2. Academic Validation
  3. Tambulin from Zanthoxylum armatum acutely potentiates the glucose-induced insulin secretion via KATP-independent Ca2+-dependent amplifying pathway

Tambulin from Zanthoxylum armatum acutely potentiates the glucose-induced insulin secretion via KATP-independent Ca2+-dependent amplifying pathway

  • Biomed Pharmacother. 2019 Dec:120:109348. doi: 10.1016/j.biopha.2019.109348.
Abdul Hameed 1,  Sayed Ali Raza 2,  M Israr Khan 2,  Janaki Baral 3,  Achyut Adhikari 4,  Mohammad Nur-E-Alam 5,  Sarfaraz Ahmed 5,  Adnan J Al-Rehaily 5,  Sajda Ashraf 6,  Zaheer Ul-Haq 6,  Rahman M Hafizur 7
Affiliations

Affiliations

  • 1 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Centre for Advanced Drug Research (CADR), COMSATS University Islamabad (CUI), Abbottabad 22060, Pakistan.
  • 2 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
  • 3 Central Department of Chemistry, Tribhuvan University, Kathmandu, Nepal.
  • 4 H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Central Department of Chemistry, Tribhuvan University, Kathmandu, Nepal.
  • 5 Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box. 2457, Riyadh 11451, Saudi Arabia.
  • 6 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
  • 7 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: [email protected].
PMID: 31629954 DOI: 10.1016/j.biopha.2019.109348
Abstract

Tambulin, a flavonol isolated from Zanthoxylum armatum, showed potent Insulin secretory activity in our preliminary anti-diabetic screening. Here, we explored the Insulin secretory mechanism(s) of tambulin focusing in glucose-dependent, KATP ‒ and CA2+‒channels dependent, and cAMP-PKA pathways. Mice islets and MIN6 cells were incubated with tambulin in the presence of pharmacological agonists/antagonists and the secreted Insulin was measured using mouse Insulin ELISA kit. The intracellular cAMP was measured by an acetylation cAMP ELISA kit. Tambulin (200 μM) showed potent Insulin secretory activity only at stimulatory glucose (11-25 mM) concentrations; however, no change in Insulin release was observed at basal glucose both in mice islets and MIN6 cells. Notably, in the presence of diazoxide, a KATP channel opener; the incomplete inhibition of tambulin-induced Insulin secretion was observed whereas, complete inhibition was found using verapamil, an L-type CA2+ channel blocker. Furthermore, the insulinotropic potential of tambulin was amplified in tolbutamide treated, and depolarized islets suggest tambulin's target Other than tolbutamide. Tambulin showed no additive effect in the IBMX-induced intracellular cAMP; whereas, exerted an additive effect in the IBMX-induced Insulin secretion. Furthermore, tambulin-induced Insulin secretion was dramatically inhibited by PKA Inhibitor (H-89), while moderate inhibition was found by using PKC Inhibitor (calphostin C). Molecular docking studies also showed the best binding affinities of tambulin with PKA suggest the PKA dependent signaling cascade is involved more in tambulin-induced Insulin secretion. Based on these findings, it is concluded that tambulin stimulates Insulin secretion in a CA2+ channel-dependent but KATP channel-independent manner, most likely by activating the cAMP-PKA pathway.

Keywords

Ca(2+) channel; Insulin secretion; K(ATP)channel; Mice islets; Protein kinase A; Tambulin; cAMP.

Figures
Products