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Endocrine

Erschienen in:

20.11.2020 | Original Article

Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and mechanism

verfasst von: Hui Li, Jian Zhang, Yongli Fu, Yixin Zhang, Chunhui Zhang, Xiaozhu Sun, Fang Wu, Jing He

Erschienen in: Endocrine | Ausgabe 2/2021

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Abstract

Purpose

This study primarily investigated the effects of hypoglycemic compounds (Imeglimin derivatives) on insulin secretion in type 2 diabetes mellitus (T2DM), and further explored the possible mechanism underlying these effects.

Methods

Firstly, Metformin was used as the initiating compound to synthesize three sets of derivatives which contained Imeglimin structure core. At the cellular level, we screened compounds with better effect on the activity of insulin receptor tyrosine protein kinase (IFcTPK) after the islet β cells were treated with the compounds of different concentrations. The insulin secretion was assessed using radioimmunoassay and the cytotoxicity to islet β cells was evaluated by means of MTT assay following treatment with the compounds. The Ca²⁺-related mechanism by which these compounds promote insulin secretion was elucidated with whole cell recordings from current-clamp mode.

Results

Totally, 48 synthesized compounds were generated, wherein 10 compounds could increase the activity of IFcTPK in HIT-T15 cells better among these compounds. The modified Imeglimin, especially in the structure of hydrophilic hydroxyl or piperidine rings, could improve the activity of the compound to promote insulin secretion. Furthermore, the compounds 8a, 8b, 8k, and 9h revealed high insulin secretion-promoting activity. These compounds enhanced insulin secretion in islet β cells by repressing the ATP-sensitive K(+) and voltage-gated K+ pathway.

Conclusions

Our findings indicate that the hypoglycemic compounds 8a, 8b, 8k, and 9h confer better promotive effect on insulin secretion, which provides a reference for the development of drugs with better hypoglycemic activity.

R.A. DeFronzo, E. Ferrannini, L. Groop, R.R. Henry, W.H. Herman, J.J. Holst, F.B. Hu, C.R. Kahn, I. Raz, G.I. Shulman, D.C. Simonson, M.A. Testa, R. Weiss, Type 2 diabetes mellitus. Nat. Rev. Dis. Prim. 1, 15019 (2015). https://doi.org/10.1038/nrdp.2015.19CrossRefPubMed

G. Ning, Decade in review-type 2 diabetes mellitus: at the centre of things. Nat. Rev. Endocrinol. 11(11), 636–638 (2015). https://doi.org/10.1038/nrendo.2015.147CrossRefPubMed

A.A. Tahrani, A.H. Barnett, C.J. Bailey, Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 12, 566–592 (2016). https://doi.org/10.1038/nrendo.2016.86CrossRefPubMed

R.F. Rocha, T. Rodrigues, A.C.O. Menegatti, G.J.L. Bernardes, H. Terenzi, The antidiabetic drug lobeglitazone has the potential to inhibit PTP1B activity. Bioorg. Chem. 100, 103927 (2020). https://doi.org/10.1016/j.bioorg.2020.103927CrossRefPubMed

D.M. Irwin, Variation in the rates of evolution of the insulin and glucagon hormone and receptor genes in rodents. Gene 728, 144296 (2020). https://doi.org/10.1016/j.gene.2019.144296CrossRefPubMed

T.D. Olver, Z.I. Grunewald, T. Ghiarone, R.M. Restaino, A.R.K. Sales, L.K. Park, P.K. Thorne, R.R. Ganga, C.A. Emter, P.W.R. Lemon, J.K. Shoemaker, C. Manrique-Acevedo, L.A. Martinez-Lemus, J. Padilla, Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction. Am. J. Physiol. Heart Circ. Physiol. 317, H1166–H1172 (2019). https://doi.org/10.1152/ajpheart.00464.2019CrossRefPubMedPubMedCentral

J.L. Tarry-Adkins, C.E. Aiken, S.E. Ozanne, Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta-analysis. PLoS Med. 16, e1002848 (2019). https://doi.org/10.1371/journal.pmed.1002848CrossRefPubMedPubMedCentral

S.J. Pilla, J.R. Dotimas, N.M. Maruthur, J.M. Clark, H.C. Yeh, Changes in metformin use and other antihyperglycemic therapies after insulin initiation in patients with type 2 diabetes. Diabetes Res. Clin. Pr. 139, 221–229 (2018). https://doi.org/10.1016/j.diabres.2018.02.032CrossRef

R. Yendapally, D. Sikazwe, S.S. Kim, S. Ramsinghani, R. Fraser-Spears, A.P. Witte, B. La-Viola, A review of phenformin, metformin, and imeglimin. Drug Dev. Res. (2020). https://doi.org/10.1002/ddr.21636

10.

G. Vial, M.A. Chauvin, N. Bendridi, A. Durand, E. Meugnier, A.M. Madec, N. Bernoud-Hubac, J.P. Pais de Barros, E. Fontaine, C. Acquaviva, S. Hallakou-Bozec, S. Bolze, H. Vidal, J. Rieusset, Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. Diabetes 64, 2254–2264 (2015). https://doi.org/10.2337/db14-1220CrossRefPubMed

11.

R.J. Perry, R.L. Cardone, M.C. Petersen, D. Zhang, P. Fouqueray, S. Hallakou-Bozec, S. Bolze, G.I. Shulman, K.F. Petersen, R.G. Kibbey, Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents. Am. J. Physiol. Endocrinol. Metab. 311, E461–E470 (2016). https://doi.org/10.1152/ajpendo.00009.2016CrossRefPubMedPubMedCentral

12.

J.Y. Cho, J. Choi, J.G. Park, Y.S. Yi, M.J. Hossen, H. Kim, J. Ro, B.C. Cha, E.S. Yoo, J.H. Kim, J. Lee, Alcohol-induced hyperlipidemia is ameliorated by orally administered DWP208, a sodium succinate form of ZYM201. Korean J. Physiol. Pharm. 18, 469–474 (2014). https://doi.org/10.4196/kjpp.2014.18.6.469CrossRef

13.

S.Y. Kodera, M. Yoshida, K. Dezaki, T. Yada, T. Murayama, M. Kawakami, M. Kakei, Inhibition of insulin secretion from rat pancreatic islets by dexmedetomidine and medetomidine, two sedatives frequently used in clinical settings. Endocr. J. 60, 337–346 (2013). https://doi.org/10.1507/endocrj.ej12-0308CrossRefPubMed

14.

R. Meng, J. Mahadevan, E. Oseid, S. Vallerie, R.P. Robertson, Silymarin Activates c-AMP phosphodiesterase and stimulates insulin secretion in a glucose-dependent manner in HIT-T15 Cells. Antioxidants 5, (2016). https://doi.org/10.3390/antiox5040047

15.

M.Y. Ali, M. Whiteman, C.M. Low, P.K. Moore, Hydrogen sulphide reduces insulin secretion from HIT-T15 cells by a KATP channel-dependent pathway. J. Endocrinol. 195, 105–112 (2007). https://doi.org/10.1677/JOE-07-0184CrossRefPubMed

16.

Z. Qi, Y. Xu, Z. Liang, S. Li, J. Wang, Y. Wei, B. Dong, Baicalein alters PI3K/Akt/GSK3beta signaling pathway in rats with diabetes-associated cognitive deficits. Int J. Clin. Exp. Med. 8, 1993–2000 (2015)PubMedPubMedCentral

17.

J. Herrington, Y.P. Zhou, R.M. Bugianesi, P.M. Dulski, Y. Feng, V.A. Warren, M.M. Smith, M.G. Kohler, V.M. Garsky, M. Sanchez, M. Wagner, K. Raphaelli, P. Banerjee, C. Ahaghotu, D. Wunderler, B.T. Priest, J.T. Mehl, M.L. Garcia, O.B. McManus, G.J. Kaczorowski, R.S. Slaughter, Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion. Diabetes 55, 1034–1042 (2006). https://doi.org/10.2337/diabetes.55.04.06.db05-0788CrossRefPubMed

18.

P. Llanos, A. Contreras-Ferrat, G. Barrientos, M. Valencia, D. Mears, C. Hidalgo, Glucose-dependent insulin secretion in pancreatic beta-cell islets from male rats requires Ca2+ release via ROS-stimulated ryanodine receptors. PLoS ONE 10, e0129238 (2015). https://doi.org/10.1371/journal.pone.0129238CrossRefPubMedPubMedCentral

19.

Z. Laron, H. Werner, Insulin: a growth hormone and potential oncogene. Pediatr. Endocrinol. Rev. 17, 191–197 (2020). https://doi.org/10.17458/per.vol17.2020.lw.insulinghpotentialoncogeneCrossRefPubMed

20.

M. Vakilian, Y. Tahamtani, K. Ghaedi, A review on insulin trafficking and exocytosis. Gene 706, 52–61 (2019). https://doi.org/10.1016/j.gene.2019.04.063CrossRefPubMed

21.

Y. Zhao, M. Sun, Metformin rescues Parkin protein expression and mitophagy in high glucose-challenged human renal epithelial cells by inhibiting NF-kappaB via PP2A activation. Life Sci. 246, 117382 (2020). https://doi.org/10.1016/j.lfs.2020.117382CrossRefPubMed

22.

L. Jennings, R. Hambly, R. Hughes, B. Moriarty, B. Kirby, Metformin use in hidradenitis suppurativa. J. Dermatol. Treat. 31, 261–263 (2020). https://doi.org/10.1080/09546634.2019.1592100CrossRef

23.

K. Hamano, K. Akita, Y. Takeuchi, T. Suwa, J. Takeda, S. Dodo, Glucose-responsive Insulinoma with Insulin Hypersecretion Suppressed by Metformin. Intern. Med. 58, 3563–3568 (2019). https://doi.org/10.2169/internalmedicine.3318-19CrossRefPubMedPubMedCentral

24.

P. Fouqueray, S. Perrimond-Dauchy, S. Bolze, Imeglimin does not induce clinically relevant pharmacokinetic interactions when combined with either metformin or sitagliptin in healthy subjects. Clin. Pharmacokinet. (2020). https://doi.org/10.1007/s40262-020-00886-y

25.

H. Yaribeygi, M. Maleki, T. Sathyapalan, T. Jamialahmadi, A. Sahebkar, Molecular mechanisms by which imeglimin improves glucose homeostasis. J. Diabetes Res. 2020, 8768954 (2020). https://doi.org/10.1155/2020/8768954CrossRefPubMedPubMedCentral

26.

G. Pacini, A. Mari, P. Fouqueray, S. Bolze, M. Roden, Imeglimin increases glucose-dependent insulin secretion and improves beta-cell function in patients with type 2 diabetes. Diabetes Obes. Metab. 17, 541–545 (2015). https://doi.org/10.1111/dom.12452CrossRefPubMed

27.

K. Harada, J. Mizukami, S. Kadowaki, I. Matsuda, T. Watanabe, Y. Oe, Y. Kodama, K. Aoki, K. Suwa, S. Fukuda, S. Yata, T. Inaba, Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure. Bioorg. Med Chem. Lett. 28, 1228–1233 (2018). https://doi.org/10.1016/j.bmcl.2018.02.044CrossRefPubMed

28.

H.J. Mest, A. Raap, J. Schloos, I. Treinies, M. Paal, U. Giese, V. Koivisto, Glucose-induced insulin secretion is potentiated by a new imidazoline compound. Naunyn Schmiedebergs Arch. Pharm. 364, 47–52 (2001). https://doi.org/10.1007/s002100100415CrossRef

29.

G. da Luz, M.J. Frederico, A.J. Castro, A.L. Moraes, F.K. de Carvalho, L. Espindola, E.C. Schmidt, Z.L. Bouzon, M.G. Pizzolatti, F.R. Silva, Triterpene derivative: A potential signaling pathway for the fern-9(11)-ene-2alpha,3beta-diol on insulin secretion in pancreatic islet. Life Sci. 154, 58–65 (2016). https://doi.org/10.1016/j.lfs.2016.04.027CrossRefPubMed

30.

J. Ryu, A.K. Galan, X. Xin, F. Dong, M.A. Abdul-Ghani, L. Zhou, C. Wang, C. Li, B.M. Holmes, L.B. Sloane, S.N. Austad, S. Guo, N. Musi, R.A. DeFronzo, C. Deng, M.F. White, F. Liu, L.Q. Dong, APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep. 7, 1227–1238 (2014). https://doi.org/10.1016/j.celrep.2014.04.006CrossRefPubMedPubMedCentral

31.

F. Oriente, S. Iovino, S. Cabaro, A. Cassese, E. Longobardi, C. Miele, P. Ungaro, P. Formisano, F. Blasi, F. Beguinot, Prep1 controls insulin glucoregulatory function in liver by transcriptional targeting of SHP1 tyrosine phosphatase. Diabetes 60, 138–147 (2011). https://doi.org/10.2337/db10-0860CrossRefPubMed

32.

E. Choi, S. Kikuchi, H. Gao, K. Brodzik, I. Nassour, A. Yopp, A.G. Singal, H. Zhu, H. Yu, Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling. Nat. Commun. 10, 1473 (2019). https://doi.org/10.1038/s41467-019-09318-3CrossRefPubMedPubMedCentral

33.

M. Niessen, F. Jaschinski, F. Item, M.P. McNamara, G.A. Spinas, T. Trub, Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. Exp. Cell. Res. 313, 805–815 (2007). https://doi.org/10.1016/j.yexcr.2006.11.015CrossRefPubMed

34.

B. Thorens, GLUT2, glucose sensing and glucose homeostasis. Diabetologia 58, 221–232 (2015). https://doi.org/10.1007/s00125-014-3451-1CrossRefPubMed

35.

A. Rathinam, L. Pari, Myrtenal ameliorates hyperglycemia by enhancing GLUT2 through Akt in the skeletal muscle and liver of diabetic rats. Chem. Biol. Interact. 256, 161–166 (2016). https://doi.org/10.1016/j.cbi.2016.07.009CrossRefPubMed

36.

N. Vedovato, O. Rorsman, K. Hennis, F.M. Ashcroft, P. Proks, Role of the C-terminus of SUR in the differential regulation of beta-cell and cardiac KATP channels by MgADP and metabolism. J. Physiol. 596, 6205–6217 (2018). https://doi.org/10.1113/JP276708CrossRefPubMedPubMedCentral

37.

V. Djokic, S. Jankovic-Raznatovic, R. Novakovic, M. Kostic, J. Rajkovic, M. Labudovic-Borovic, J. Rakocevic, J. Stanisic, M. Djuric, L. Gojkovic-Bukarica, Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels. Exp. Mol. Pathol. 111, 104323 (2019). https://doi.org/10.1016/j.yexmp.2019.104323CrossRefPubMed

38.

Y. Sha, Y. Zhang, J. Cao, K. Qian, B. Niu, Q. Chen,, Loureirin B promotes insulin secretion through inhibition of KATP channel and influx of intracellular calcium. J. Cell Biochem. 119, 2012–2021 (2018). https://doi.org/10.1002/jcb.26362CrossRefPubMed

39.

Y. Yang, K. Shimomura, K. Sakuma, Y. Maejima, Y. Iwasaki, J. Galvanovskis, K. Dezaki, M. Nakata, T. Yada, Bupropion can close KATP channel and induce insulin secretion. J. Pediatr. Endocrinol. Metab. 26, 343–346 (2013). https://doi.org/10.1515/jpem-2012-0295CrossRefPubMed

40.

C.H. Lee, C.S. Chu, H.J. Tsai, L.Y. Ke, H.C. Lee, J.L. Yeh, C.H. Chen, B.N. Wu, Xanthine-derived KMUP-1 reverses glucotoxicity-activated Kv channels through the cAMP/PKA signaling pathway in rat pancreatic beta cells. Chem. Biol. Interact. 279, 171–176 (2018). https://doi.org/10.1016/j.cbi.2017.11.017CrossRefPubMed

41.

J. Gao, X. Zhong, Y. Ding, T. Bai, H. Wang, H. Wu, Y. Liu, J. Yang, Y. Zhang, Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. Eur. J. Pharm. 777, 41–48 (2016). https://doi.org/10.1016/j.ejphar.2016.02.060CrossRef

Titel: Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and mechanism
verfasst von: Hui Li
Jian Zhang
Yongli Fu
Yixin Zhang
Chunhui Zhang
Xiaozhu Sun
Fang Wu
Jing He
Publikationsdatum: 20.11.2020
Verlag: Springer US
Erschienen in: Endocrine / Ausgabe 2/2021
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-020-02537-5

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