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

Abstract

Isoflavones widely distributed in plants prevent diabetes. This study investigated the in vivo and in vitro effect of 3',4'-dihydroxy-6″,6″,6″',6″'-tetramethylbis(pyrano[2″,3″:5,6::2″',3″':7,8]isoflavone (bis-pyrano prenyl isoflavone) on glucose homeostasis in hyperglycemic rats. The ethyl acetate fraction from aerial parts of Polygala molluginifolia that contain isoflavones was assayed on glucose tolerance, on in vitro maltase activity and on protein glycation. The isoflavone bis-pyrano prenyl isolated from this fraction was investigated on glucose homeostasis. The in vivo action of the isoflavone exhibits an anti-hyperglycemic effect by improving glucose tolerance, augmenting the liver glycogen, inhibiting maltase activity, and stimulating glucagon-like peptide-1 (GLP-1) and insulin secretion. The in vitro isoflavone inhibits dipeptidyl peptidase-4 (DPP-4) activity since the glucose tolerance was improved in the presence of the isoflavone as much as sitagliptin, an inhibitor of DPP-4. However, the co-incubation with isoflavone and sitagliptin exhibited an additive anti-hyperglycemic action. The isoflavone increased the GLP-1 faster than the positive hyperglycemic group, which shows that the intestine is a potential target. Thus, to clarify the main site of action in which isoflavone improves glucose balance, the in vitro mechanism of action of this compound was tested in intestine using calcium influx as a trigger for the signal pathways for GLP-1 secretion. The isoflavone stimulates calcium influx in intestine and its mechanism involves voltage-dependent calcium channels, phospholipase C, protein kinase C, and stored calcium contributing for GLP-1 secretion. In conclusion, the isoflavone regulates glycaemia by acting mainly in a serum target, the DPP-4 inhibitor. Furthermore, the long-term effect of isoflavone prevents protein glycation. J. Cell. Biochem. 118: 92-103, 2017. © 2016 Wiley Periodicals, Inc.

Glucagon-like peptide-1 levels and dipeptidyl peptidase-4 activity in type 2 diabetes

“…Altenhofen et al [38] showed that the acute in vivo effect of the major compound isolated from the aerial parts of Polygala molluginifolia, bis-pyrano prenyl isoflavone, exhibits an antihyperglycemic effect by improving glucose tolerance, stimulating GLP-1 secretion (increased serum GLP-1 levels) and inhibiting DPP-4 activity (decreased serum DPP-4 activity) beyond the increase of insulin secretion in hyperglycemic rats. Furuhashi et al [39] reported on a study where sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases GLP-1, was administered to patients with type 2 diabetes (n = 24) for 12 weeks.…”

Active phytochemicals of Pueraria tuberosa for DPP-IV inhibition: in silico and experimental approach

“…Therefore, this herbal drug provides a hypoglycemic response through DPP-IV inhibition pathway. Flavonoids play a role in DPP-IV inhibition [ 8 , 4 , 30 ] and have also been studied as GLP-1 receptor agonists [ 31 ]. In our previous study, we have proved PTWE as a competitive inhibitor of DPP-IV [ 15 ].…”

“…It has been studied that DPP-IV inhibitor bis-pyranoprenyl isolated from ethyl acetate fraction from aerial parts of Polygala molluginifolia contributes to GLP-1 secretion through the stimulation of calcium influx in the intestine. The overall mechanism involves voltage-dependent calcium channels, phospholipase C, protein kinase C, and stored calcium [ 30 ]. As the compositions of all DPP-IV inhibitory plants found in nature are different, the above-discussed pathway must be the common mechanism, with minor modifications for each plant, through which GLP-1 secretion could be enhanced through DPP-IV inhibition.…”

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

“…GLP-1 was estimated by means of colorimetric measurements at 450 and 590 nm with an ELISA plate reader (Organon Teknika, Roseland, NJ) by interpolation from a standard curve. Samples were analyzed in duplicate in each group and results were expressed as serum GLP-1 (pM; Altenhofen et al, 2017).…”