ZYGK1 is a novel small molecule glucokinase (GK) activator. The purpose of this study was to assess the repeated dose toxicity of ZYGK1 in male and female Wistar rats and its effect on pregnancy and embryo-fetal development in pregnant female Wistar rats. ZYGK1 was administered by oral gavage to rats at 15, 30, 60, and 120 mg/kg, once a day, for 28 consecutive days. For studying the effect on pregnancy and embryo-fetal development, ZYGK1 was administered by oral gavage at 60 and 120 mg/kg from gestation day (GD) 6 to 15, to presumed pregnant female Wistar rats. Hypoglycemia was observed at all doses of ZYGK1 in male and female rats in the general toxicity study, but no toxic effects were observed, except partially reversible axonal degeneration in peripheral nerves. ZYGK1 treatment in pregnant female rats caused hypoglycemia and decreased the fetal body weight. Treatment from GD 6 to 15 caused no significant fetal abnormalities, except incidental fetal skeleton anomalies. Thus, ZYGK1 may lead to maternal hypoglycemia, but no significant developmental toxicity was observed.
SternishaSMMillerBG. Molecular and cellular regulation of human glucokinase. Arch Biochem Biophys. 2019;663:199-213. doi:10.1016/j.abb.2019.01.011
2.
MatschinskyFM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes. 2002;51(Suppl 3):S394-S404. doi:10.2337/diabetes.51.2007.s394
3.
MatschinskyFMZelentBDolibaN, et al.Glucokinase activators for diabetes therapy: May 2010 status report. Diabetes Care. 2011;34(Suppl 2):S236-S243. doi:10.2337/dc11-s236
4.
Al-HasaniHTschöpMHCushmanSW. Two birds with one stone: novel glucokinase activator stimulates glucose-induced pancreatic insulin secretion and augments hepatic glucose metabolism. Mol Interv. 2003;3(7):367-370. doi:10.1124/mi.3.7.367
5.
MeiningerGEScottRAlbaM, et al.Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care. 2011;34(12):2560-2566. doi:10.2337/dc11-1200
6.
RudlandVL. Diagnosis and management of glucokinase monogenic diabetes in pregnancy: current perspectives. Diabetes Metab Syndr Obes. 2019;12:1081-1089. doi:10.2147/DMSO.S186610
7.
PataniKJoharapurkarASundarR, et al.Pharmacological effect of ZYGK1, a novel glucokinase activator, in hyperglycemic and sulfonylurea-resistant type 2 diabetes in mice models. J Diabetes Complications. 2025;39:108977. doi:10.1016/j.jdiacomp.2025.108977
8.
HayWWJ. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006;117:321-340.
9.
HofmannTHorstmannGStammbergerI. Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits. Int J Toxicol. 2002;21(3):181-189. doi:10.1080/10915810290096315
10.
LandauerW. Is insulin a teratogen?Teratology. 1972;5(2):129-135. doi:10.1002/tera.1420050202
11.
BuchananTASchemmerJKFreinkelN. Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat. J Clin Investig. 1986;78(3):643-649. doi:10.1172/JCI112622
12.
AminianfarAZolfaghariHSoltaniS, et al.Dietary insulin load and index in relation to incident gestational diabetes mellitus: a prospective cohort study. Sci Rep. 2024;14(1):31571. doi:10.1038/s41598-024-68125-z
13.
KuwataCSaekiNHondaKMatsuokaTTsuchiyaYShimomuraK. Effects of maternal hypoglycemia on fetal eye and skeleton development in rats. Reprod Toxicol. 2017;71:135-141. doi:10.1016/j.reprotox.2017.05.009
14.
SchaferKAEighmyJFikesJD, et al.Use of severity grades to characterize histopathologic changes. Toxicol Pathol. 2018;46(3):256-265. doi:10.1177/0192623318761348
15.
BarrMJBeaudoinAR. An exploration of the role of hydroxyurea injection time in fetal growth and teratogenesis in rats. Teratology. 1981;24(2):163-167. doi:10.1002/tera.1420240207
16.
PatelSPatelSKotadiyaA, et al.Age-related changes in hematological and biochemical profiles of Wistar rats. Lab Anim Res. 2024;40(1):7. doi:10.1186/s42826-024-00194-7
17.
JensenVFHMølckAMHeydenreichA, et al.Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia. J Toxicol Pathol. 2016;29(1):17-30. doi:10.1293/tox.2015-0041
18.
TirmensteinMHorvathJGrazianoM, et al.Utilization of the Zucker diabetic fatty (ZDF) rat model for investigating hypoglycemia-related toxicities. Toxicol Pathol. 2015;43(6):825-837. doi:10.1177/0192623315581020
19.
YangWZhuDGanS, et al.Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2022;28(5):974-981. doi:10.1038/s41591-022-01803-5
20.
YangWWuHCaiXLinCJiaoRJiL. Evaluation of efficacy and safety of glucokinase activators-a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023;14:1175198. doi:10.3389/fendo.2023.1175198
21.
PettersenJCLitchfieldJNeefN, et al.The relationship of glucokinase activator-induced hypoglycemia with arteriopathy, neuronal necrosis, and peripheral neuropathy in nonclinical studies. Toxicol Pathol. 2014;42(4):696-708. doi:10.1177/0192623314526006
22.
VieiraRSoutoSBSánchez-LópezE, et al.Sugar-lowering drugs for type 2 diabetes mellitus and metabolic syndrome-review of classical and new compounds: Part-I. Pharmaceuticals. 2019;12(4):152. doi:10.3390/ph12040152
23.
SjöholmÅ. Glucokinase activators and imeglimin: new weaponry in the armamentarium against type 2 diabetes. BMJ Open Diabetes Res care. 2024;12(4):e004291. doi:10.1136/bmjdrc-2024-004291
24.
De CeuninckFKargarCIlicC, et al.Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans. Br J Pharmacol. 2013;168(2):339-353. doi:10.1111/j.1476-5381.2012.02184.x
25.
TsumuraYTsushimaYTamuraA, et al.TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models. PLoS One. 2017;12(2):e0172252. doi:10.1371/journal.pone.0172252
26.
VaxillaireMCavalcanti-ProençaCDechaumeA, et al.The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes. 2008;57(8):2253-2257. doi:10.2337/db07-1807
27.
SarabuRBizzarroFTCorbettWL, et al.Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients. J Med Chem. 2012;55(16):7021-7036. doi:10.1021/jm3008689
28.
HaddadDDsouzaVSAl-MullaFAl MadhounA. New-generation glucokinase activators: potential game-changers in type 2 diabetes treatment. Int J Mol Sci. 2024;25(1):571. doi:10.3390/IJMS25010571/S1
29.
MohseniS. Chapter 33 - neurologic damage in hypoglycemia. In:ZochodneDWMalikRA, eds. Handbook of Clinical Neurology. Vol 126. Diabetes and the Nervous System. Elsevier; 2014:513-532. doi:10.1016/B978-0-444-53480-4.00036-9
30.
SteckerMStevensonM. Effects of insulin on peripheral nerves. J Diabetes Complications. 2016;30(5):770-777. doi:10.1016/j.jdiacomp.2016.03.009
31.
YasakiSDyckPJ. Duration and severity of hypoglycemia needed to induce neuropathy. Brain Res. 1990;531(1-2):8-15. doi:10.1016/0006-8993(90)90752-w
32.
KuwataCMatsuokaTOhshimaY, et al.Effects of glucokinase activator, DS-7309, on embryo-fetal developmental toxicity in rats and rabbits. Regul Toxicol Pharmacol. 2022;129:105119. doi:10.1016/j.yrtph.2022.105119
JensenVFHMølckAMLykkesfeldtJ, et al.Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats. Reprod Toxicol. 2020;91:14-26. doi:10.1016/j.reprotox.2019.10.003
35.
KuwataCMaejimaTHakamataSYahagiSMatsuokaTTsuchiyaY. Disruption of fetal eye development caused by insulin-induced maternal hypoglycemia in rats. Reprod Toxicol. 2022;112:68-76. doi:10.1016/j.reprotox.2022.06.008
36.
HollstedtCOlssonORydbergU. The effect of alcohol on the developing organism. Genetical, teratological and physiological aspects. Med Biol. 1977;55(1):1-14.
