Pharmacological Evaluation of SKL-18287, a New Long-Acting Glucagon-Like Peptide-1 Receptor Agonist with Enhanced Aggregation Propensity, in Rodent Models

  • Mitsuaki Takeuchi
  • Masayuki Okamoto
  • Nobuhide WatanabeEmail author


Very recently, we have reported a new glucagon-like peptide-1 (GLP-1) receptor agonist, SKL-18287, (EC50: 1.2 and 0.13 nM for mouse and human, respectively) with extended in vivo half-life (T1/2: 5.8 h in rats), which is a medium-sized oligopeptide comprised of only natural l-amino acids. SKL-18287 is believed to exist in oligomeric form in vivo with a molecular weight of approximately 40,000 Da, which accounts for its extended in vivo half-life. This unique property may set SKL-18287 apart from other marketed GLP-1-based drugs. In this study, we report the pharmacological effects of SKL-18287 on type 2 diabetes mellitus (T2DM) and gastric emptying (GE) in several animal models. In intraperitoneal glucose tolerance tests, SKL-18287 lowered blood glucose level in a dose-dependent manner. Significant differences were observed between the control- and SKL-18287-treated groups at 0–1 h after the 1st and 2nd glucose loading. SKL-18287 glucose-lowering effect was virtually the same for both glucose loadings. In non-obese type 2 diabetic Goto-Kakizaki (GK) rats, SKL-18287, given a range of 6–12 nmol/kg/daily, produced a robust beneficial effect on glycohemoglobin (GHb). As for liraglutide, the 8 nmol/kg/daily dose failed to produce any significant effect on GHb. SKL-18287 had more potent therapeutic effects than liraglutide in GK rats, while it had marginal effect on GE. These results suggested that SKL-18287 was more pancreas-selective than liraglutide and would mitigate gastrointestinal adverse effects such as nausea and vomiting. SKL-18287 might be useful for non-obese patients with T2DM.


Glucagon-like peptide-1 receptor agonists Gastric emptying effect Gastrointestinal side effects Pancreas-selective 



Our special thanks are to Professor Jun-ichi Miyazaki (Osaka University, Osaka, Japan) for donating MIN6 mouse insulinoma cells. We also thank Ryuji Okamoto, Tomohiro Shigemori, Hiroshi Kinoshita, Katsura Tsukamoto, Miyuki Tamura, Takayo Murase, Shinji Furuta, and Yoshiyuki Furuta for their comments and data production. Finally, we thank Chika Otani and Asako Ohara for their experimental support.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10989_2018_9777_MOESM1_ESM.pdf (201 kb)
Supplementary material 1 (PDF 201 KB)


  1. Akash MS, Rehman K, Chen S (2013) Goto-Kakizaki rats: its suitability as non-obese diabetic animal model for spontaneous type 2 diabetes mellitus. Curr Diabetes Rev 9:387–396CrossRefGoogle Scholar
  2. Bergstrom RW, Wahl PW, Leonetti DL, Fujimoto WY (1990) Association of fasting glucose levels with a delayed secretion of insulin after oral glucose in subjects with glucose intolerance. J Clin Endocrinol Metab 71:1447–1453CrossRefGoogle Scholar
  3. Byrne MM, Sturis J, Sobel RJ, Polonsky KS (1996) Elevated plasma glucose 2 h postchallenge predicts defects in beta-cell function. Am J Physiol 270:E572–E579PubMedGoogle Scholar
  4. Calanna S, Christensen M, Holst JJ, Laferrère B, Gluud LL, Vilsbøll T, Knop FK (2013) Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia 56:965–972CrossRefGoogle Scholar
  5. Chen X, Yang W (2014) Epidemic trend of diabetes in China. J Diabetes Invest 5:478–481CrossRefGoogle Scholar
  6. Guo X-H (2016) The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide. Curr Med Res Opin 32:61–76CrossRefGoogle Scholar
  7. Imai K, Tsujimoto T, Goto A, Goto M, Kishimoto M, Yamamoto-Honda R, Noto H, Kajio H, Noda M (2014) Prediction of response to GLP-1 receptor agonist therapy in Japanese patients with type 2 diabetes. Diabetol Metab Syndr 6:110CrossRefGoogle Scholar
  8. Ito D, Iuchi T, Kurihara S, Inoue I, Katayama S, Inukai K (2015) Efficacy and clinical characteristics of liraglutide in Japanese patients with type 2 diabetes. J Clin Med Res 7:694–699CrossRefGoogle Scholar
  9. Jelsing J, Vrang N, Hansen G, Raun K, Tang-Christensen M, Knudsen LB (2012) Liraglutide: short-lived effect on gastric emptying - long lasting effects on body weight. Diabetes Obes Metab 14:531–538CrossRefGoogle Scholar
  10. Jespersen MJ, Knop FK, Christensen M (2013) GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 9:17–29CrossRefGoogle Scholar
  11. Meier JJ, Kemmeries G, Holst JJ, Nauck MA (2005) Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes 54:2212–2218CrossRefGoogle Scholar
  12. Nauck MA, Kemmeries G, Holst JJ, Meier JJ (2011) Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60:1561–1565CrossRefGoogle Scholar
  13. Prasad-Reddy L, Isaacs D (2015) A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context 4:212283CrossRefGoogle Scholar
  14. Sanger GJ, Broad J, Andrews PL (2013) The relationship between gastric motility and nausea: gastric prokinetic agents as treatments. Eur J Pharmacol 715:10–14CrossRefGoogle Scholar
  15. Seino Y, Kurahachi H, Goto Y, Taminato T, Ikeda M, Imura H (1975) Comparative insulinogenic effects of glucose, arginine and glucagon in patients with diabetes mellitus, endocrine disorders and liver disease. Acta Diabetol Lat 12:89–99CrossRefGoogle Scholar
  16. Seino Y, Kuwata H, Yabe D (2016) Incretin-based drugs for type 2 diabetes: focus on East Asian perspectives. J Diabetes Invest 7 Suppl:1:102–109CrossRefGoogle Scholar
  17. Seufert J, Gallwitz B (2014) The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab 16:673–688CrossRefGoogle Scholar
  18. Steensgaard DB, Thomsen JK, Olsen HB, Knudsen LB (2008) The molecular basis for the delayed absorption of the once-daily human GLP-1 analogue, liraglutide (Abstract 552-P). Diabetes 57(Suppl. 1):A164Google Scholar
  19. Steiner KE, Mouton SM, Williams PE, Lacy WW, Cherrington AD (1986) Relative importance of first- and second-phase insulin secretion in glucose homeostasis in conscious dog. II. effects on gluconeogenesis. Diabetes 35:776–784CrossRefGoogle Scholar
  20. Takeuchi M, Okamoto M, Okamoto R, Kinoshita H, Yamaguchi Y, Watanabe N (2018) Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity. Peptides 102:8–15CrossRefGoogle Scholar
  21. Toyoda M, Yokoyama H, Abe K, Nakamura S, Suzuki D (2014) Predictors of response to liraglutide in Japanese type 2 diabetes. Diabetes Res Clin Pract 106:451–457CrossRefGoogle Scholar
  22. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14:88–98CrossRefGoogle Scholar
  23. Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Mitsuaki Takeuchi
    • 1
    • 2
  • Masayuki Okamoto
    • 1
  • Nobuhide Watanabe
    • 1
    • 2
    Email author
  1. 1.Mie Research ParkSanwa Kagaku Kenkyusho, Co., Ltd.Inabe-cityJapan
  2. 2.Licensing & Business Development, R&D Strategy CenterSanwa Kagaku Kenkyusho, Co., Ltd.TokyoJapan

Personalised recommendations