Incretinomimetic and Insulinomimetic Effect of (2E)‐N′‐(1′‐Naphthyl)‐3,4,5‐Trimethoxybenzohydrazide for Glycemic Homeostasis

Abstract

To characterize the role and the mechanism of action of (2E)-N'-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (BZD) on incretin secretion, glucose uptake in skeletal muscle and α-glucosidase activity on intestine, targets for glucose homeostasis. It was assayed on glucose tolerance test (GTT) to analyze GLP-1 secretion and the activity of DPP-4 enzyme in vitro. In skeletal muscle, mechanism of action on glucose uptake was carried out by in vitro experiments. The activity of intestinal disaccharidases was performed after in vivo and in vitro experiments. The compound improved the glucose tolerance around 30%, 25%, and 20% at 15, 30, and 60 min, respectively and potentiated the sitagliptin effect, an inhibitor of the enzyme that removes GLP-1, about 50, 45, and 54% at 15, 30, and 60 min, respectively. Additionally, BZD did not modify the activity of DPP-4 enzyme. The acute effect of BZD on glucose uptake is mediated by increasing GLUT4 expression (around 140%) and its translocation to the plasma membrane in soleus muscle. The genomic effect as well as GLUT4 translocation involve the activation of PI-3K and MAPK pathways and require the microtubules integrity to the complete stimulatory effect of this compound on glucose uptake. Beyond, BZD acts in an alternative target to ameliorate glycaemia, intestinal disaccharidases. In a whole, these data point an incretino- and insulinomimetic effect of the compound for glycemic control.

Effect of magnesium sulfate administration to improve insulin resistance in type 2 diabetes animal model: using the hyperinsulinemic‐euglycemic clamp technique

“…After that slides were processed with AEC Reagent (Zymed Laboratories, San Francisco, CA) and counterstained with hematoxylin (Sigma Co, St. Louis, MO). Ultimately cells were examined and taken the images under bright field .…”

Bis‐Pyrano Prenyl Isoflavone Improves Glucose Homeostasis by Inhibiting Dipeptidyl Peptidase‐4 in Hyperglycemic Rats

“…GLP‐1 was estimated by means of colorimetric measurements at 450 and 590 nm with an ELISA plate reader (Organon Teknika) by interpolation from a standard curve. Samples were analyzed in duplicate using five rats in each group and results were expressed as serum pM of GLP‐1 [Silva Frederico et al, ].…”

“…Then the plate was incubated for 30 min at 37°C. After, the measurement of fluorescence in a multimode reader Infinite M200-TECAN 1 using a black 96-well plate [Silva Frederico et al, 2015], and the results were expresses as relative DPP-4.…”

“…In some experiments agonist/antagonist were added during the last 15 min of preincubation and maintained during the incubation period in the presence/absence of isoflavone (see figure and legends). The following drugs were used: 300 mM glibenclamide [Papworth and Patrick, 1970], 250 mM diazoxide, 10 mM flunarizine, 1 mM U-73122, 20 mM nifedipine, 10 mM H89 [Kitahara et al, 2011], 50 mM dantrolene, 50 mM BAPTA-AM, 1 mM ST [Frederico et al, 2012], and 100 nM PMA [Silva Frederico et al, 2015].…”

Sulfonyl(thio)urea derivative induction of insulin secretion is mediated by potassium, calcium, and sodium channel signal transduction

“…Studies have shown that sulfonylureas activate TRPA1 receptors, potentiating the secretory effect of β cells; however, the mechanism of activation of these channels has not been elucidated (Babes et al, 2013). As such, new compounds based on the fundamental structure of glibenclamide, such as sulfonamides (Hosseinzadeh et al, 2013;Frederico et al, 2016;Frederico et al, 2017) and sulfonyl(thio)urea (Mascarello et al, 2014), have been developed with a view to determine their insulin secretagogue activities and actions on target tissues of glucose homeostasis.…”