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Studies on teratogenicity of maternal hypoglycemia in rats and rabbits

桑田, 千春 北海道大学

2022.12.26

概要

Diabetes during pregnancy is one of the most common maternal disorders and its prevalence is increasing 33) . Insulin is currently the only option for treating diabetes in pregnant women according to several sets of practice guidelines 6,37). Because of its large molecular size, insulin cannot pass the placental barrier by facilitated diffusion, so it rarely affects fetuses directly 23,63,81) . Meanwhile, almost all launched oral antidiabetic drugs, which have a small molecular size and can reach the fetus through the placenta unlike insulin, are contraindicated during pregnancy because they showed teratogenic potential and/or embryo-fetal lethality when administered to animals in non-clinical study during development 43,80) .

When developing a new drug, nonclinical embryo-fetal developmental toxicity (EFD) studies have to be conducted to support human clinical trials and marketing authorization, in accordance with to the International Conference on Harmonisation (ICH) guidelines 35) . To detect unexpected adverse effects on reproduction and embryo-fetal development for human risk assessment during pregnancy, EFD studies in two experimental animal species treated throughout the period of organogenesis are required. In EFD studies, a dose level that is higher than the therapeutic dose should be tested to evaluate potential adverse effects by investigating pregnant maintenance, fetal viability, fetal developmental retardation, and teratogenicity.

Generally, there are two possible mechanisms underlying the teratogenicity of drugs. One is a direct effect of drugs on fetuses by crossing the placenta from mother to fetus. The other is an indirect effect of drugs on fetuses due to maternal conditions induced by drugs. If the drug has a direct effect on fetuses, then it should be contraindicated in pregnant woman due to its own teratogenic potential; however, if the drug shows an indirect effect on fetuses, its use during pregnancy may be acceptable by controlling the maternal conditions. Therefore, it is very important to elucidate the underlying mechanism when a candidate drug shows teratogenicity in animal studies.

Antidiabetic drugs can cause maternal hypoglycemia due to their exacerbated pharmacological action. Subsequently, these drugs may induce teratogenicity in fetuses via maternal hypoglycemia, although it remains controversial whether maternal hypoglycemia can cause teratogenicity in fetuses. Eriksson 19) and Landauer 43) reported that insulin caused fetal teratogenicity due to maternal hypoglycemia without crossing the placental barrier. It was also shown that the administration of insulin to pregnant animals from an early stage of pregnancy caused eye anomalies in their fetuses in rats 52,53) or rabbits 14) and axial skeleton anomalies in their fetuses in rats 76) or mice 72) when examined at a late stage of pregnancy. In addition to the aforementioned in vivo studies, Akazawa et al. 2,3) showed that insulininduced hypoglycemia interrupted neural embryogenesis in rats in early pregnancy period by whole-embryo culture. However, some other in vivo studies demonstrated that insulin did not show teratogenicity despite causing severe hypoglycemia lasting for 1 to 7 h or mild hypoglycemia for 48 h 29,31,38,65). The reason for this discrepancy has not yet been fully elucidated and the detailed pathogenesis of the anomalies in fetuses caused by insulin also remains unclear.

DS-7309 was developed for the treatment of type 2 diabetes mellitus (T2DM) by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). DS-7309 activates glucokinase (GK), which is distributed primarily in the liver and beta cells of the pancreas and catalyzes the phosphorylation of glucose to synthesize glucose-6-phosphate 73). In response to a high blood glucose level, GK promotes the secretion of insulin from beta cells and subsequent glycogenesis in the liver, and induces reduction of the blood glucose level 47,48). Therefore, GK is an attractive target for treating T2DM 28,49,79) .

The teratogenic potential of DS-7309 has been recognized in EFD studies using rats and rabbits. However, it is unclear how fetal anomalies developed and whether the teratogenicity of DS-7309 is due to a direct effect on fetuses or an indirect effect caused via maternal hypoglycemia. Therefore, in this work, comprehensive investigation of teratogenicity induced by DS-7309 was conducted as follows: As described in Chapter 1, the toxicological effects of DS-7309 on pregnancy and embryo-fetal development in rats and rabbits and maternal blood glucose levels were examined. Then, as indicated in Chapter 2, four different types of insulin, which rarely affect fetuses directly, were used to cause different types of maternal hypoglycemia (in terms of the severity and duration) in order to characterize the teratogenicity induced by maternal hypoglycemia and to investigate the relationship between the duration and severity of maternal hypoglycemia and teratogenicity in detail. Finally, as shown in Chapter 3, the pathogenesis of and factors contributing to hypoglycemia-induced eye anomalies were further investigated.

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参考文献

1) Agency EP. Guidelines for Developmental Toxicity Risk Assessment. Federal Register 56, 63798-63826, 1991.

2) Akazawa M, Akazawa S, Hashimoto M, Akashi M, Yamazaki H, Tahara D, Yamamoto H, Yamaguchi Y, Nakanishi T, Nagataki S. Effects of brief exposure to insulin-induced hypoglycemic serum during organogenesis in rat embryo culture. Diabetes 38, 1573-1578, 1989.

3) Akazawa S, Akazawa M, Hashimoto M, Yamaguchi Y, Kuriya N, Toyama K, Ueda Y, Nakanishi T, Mori T, Miyake S, et al. Effects of hypoglycaemia on early embryogenesis in rat embryo organ culture. Diabetologia 30, 791-796, 1987.

4) Andley UP. Crystallins in the eye: Function and pathology. Prog Retin Eye Res 26, 78-98, 2007.

5) Andley UP. The lens epithelium: focus on the expression and function of the alphacrystallin chaperones. Int J Biochem Cell Biol 40, 317-323, 2008.

6) Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. Diabetol Int 11, 165-223, 2020.

7) Balakrishnan S, Sadasivam M, Kannan A, Panneerselvam A, Prahalathan C. Glucose modulates Pax6 expression through the JNK/p38 MAP kinase pathway in pancreatic beta-cells. Life Sci 109, 1-7, 2014.

8) Baumer N, Marquardt T, Stoykova A, Spieler D, Treichel D, Ashery-Padan R, Gruss P. Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6. Development 130, 2903-2915, 2003.

9) Buchanan TA, Schemmer JK, Freinkel N. Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat. J Clin Invest 78, 643-649, 1986.

10) Burgess D, Zhang Y, Siefker E, Vaca R, Kuracha MR, Reneker L, Overbeek PA, Govindarajan V. Activated Ras alters lens and corneal development through induction of distinct downstream targets. BMC Dev Biol 10, 13, 2010.

11) Burmeister M, Novak J, Liang MY, Basu S, Ploder L, Hawes NL, Vidgen D, Hoover F, Goldman D, Kalnins VI, Roderick TH, Taylor BA, Hankin MH, McInnes RR. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 12, 376-384, 1996.

12) Carter-Dawson LD, LaVail MM. Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine. J Comp Neurol 188, 263-272, 1979.

13) CDER/FDA. Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, 2005.

14) Chomette G. [Developmental disorders after insulin shock in pregnant rabbits]. Beitr Pathol Anat 115, 439-451, 1955.

15) Chow RL, Lang RA. Early eye development in vertebrates. Annu Rev Cell Dev Biol 17, 255-296, 2001.

16) Cvekl A, Ashery-Padan R. The cellular and molecular mechanisms of vertebrate lens development. Development 141, 4432-4447, 2014.

17) Davis-Silberman N, Kalich T, Oron-Karni V, Marquardt T, Kroeber M, Tamm ER, Ashery-Padan R. Genetic dissection of Pax6 dosage requirements in the developing mouse eye. Hum Mol Genet 14, 2265-2276, 2005.

18) Dawson AB. A note on the staining of the skeleton of cleared specimens with alizarin red S. Strain technol 1, 1926.

19) Eriksson UJ. Congenital malformations in diabetic animal models--a review. Diabetes Res 1, 57-66, 1984.

20) F.J. Lovicu MLRE. Lens induction and determination, Cambridge University Press, New York. pp. 27-47, 2004.

21) Fuhrmann S. Eye morphogenesis and patterning of the optic vesicle. Curr Top Dev Biol 93, 61-84, 2010.

22) Fuhrmann S, Levine EM, Reh TA. Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development 127, 4599-4609, 2000.

23) Garcia-Bournissen F, Feig DS, Koren G. Maternal-fetal transport of hypoglycaemic drugs. Clin Pharmacokinet 42, 303-313, 2003.

24) Gosmain Y, Katz LS, Masson MH, Cheyssac C, Poisson C, Philippe J. Pax6 is crucial for beta-cell function, insulin biosynthesis, and glucose-induced insulin secretion. Mol Endocrinol 26, 696-709, 2012.

25) Graw J. Eye development. Curr Top Dev Biol 90, 343-386, 2010.

26) Graw J. Genetic aspects of embryonic eye development in vertebrates. Dev Genet 18, 181-197, 1996.

27) Greuter MJ, van Emmerik NM, Wouters MG, van Tulder MW. Quality of guidelines on the management of diabetes in pregnancy: a systematic review. BMC Pregnancy Childbirth 12, 58, 2012.

28) Grimsby J, Sarabu R, Corbett WL, Haynes NE, Bizzarro FT, Coffey JW, Guertin KR, Hilliard DW, Kester RF, Mahaney PE, Marcus L, Qi L, Spence CL, Tengi J, Magnuson MA, Chu CA, Dvorozniak MT, Matschinsky FM, Grippo JF. Allosteric activators of glucokinase: potential role in diabetes therapy. Science 301, 370-373, 2003.

29) Hannah RS, Moore KL. Effects of fasting and insulin on skeletal development in rats. Teratology 4, 135-140, 1971.

30) Hay WW, Jr. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc 117, 321-339; discussion 339-340, 2006.

31) Hofmann T, Horstmann G, Stammberger I. Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits. Int J Toxicol 21, 181-189, 2002.

32) Horsford DJ, Nguyen MT, Sellar GC, Kothary R, Arnheiter H, McInnes RR. Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity. Development 132, 177-187, 2005.

33) Hunt KJ, Schuller KL. The increasing prevalence of diabetes in pregnancy. Obstet Gynecol Clin North Am 34, 173-199, vii, 2007.

34) Hyer J, Mima T, Mikawa T. FGF1 patterns the optic vesicle by directing the placement of the neural retina domain. Development 125, 869-877, 1998.

35) ICH. International council for harmonisation of technical requirements for pharmaceuticals for human use. Detection of reproductive and developmental toxicity for human pharmaceuticals. S5 (R3), 2020.

36) Jensen VFH, Molck AM, Lykkesfeldt J, Fels JJ, Andersen L, Renaut R, McGuigan F, Akesson KE, Bogh IB. Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats. Reprod Toxicol 91, 14-26, 2020.

37) Jovanovic L. American Diabetes Association's Fourth International WorkshopConference on Gestational Diabetes Mellitus: summary and discussion. Therapeutic interventions. Diabetes Care 21 Suppl 2, B131-137, 1998.

38) Kawaguchi M, Tanigawa K, Tanaka O, Kato Y. Embryonic growth impaired by maternal hypoglycemia during early organogenesis in normal and diabetic rats. Acta Diabetol 31, 141-146, 1994.

39) Knobloch J, Schmitz I, Gotz K, Schulze-Osthoff K, Ruther U. Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspasedependent cell death. Mol Cell Biol 28, 529-538, 2008.

40) Kumar PA, Reddy PY, Srinivas PN, Reddy GB. Delay of diabetic cataract in rats by the antiglycating potential of cumin through modulation of alpha-crystallin chaperone activity. J Nutr Biochem 20, 553-562, 2009.

41) Kuwata C, Saeki N, Honda K, Matsuoka T, Tsuchiya Y, Shimomura K. Effects of maternal hypoglycemia on fetal eye and skeleton development in rats. Reprod Toxicol 71, 135-141, 2017.

42) Laakso M. Not for the eyes only: PAX6 and glucose metabolism. Diabetologia 52, 381-384, 2009.

43) Landauer W. Is Insulin a teratogen? Teratology 5, 129-135, 1972.

44) Lapolla A, Dalfra MG, Fedele D. Insulin therapy in pregnancy complicated by diabetes: are insulin analogs a new tool? Diabetes Metab Res Rev 21, 241-252, 2005.

45) Lau C, Narotsky MG, Lui D, Best D, Setzer RW, Mann PC, Wubah JA, Knudsen TB. Exposure-disease continuum for 2-chloro-2'-deoxyadenosine (2-CdA), a prototype teratogen: induction of lumbar hernia in the rat and species comparison for the teratogenic responses. Teratology 66, 6-18, 2002.

46) Liu IS, Chen JD, Ploder L, Vidgen D, van der Kooy D, Kalnins VI, McInnes RR. Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13, 377- 393, 1994.

47) Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes 39, 647-652, 1990.

48) Matschinsky FM, Magnuson MA, Zelent D, Jetton TL, Doliba N, Han Y, Taub R, Grimsby J. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55, 1-12, 2006.

49) Matschinsky FM, Zelent B, Doliba N, Li C, Vanderkooi JM, Naji A, Sarabu R, Grimsby J. Glucokinase activators for diabetes therapy: May 2010 status report. Diabetes Care 34 Suppl 2, S236-243, 2011.

50) Matsubara Y, Mikami T. [Teratogenic potentially of single dose of thalidomide in JW-NIBS rabbits]. Jikken Dobutsu 34, 295-302, 1985.

51) Matthew H. Kaufman JBLB. The Anatomical Basis of Mouse Development, Academic Press, 1999.

52) Miyamoto M, Sakaguchi T, Midorikawa O. Teratogenic Effects of Sulfonylureas and Insulin in Rats. Congenital Anomalies 17, 31-37, 1977.

53) Miyamoto M, Sakaguchi T, Midorikawa O. Teratogenicity of Regular Insulin and Ultralente Insulin in Rats Congenital Anomalies 19, 291-297, 1979.

54) Nguyen M, Arnheiter H. Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF. Development 127, 3581-3591, 2000.

55) NovoNordiskInc. Levemir (insulin detemir) [FDA: Pharmacology and Toxicology Review], Available from: http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process &ApplNo=021536, 2005.

56) NovoNordiskInc. Novolin FlexPen, InnoLet, Novolin R 100 IU/mL (insulin human) [PMDA: Interview form], Available form: http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/2492403A4, 2021.

57) NovoNordiskInc. Novolog (insulin aspart recombinant) [FDA: Pharmacology Review (s)], Available form: http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process &ApplNo=020986, 2000.

58) O'Hara MF, Charlap JH, Craig RC, Knudsen TB. Mitochondrial transduction of ocular teratogenesis during methylmercury exposure. Teratology 65, 131-144, 2002.

59) Ogino H, Ochi H, Reza HM, Yasuda K. Transcription factors involved in lens development from the preplacodal ectoderm. Dev Biol 363, 333-347, 2012.

60) Peiffer RL, McCullen R, Alles AJ, Sulik KK. Relationship of cell death to cyclophosphamide-induced ocular malformations. Teratog Carcinog Mutagen 11, 203-212, 1991.

61) Pittack C, Grunwald GB, Reh TA. Fibroblast growth factors are necessary for neural retina but not pigmented epithelium differentiation in chick embryos. Development 124, 805-816, 1997.

62) Pontoriero GF, Smith AN, Miller LA, Radice GL, West-Mays JA, Lang RA. Cooperative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival. Dev Biol 326, 403-417, 2009.

63) Poon K, King AB. Glargine and detemir: Safety and efficacy profiles of the longacting basal insulin analogs. Drug Healthc Patient Saf 2, 213-223, 2010.

64) Rapaport DH, Wong LL, Wood ED, Yasumura D, LaVail MM. Timing and topography of cell genesis in the rat retina. J Comp Neurol 474, 304-324, 2004.

65) Ream JR, Jr., Weingartern PL, Pappas AM. Evaluation of the prenatal effects of massive doses of insulin in rats. Teratology 3, 29-32, 1970.

66) Reddy VS, Kumar CU, Reddy GB. Effect of chronic hyperglycemia on crystallin levels in rat lens. Biochem Biophys Res Commun 446, 602-607, 2014.

67) Reese BE. Development of the retina and optic pathway. Vision Res 51, 613-632, 2011.

68) Reis LM, Semina EV. Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma. Birth Defects Res C Embryo Today 105, 96-113, 2015.

69) SanofiAventisUS. Lantus (insulin glargine recombinant) [FDA: Pharmacology Review (s)], Available form http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process &ApplNo=021081, 2000.

70) Shaham O, Menuchin Y, Farhy C, Ashery-Padan R. Pax6: a multi-level regulator of ocular development. Prog Retin Eye Res 31, 351-376, 2012.

71) Sidman RL. Histogenesis of mouse retina studied with thymidine-H3, Academic Press., New York. pp. 487-505, 1961.

72) Smithberg M, Runner MN. Teratogenic Effects of Hypoglycemic Treatments in Inbred Strains of Mice. Am J Anat 113, 479-489, 1963.

73) Sternisha SM, Miller BG. Molecular and cellular regulation of human glucokinase. Arch Biochem Biophys 663, 199-213, 2019.

74) Sulik KK, Dehart DB, Rogers JM, Chernoff N. Teratogenicity of low doses of alltrans retinoic acid in presomite mouse embryos. Teratology 51, 398-403, 1995.

75) Tan RR, Zhang SJ, Li YF, Tsoi B, Huang WS, Yao N, Hong M, Zhai YJ, Mao ZF, Tang LP, Kurihara H, Wang Q, He RR. Proanthocyanidins Prevent High GlucoseInduced Eye Malformation by Restoring Pax6 Expression in Chick Embryo. Nutrients 7, 6567-6581, 2015.

76) Tanigawa K, Kawaguchi M, Tanaka O, Kato Y. Skeletal malformations in rat offspring. Long-term effect of maternal insulin-induced hypoglycemia during organogenesis. Diabetes 40, 1115-1121, 1991.

77) Tibaldi JM. Evolution of insulin: from human to analog. Am J Med 127, S25-38, 2014.

78) Torlone E, Di Cianni G, Mannino D, Lapolla A. Insulin analogs and pregnancy: an update. Acta Diabetol 46, 163-172, 2009.

79) Toulis KA, Nirantharakumar K, Pourzitaki C, Barnett AH, Tahrani AA. Glucokinase Activators for Type 2 Diabetes: Challenges and Future Developments. Drugs 80, 467-475, 2020.

80) Tran ND, Hunter SK, Yankowitz J. Oral hypoglycemic agents in pregnancy. Obstet Gynecol Surv 59, 456-463; quiz 485, 2004.

81) Trujillo AL. Insulin Analogs and Pregnancy. Diabetes Spectrum 20, 94-101, 2007.

82) Wang Q, Fang WH, Krupinski J, Kumar S, Slevin M, Kumar P. Pax genes in embryogenesis and oncogenesis. J Cell Mol Med 12, 2281-2294, 2008.

83) Wilson JG. Methods for administrating agents and detecting malformations in experimrntal animals. Chicago: University of Cicago Press, 1965.

84) Young RW. Cell differentiation in the retina of the mouse. Anat Rec 212, 199-205, 1985.

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