide sensitive-factor attachment receptor (SNARE) proteins have crucial roles in driving exocytic membrane fusion. Molecular recognition between vesicle-associated (v)-SNARE and target membrane (t)-SNARE leads to the formation of a four-helix bundle, which facilitates the merging of two apposing membranes. Synthetic peptides patterned after the SNARE motifs are predicted to block SNARE complex formation by competing with the parental SNAREs, inhibiting neuronal exocytosis. As an initial attempt to identify the peptide sequences that block SNARE assembly and membrane fusion, we created thirteen 17-residue synthetic peptides derived from the SNARE motifs of v- and t-SNAREs. The effects of these peptides on SNARE-mediated membrane fusion were investigated using an in vitro lipid-mixing assay, in vivo neurotransmitter release and SNARE complex formation assays in PC12 cells. Peptides derived from the N-terminal region of SNARE motifs had significant inhibitory effects on neuroexocytosis, whereas middle- and C-terminal-mimicking peptides did not exhibit much inhibitory function. N-terminal mimicking peptides blocked N-terminal zippering of SNAREs, a rate-limiting step in SNARE-driven membrane fusion. Therefore, the results suggest that the N-terminal regions of SNARE motifs are excellent targets for the development of drugs to block SNARE-mediated membrane fusion and neurotransmitter release.