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Role of Epac2A/Rap1 Signaling in Interplay Between Incretin and Sulfonylurea in Insulin Secretion
Takahashi, Harumi,Shibasaki, Tadao,Park, Jae-Hyung,Hidaka, Shihomi,Takahashi, Toshimasa,Ono, Aika,Song, Dae-Kyu,Seino, Susumu American Diabetes Association 2015 Diabetes Vol.64 No.4
<P>Incretin-related drugs and sulfonylureas are currently used worldwide for the treatment of type 2 diabetes. We recently found that Epac2A, a cAMP binding protein having guanine nucleotide exchange activity toward Rap, is a target of both incretin and sulfonylurea. This suggests the possibility of interplay between incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion. In this study, we examined the combinatorial effects of incretin and various sulfonylureas on insulin secretion and activation of Epac2A/Rap1 signaling. A strong augmentation of insulin secretion by combination of GLP-1 and glibenclamide or glimepiride, which was found in <I>Epac2A</I><SUP>+/+</SUP> mice, was markedly reduced in <I>Epac2A</I><SUP>−/−</SUP> mice. In contrast, the combinatorial effect of GLP-1 and gliclazide was rather mild, and the effect was not altered by Epac2A ablation. Activation of Rap1 was enhanced by the combination of an Epac-selective cAMP analog with glibenclamide or glimepiride but not gliclazide. In diet-induced obese mice, ablation of Epac2A reduced the insulin secretory response to coadministration of the GLP-1 receptor agonist liraglutide and glimepiride. These findings clarify the critical role of Epac2A/Rap1 signaling in the augmenting effect of incretin and sulfonylurea on insulin secretion and provide the basis for the effects of combination therapies of incretin-related drugs and sulfonylureas.</P>
Sato Harumi,Murakami Rumi,Zhang Jianming,Ozaki Yukihiro,Mori Katsuhito,Takahashi Isao,Terauchi Hikaru,Noda Isao The Polymer Society of Korea 2006 Macromolecular Research Vol.14 No.4
Temperature-dependent, wide-angle, x-ray diffraction (WAXD) patterns and infrared (IR) spectra were measured for biodegradable poly(3-hydroxybutyrate) (PHB) and its copolymers, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) P(HB-co-HHx) (HHx=2.5, 3.4, 10.5, and 12 mol%), in order to explore their crystal and lamellar structure and their pattern of C-H...O=C hydrogen bonding. The WAXD patterns showed that the P(HB-co-HHx) copolymers have the same orthorhombic system as PHB. It was found from the temperature-dependent WAXD measurements of PHB and P(HB-co-HHx) that the a lattice parameter is more enlarged than the b lattice parameter during heating and that only the a lattice parameter shows reversibility during both heating and cooling processes. These observations suggest that an interaction occurs along the a axis in PHB and P(HB-co-HHx). This interaction seems to be due to an intermolecular C-H...O=C hydrogen bonding between the C=O group in one helical structure and the $CH_3$ group in the other helical structure. The x-ray crystallographic data of PHB showed that the distance between the O atom of the C=O group in one helical structure and the H atom of one of the three C-H bonds of the $CH_3$ group in the other helix structure is $2.63{\AA}$, which is significantly shorter than the sum of the van der Waals separation ($2.72{\AA}$). This result and the appearance of the $CH_3$ asymmetric stretching band at $3009 cm^{-1}$ suggest that there is a C-H...O=C hydrogen bond between the C=O group and the $CH_3$ group in PHB and P(HB-co-HHx). The temperature-dependent WAXD and IR measurements revealed that the crystallinity of P(HB-co-HHx) (HHx =10.5 and 12 mol%) decreases gradually from a fairly low temperature, while that of PHB and P(HB-co-HHx) (HHx = 2.5 and 3.5 mol%) remains almost unchanged until just below their melting temperatures. It was also shown from our studies that the weakening of the C-H...O = C interaction starts from just above room temperature and proceeds gradually increasing temperature. It seems that the C-H...O=C hydrogen bonding stabilizes the chain holding in the lamellar structure and affects the thermal behaviour of PHB and its copolymers.
Yasunori Yoshida,Harumi Takahashi,Hiroomi Kanda,Kazunori Okuyama,Kota Sato,Koki Kanahama 한국원예학회 2010 Horticulture, Environment, and Biotechnology Vol.51 No.1
The effects of different gibberellin A3 (GA) concentrations on the development of main shoots and aerial and new tubers in the Japanese yam were examined in an unheated plastic house and open field. In the unheated plastic house, treatment with GA 25 (25 ㎎ · L?¹) or GA 200 (200 ㎎ · L?¹) promoted new tuber growth in the plants by inhibiting aerial tuber growth. Plants treated with GA 100 (100 ㎎ · L?¹) had the greatest fresh weight of new tubers among all GA treated plants. These effective GA concentrations showed similar results in Dioscorea oppositifolia ‘Ichoimo’ and ‘Nagaimo’ that were grown in the unheated plastic house. In the open field, although treatment with GA 25, GA 50 and GA100 promoted new tuber growth by inhibiting aerial tuber growth, the yield of new tubers decreased with increasing GA concentration. Furthermore, although GA inhibited aerial tuber growth, the fresh weight of new tubers after GA 200 treatment was almost equal to that of the GA 0- treated plants. The different effects of GA concentrations under unheated plastic house and open field conditions were due to the negative influence of GA treatment (it decreased the number of leaves on the shoots). In fact, the number of leaves on the shoots of plants grown in the unheated plastic house was significantly lower among GA 25-and GA 200-treated plants than those of GA 0-treated plants. This implies that GA had a negative effect on plants grown in the open field.