Skip to main content

Advertisement

SpringerLink
Log in

Xenin-25[Lys13PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aims

Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.

Methods

This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys13PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.

Results

Initial studies confirmed the significant persistent glucose-lowering (p < 0.05) and insulin-releasing (p < 0.05) actions of xenin-25[Lys13PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys13PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p < 0.05) lowered by xenin-25[Lys13PAL] treatment. These changes were accompanied by significant improvements in i.p. (p < 0.05) and oral (p < 0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys13PAL] and saline-treated high-fat mice. However, xenin-25[Lys13PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys13PAL]. In contrast, ambulatory activity was significantly (p < 0.05 to p < 0.001) increased during the dark phase in xenin-25[Lys13PAL] mice compared with high-fat controls.

Conclusions

These data indicate that sustained administration of a stable analogue of xenin-25 exerts a spectrum of beneficial metabolic effects in high-fat-fed mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Feurle GE, Ikonomu S, Partoulas G, Stoschus B, Hamscher G (2003) Xenin plasma concentrations during modified sham feeding and during meals of different composition demonstrated by radioimmunoassay and chromatography. Regul Pept 111:153–159

    Article  CAS  PubMed  Google Scholar 

  2. Cooke JH, Patterson M, Patel SR, Smith KL, Ghatei MA, Bloom SR, Murphy KG (2009) Peripheral and central administration of xenin and neurotensin suppress food intake in rodents. Obesity (Silver Spring) 17:1135–1143

    CAS  Google Scholar 

  3. Taylor AI, Irwin N, McKillop AM, Patterson S, Flatt PR, Gault VA (2010) Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety. J Endocrinol 207:87–93

    Article  CAS  PubMed  Google Scholar 

  4. Kamiyama Y, Aihara R, Nakabayashi T, Mochiki E, Asao T, Kuwano H (2007) The peptide hormone xenin induces gallbladder contractions in conscious dogs. Neurogastroenterol Motil 19:33–240

    Article  Google Scholar 

  5. Leckstrom A, Kim ER, Wong D, Mizuno TM (2009) Xenin, a gastrointestinal peptide, regulates feeding independent of the melanocortin signaling pathway. Diabetes 58:87–94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Wice BM, Wang S, Crimmins DL, Diggs-Andrews KA, Althage MC, Ford EL, Tran H, Ohlendorf M, Griest TA, Wang Q, Fisher SJ, Ladenson JH, Polonsky KS (2010) Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J Biol Chem 2285:19842–19853

    Article  Google Scholar 

  7. Martin CM, Gault VA, McClean S, Flatt PR, Irwin N (2012) Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25. Biochem Pharmacol 84:312–319

    Article  CAS  PubMed  Google Scholar 

  8. Holst JJ, Knop FK, Vilsbøll T, Krarup T, Madsbad S (2011) Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 34:S251–S257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Pederson RA, Brown JC (1976) The insulinotropic action of gastric inhibitory polypeptide in the perfused isolated rat pancreas. Endocrinology 99:780–785

    Article  CAS  PubMed  Google Scholar 

  10. Gallwitz B (2011) Glucagon-like peptide-1 analogues for Type 2 diabetes mellitus: current and emerging agents. Drugs 71:1675–1688

    Article  CAS  PubMed  Google Scholar 

  11. Martin CM, Parthsarathy V, Pathak V, Gault VA, Flatt PR, Irwin N (2014) Characterisation of the biological activity of xenin-25 degradation fragment peptides. J Endocrinol 221:193–200

    Article  CAS  PubMed  Google Scholar 

  12. Mieczkowska A, Irwin N, Flatt PR, Chappard D, Mabilleau G (2013) Glucose-dependent insulinotropic polypeptide (GIP) receptor deletion leads to reduced bone strength and quality. Bone 56:337–342

    Article  CAS  PubMed  Google Scholar 

  13. Flatt PR, Bailey CJ (1981) Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice. Diabetologia 20:573–577

    Article  CAS  PubMed  Google Scholar 

  14. Irwin N, Flatt PR (2009) Therapeutic potential for GIP receptor agonists and antagonists. Best Pract Res Clin Endocrinol Metab 23:499–512

    Article  CAS  PubMed  Google Scholar 

  15. Porter DW, Kerr BD, Flatt PR, Holscher C, Gault VA (2010) Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance. Diabetes Obes Metab 12:891–899

    Article  CAS  PubMed  Google Scholar 

  16. Gault VA, Porter DW, Irwin N, Flatt PR (2011) Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high-fat fed mice. J Endocrinol 208:265–271

    CAS  PubMed  Google Scholar 

  17. Irwin N, Clarke GC, Green BD, Greer B, Harriott P, Gault VA, O’Harte FP, Flatt PR (2006) Evaluation of the antidiabetic activity of DPP IV resistant N-terminally modified versus mid-chain acylated analogues of glucose-dependent insulinotropic polypeptide. Biochem Pharmacol 72:719–728

    Article  CAS  PubMed  Google Scholar 

  18. Wice BM, Reeds DN, Tran HD, Crimmins DL, Patterson BW, Dunai J, Wallendorf MJ, Ladenson JH, Villareal DT, Polonsky KS (2012) Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. Diabetes 61:1793–1800

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Pathak V, Vasu S, Flatt PR, Irwin N (2014) Effects of chronic exposure of clonal β-cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP-1. Diabetes Obes Metab 16:357–365

    Article  CAS  PubMed  Google Scholar 

  20. Piteau S, Olver A, Kim SJ, Winter K, Pospisilik JA, Lynn F, Manhart S, Demuth HU, Speck M, Pederson RA, McIntosh CH (2007) Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochem Biophys Res Commun 362:1007–1012

    Article  CAS  PubMed  Google Scholar 

  21. Salera M, Giacomoni P, Pironi L, Cornia G, Capelli M, Marini A, Benfenati F, Miglioli M, Barbara L (1982) Gastric inhibitory polypeptide release after oral glucose: relationship to glucose intolerance, diabetes mellitus, and obesity. J Clin Endocrinol Metab 55:329–336

    Article  CAS  PubMed  Google Scholar 

  22. Marks V (1988) In: James WPT, Parker SW (eds) Current approaches: obesity. Southampton, Duphar Medical Relations, pp 13–19

  23. Yip RG, Wolfe MM (2000) GIP biology and fat metabolism. Life Sci 66:91–103

    Article  CAS  PubMed  Google Scholar 

  24. Kwasowski P, Flatt PR, Bailey CJ, Marks V (1985) Effects of fatty acid chain length and saturation on gastric inhibitory polypeptide release in obese hyperglycaemic (ob/ob) mice. Biosci Rep 5:701–705

    Article  CAS  PubMed  Google Scholar 

  25. Silvestre RA, Rodríguez-Gallardo J, Egido EM, Hernández R, Marco J (2003) Stimulatory effect of xenin-8 on insulin and glucagon secretion in the perfused rat pancreas. Regul Pept 115:25–29

    Article  CAS  PubMed  Google Scholar 

  26. Chowdhury S, Reeds DN, Crimmins DL, Patterson BW, Laciny E, Wang S, Tran HD, Griest TA, Rometo DA, Dunai J, Wallendorf MJ, Ladenson JH, Polonsky K, Wice BM (2014) Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes. Am J Physiol Gastrointest Liver Physiol 306:G301–G309

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738–742

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

These studies were supported by the Department of Education and Learning, Northern Ireland, University of Ulster Proof of Principle Funding Programme, the European Foundation for the Study of Diabetes and a research grant from Invest Northern Ireland Proof of Concept funding.

Conflict of interest

V.A.G., P.R.F. and N.I. hold stock in Diabetica Ltd. which has patents for exploitation of incretin-based drugs and other peptide therapeutics. C.M.A.M. and V.P. declare that they have no conflict of interest.

Ethical standard

All animal experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and approved by the University of Ulster Animal Ethics Review Committee. All necessary steps were taken to ameliorate any potential animal suffering.

Human and animal rights disclosure

This article does not contain any studies with human subjects. All animal experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986.

Author information

Authors and Affiliations

  1. SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK

    V. A. Gault, C. M. A. Martin, P. R. Flatt, V. Parthsarathy & N. Irwin

Authors
  1. V. A. Gault
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. M. A. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. R. Flatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Parthsarathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Irwin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Irwin.

Additional information

Managed by Massimo Porta.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gault, V.A., Martin, C.M.A., Flatt, P.R. et al. Xenin-25[Lys13PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential. Acta Diabetol 52, 461–471 (2015). https://doi.org/10.1007/s00592-014-0681-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-014-0681-0

Keywords

Search

Navigation