Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance
-
Opeolu O. Ojo
, Peter R. Flatt
Abstract
The frog skin host-defense peptide tigerinin-1R stimulates insulin release in vitro and improves glucose tolerance and insulin sensitivity in animal models of type 2 diabetes. This study extends these observations by investigating the molecular mechanisms of action underlying the beneficial metabolic effects of the analogue [Arg4]tigerinin-1R in mice with diet-induced obesity, glucose intolerance and insulin resistance. The study also investigates the electrophysiological effects of the peptide on KATP and L-type Ca2+ channels in BRIN-BD11 clonal β cells. Non-fasting plasma glucose and glucagon concentrations were significantly (p<0.05) decreased and plasma insulin increased by twice daily treatment with [Arg4]tigerinin-1R (75 nmol/kg body weight) for 28 days. Oral and intraperitoneal glucose tolerance were significantly (p<0.05) improved accompanied by enhanced secretion and action of insulin. The peptide blocked KATP channels and, consistent with this, improved beta cell responses of isolated islets to a range of secretagogues. Peptide administration resulted in up-regulation of key functional genes in islets involved insulin secretion (Abcc8, Kcnj11, Cacna1c and Slc2a2) and in skeletal muscle involved with insulin action (Insr, Irs1, Pdk1,Pik3ca, and Slc2a4). These observations encourage further development of tigerinin-1R analogues for the treatment of patients with type 2 diabetes.
Acknowledgments
Funding for this study was provided by a project grant from Diabetes UK (Grant Number 12/0004457) and an award of a University Vice Chancellor Research Studentship to DKS.
Conflict of interest statement: The authors declare that they have no conflicts of interest.
References
Abdel-Wahab, Y.H.A., Power, G.J., Ng, T.M., Flatt, P.R., and Conlon, J.M. (2008). Insulin-releasing properties of the frog skin peptide pseudin-2 and its [Lys18]-substituted analogue. Biol. Chem. 389, 143–148.10.1515/BC.2008.018Search in Google Scholar
Andrali, S.S., Sampley, M.L., Vanderford, N.L., and Ozcan, S. (2008). Glucose regulation of insulin gene expression in pancreatic beta-cells. Biochem. J. 415, 1–10.10.1042/BJ20081029Search in Google Scholar
Bustillo, M.E., Fischer, A.L., LaBouyer, M.A., Klaips, J.A., Webb, A.C., and Elmore, D.E. (2014). Modular analysis of hipposin, a histone-derived antimicrobial peptide consisting of membrane translocating and membrane permeabilizing fragments. Biochim. Biophys. Acta 1838, 2228–2233.10.1016/j.bbamem.2014.04.010Search in Google Scholar
Chan, S.M. and Ye, J.M. (2013). Strategies for the discovery and development of anti-diabetic drugs from the natural products of traditional medicines. J. Pharm. Pharm. Sci. 16, 207–216.10.18433/J3T60GSearch in Google Scholar
Conlon, J.M., Mechkarska, M., Lukic, M.L., and Flatt, P.R. (2014). Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents. Peptides 57, 67–77.10.1016/j.peptides.2014.04.019Search in Google Scholar
Consoli, A. and Formoso, G. (2015). Potential side effects to GLP-1 agonists: understanding their safety and tolerability. Expert Opin. Drug Saf. 14, 207–218.10.1517/14740338.2015.987122Search in Google Scholar
D’Alessio, D. (2011). The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes. Metab. 13, 126–132.10.1111/j.1463-1326.2011.01449.xSearch in Google Scholar
De Marinis, Y.Z., Salehi, A., Ward, C.E., Zhang, Q., Abdulkader, F., Bengtsson, M., Braha, O., Braun, M., Ramracheya, R., Amisten, S., et al. (2010). GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metab. 11, 543–553.10.1016/j.cmet.2010.04.007Search in Google Scholar
Eng, J., Kleinman, W.A., Singh, L., Singh, G., and Raufman. J.P. (1992). Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. J. Biol. Chem. 267, 7402–7405.10.1016/S0021-9258(18)42531-8Search in Google Scholar
Flatt, P.R. and Bailey, C.J. (1981). Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice. Diabetologia 20, 573–577.10.1007/BF00252768Search in Google Scholar PubMed
Gao, M., Ma, Y., and Liu, D. (2015). High-fat diet-induced adiposity, adipose inflammation, hepatic steatosis and hyperinsulinemia in outbred CD-1 mice. PLoS One 10, e0119784.10.1371/journal.pone.0119784Search in Google Scholar
Ginn, C., Khalili, H., Lever, R., and Brocchini, S. (2014). PEGylation and its impact on the design of new protein-based medicines. Future Med. Chem. 6, 1829–1846.10.4155/fmc.14.125Search in Google Scholar
Kahn, S., Cooper, M.E., and Del Prato, S. (2014). Pathophysiology and treatment of type 2 diabetes: perspective on the past, present and future. Lancet 383, 1068–1083.10.1016/S0140-6736(13)62154-6Search in Google Scholar
Lee, H.S., Park, C.B., Kim, J.M., Jang, S.A., Park, I.Y., Kim, M.S., Cho, J.H., and Kim, S.C. (2008). Mechanism of anticancer activity of buforin IIb, a histone H2A-derived peptide. Cancer Lett. 271, 47–55.10.1016/j.canlet.2008.05.041Search in Google Scholar PubMed
Moran, B.M., Abdel-Wahab, Y.H., Flatt, P.R., and McKillop, A.M. (2014). Activation of GPR119 by fatty acid agonists augments insulin release from clonal B-cells and isolated pancreatic islets and improves glucose tolerance in mice. Biol. Chem. 395, 453–464.10.1515/hsz-2013-0255Search in Google Scholar PubMed
Ojo, O.O., Abdel-Wahab, Y.H.A., Flatt, P.R., Mechkarska, M., and Conlon, J.M. (2011). Tigerinin-1R: a potent, non-toxic insulin-releasing peptide isolated from the skin of the Asian frog, Hoplobatrachus rugulosus. Diabetes Obes. Metab. 13, 1114–1122.10.1111/j.1463-1326.2011.01470.xSearch in Google Scholar PubMed
Ojo, O.O., Abdel-Wahab, Y.H., Flatt, P.R., and Conlon, J.M. (2013). Insulinotropic actions of the frog skin host-defense peptide alyteserin-2a: a structure-activity study. Chem. Biol. Drug Des. 82, 196–204.10.1111/cbdd.12151Search in Google Scholar PubMed
Ojo, O.O., Srinivasan, D.K., Owolabi, B.O., Flatt, P.R., and Abdel-Wahab, Y.H.A. (2015a). Beneficial effects of tigerinin-1R on glucose homeostasis and beta cell function in mice with diet-induced obesity-diabetes. Biochimie 109, 18–26.10.1016/j.biochi.2014.11.018Search in Google Scholar PubMed
Ojo, O.O., Srinivasan, D.K., Owolabi, B.O., Conlon, J.M., Flatt, P.R., Abdel-Wahab, Y.H.A. (2015b). Magainin-AM2 improves glucose homeostasis and beta cell function in high-fat fed mice. Biochim. Biophys. Acta 1850, 80–87.10.1016/j.bbagen.2014.10.011Search in Google Scholar PubMed
Østergaard, L., Frandsen, C.S., and Madsbad, S. (2016) Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. Expert Rev. Clin. Pharmacol. 8, 1–25.10.1586/17512433.2016.1121808Search in Google Scholar PubMed
Owolabi, B.O., Ojo, O.O., Srinivasan, D.K., Conlon, J.M., Flatt, P.R., and Abdel-Wahab, Y.H. (2016). In vitro and in vivo insulinotropic properties of the multifunctional frog skin peptide hymenochirin-1B: a structure-activity study. Amino Acids 48, 535–547.10.1007/s00726-015-2107-xSearch in Google Scholar PubMed
Pantic, J.M., Mechkarska, M., Lukic, M.L., and Conlon, J.M. (2014) Effects of tigerinin peptides on cytokine production by mouse peritoneal macrophages and spleen cells and by human peripheral blood mononuclear cells. Biochimie 101, 83–92.10.1016/j.biochi.2013.12.022Search in Google Scholar PubMed
Pukala, T.L., Bowie, J.H., Maselli, V.M., Musgrave, I.F., and Tyler, M.J. (2006). Host-defence peptides from the glandular secretions of amphibians: structure and activity. Nat. Prod. Rep. 23, 368–393.10.1039/b512118nSearch in Google Scholar PubMed
Richter, E.A. and Hargreaves, M. (2013). Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol. Rev. 93, 993–1017.10.1152/physrev.00038.2012Search in Google Scholar PubMed
Saini, V. (2010). Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World J. Diabetes 1, 68–75.10.4239/wjd.v1.i3.68Search in Google Scholar PubMed PubMed Central
Samuel, V.T. and Shulman, G.I. (2012). Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852–871.10.1016/j.cell.2012.02.017Search in Google Scholar PubMed PubMed Central
Scholfield, C.N. and Curtis, T.M. (2000). Heterogeneity in cytosolic calcium regulation among different microvascular smooth muscle cells of the rat retina. Microvasc. Res. 59, 233–242.10.1006/mvre.1999.2227Search in Google Scholar PubMed
Srinivasan, D., Ojo, O.O., Abdel-Wahab, Y.H.A., Flatt, P.R., Guilhaudis, L., and Conlon, J.M. (2014). Insulin-releasing and cytotoxic properties of the frog skin peptide, tigerinin-1R: A structure-activity study. Peptides 55, 23–31.10.1016/j.peptides.2014.02.002Search in Google Scholar PubMed
Srinivasan, D.K., Ojo, O.O., Owolabi, B.O., Conlon, J.M., Flatt, P.R., and Abdel-Wahab, Y.H.A. (2015). The frog skin host-defense peptide CPF-SE1 improves glucose tolerance, insulin sensitivity and islet function and decreases plasma lipids in high-fat fed mice. Eur. J. Pharmacol. 5, 38–47.10.1016/j.ejphar.2015.06.042Search in Google Scholar PubMed
Srinivasan, D.K., Ojo, O.O., Owolabi, B.O., Conlon, J.M., Flatt, P.R., and Abdel-Wahab, Y.H.A. (2016). [I10W]tigerinin-1R enhances both insulin sensitivity and pancreatic beta cell function and decreases adiposity and plasma triglycerides in high-fat mice. Acta Diabetol. in press.10.1007/s00592-015-0783-3Search in Google Scholar PubMed
Syed, Y.Y. and McCormack, P.L. (2015). Exenatide extended-release: An updated review of its use in Type 2 Diabetes Mellitus. Drugs 75, 1141–1152.10.1007/s40265-015-0420-zSearch in Google Scholar
Wald, N.J., Bestwick, J.P., and Morris, J.K. (2012). Body weight reduction to avoid the excess risk of type 2 diabetes. Br. J. Gen. Pract. 62, e411–e414.10.3399/bjgp12X649098Search in Google Scholar
White, M.F., Shoelson, S.E., Keutmann H., and Kahn, C.R., 1988. A cascade of tyrosine autophosphorylation in the beta-subunit activates the phosphotransferase of the insulin receptor. J. Biol. Chem. 263, 2969–2980.10.1016/S0021-9258(18)69163-XSearch in Google Scholar
Wilcox, G. (2005). Insulin and insulin resistance. Clin. Biochem. Rev. 26, 19–36.Search in Google Scholar
Winzell, M.S.and Ahren, B. (2004). The high-fat diet-fed mouse: A model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 53, S215–S219.10.2337/diabetes.53.suppl_3.S215Search in Google Scholar PubMed
Xu, X. and Lai, R. (2015). The chemistry and biological activities of peptides from amphibian skin secretions. Chem. Rev. 115, 1760–1846.10.1021/cr4006704Search in Google Scholar PubMed
Supplemental Material:
The online version of this article (DOI: 10.1515/hsz-2016-0120) offers supplementary material, available to authorized users.
©2016 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Reviews
- Endocytosis of pro-inflammatory cytokine receptors and its relevance for signal transduction
- The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction
- Research Articles/Short Communications
- Genes and Nucleic Acids
- Genetic association of NAD(P)H quinone oxidoreductase (NQO1*2) polymorphism with NQO1 levels and risk of diabetic nephropathy
- Protein Structure and Function
- Troponins, intrinsic disorder, and cardiomyopathy
- Molecular Medicine
- Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance
- Cell Biology and Signaling
- Adenovirus-mediated expression of vascular endothelial growth factor-a potentiates bone morphogenetic protein9-induced osteogenic differentiation and bone formation
- Proteolysis
- The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2
- Novel Techniques
- A systematic comparison of two new releases of exome sequencing products: the aim of use determines the choice of product
Articles in the same Issue
- Frontmatter
- Reviews
- Endocytosis of pro-inflammatory cytokine receptors and its relevance for signal transduction
- The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction
- Research Articles/Short Communications
- Genes and Nucleic Acids
- Genetic association of NAD(P)H quinone oxidoreductase (NQO1*2) polymorphism with NQO1 levels and risk of diabetic nephropathy
- Protein Structure and Function
- Troponins, intrinsic disorder, and cardiomyopathy
- Molecular Medicine
- Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance
- Cell Biology and Signaling
- Adenovirus-mediated expression of vascular endothelial growth factor-a potentiates bone morphogenetic protein9-induced osteogenic differentiation and bone formation
- Proteolysis
- The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2
- Novel Techniques
- A systematic comparison of two new releases of exome sequencing products: the aim of use determines the choice of product