Development of Rats Filial (F1) Born From Valproic Acid-Treated Female Rats as a Diabetic Mellitus Model



To do research and development of antidiabetic drugs, animal models of diabetes in accordance with the conditions is required. The aim of this research was to develop a diabetic model that is fit to the pathophysiology of diabetic condition. The pregnant female rats were divided into 2 groups, one group was orally treated by a single dose of valproic acid (250 mg/kg bw) on day 9th of pregnancy and the other was a control. At the ages of 8, 16 and 24 weeks the blood samples of litters (F1) were taken for glucose, insulin and triglyceride determination. At the same time, pancreatic tissues were collected under deep anesthetic condition for immunohistological study. Results of blood glucose concentrations and histological finding of litters (F1) indicated that at the age of 8 weeks both had showed a similar pattern as compared to control. At the ages of 16 and 24 weeks, blood glucose and insulin level showed a significant increase, while positive insulin cells slightly decreased in number. It can be concluded that treating rat with valproic acid on days 9 of gestation will inhibit pancreatic β cells function. There is an indication that F1 of valproic acid treated pregnant mother start showing a metabolic syndrome at 16 weeks and being pronounce by aging.


1. Marks DB, Marks AD, Smith CM. Basic medical biochemistry: A clinical approach. William and Wilkins; 2000. 381-578.
2. Gray SG, De Meyts P. Role of histone and transcription factor acetylation in diabetes pathogenesis. Diabetes Metab Res Rev. 2005.21:416–33. doi: 10.1002/dmrr.559.
3. Nugroho AE. Animal models of diabetes mellitus: Pathology and mechanism of some diabetogenics, Biodiversitas. 2006.7(4):378-82.
4. Szkudelski T. The mechanism of alloxan and streptozotocin action in b cells of the rat pancreas. Physiol Res. 2001.50:536-46.
5. Kuwabara T, Kagalwala M, Akizuki S, Warashina M, Sanosaka T, Nakashima K, Gage FH, Asashima M. De novo insulin biosynthesis from newborn cells in adult hippocampus and pancreas. NSC IPC. 2009.
6. Jorgensen MC, Ahnfelt RJ, Hald J, Madsen OD, Serup P, Hecksher-Sorensen J. An illustrated review of early pancreas development in the mouse. Endocrine Reviews. The Endocrine Society; 2007.28(6):685-705.
7. Christensen DP, Dahllof M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N, Grunnet LG, Maundrup PT. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol Med. 2011. 17(5-6):378-90.
8. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S,Sleeman JP, Coco FL, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. The EMBO Journal. 2001. 20(24): 6969-78.
9. Hogan B, Beddington R, Costantini F, Lacy E. Manipulating the mouse embryo. A Laboratory Manual. 2nd Ed. USA: Cold Spring Harbor Laboratory Press; 1994.
10. Lienhard GE, Slout JW, James DE, Mueckler M. How cells absord glucose. Journal of Scientific American. 2002.3:235-8.
11. Holt RIG, Hanley A. Essenstial endrocrinology and diabetes. 5th Ed. Massachussets: Blackwell Publishing; 2007. 216-63.
12. Kahn SE, Hull RL, Utzschneider KM. Mechanism linking obesity to insulin resistance and type 2 diabetes.nature. 2006. 444(14):840-6.
13. Riedel MJ, Asadi A, Wang R, Ao Z, Warnock GL, Kieffer TJ. Immunohistochemical caharacterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetolgia. 2012. 55:372-81.
14. Larsen LM, Tonnesen SG, Storling RJ, Jorgensen S, Mascagni P, Dinarcello CA, et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Dibetolgia. 2007. 50:779-89.
15. Cerveny L, Svecova L, Azenbacherova E, Vrzal R, Staud F, Dvorak Z, et al. Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metabolism and Disposition. 2007. 35(7):1033-41.
16. Peraza MA, Burdick AD, Marin HE, Gonzales FJ, Peters JM. The toxicology of ligands for peroxisome 284 SUNARYO ET AL.
proliferator-activated receptors (PPAR). Toxicological Sciences. 2006. 90(2):269–95.
17. Lampen A, Carlberg C, Nau H. Peroxisome proliferator-activated receptor δ is a specific sensor for teratogenic valproic acid derivatives. European Journal of Pharmacology. 2001. 431:25-33.
18. Werling U, Siehler S, Litfin M, Nau H, Gottlicher M. Induction of differentiation in F9 cells and activation of peroxisome proliferator-activated receptor δ by valproic acid and its teratogenic derivatives. Mol Pharmacol. 2001. 59:1269-76. 280-
How to Cite
SUNARYO, HADI et al. Development of Rats Filial (F1) Born From Valproic Acid-Treated Female Rats as a Diabetic Mellitus Model. JURNAL ILMU KEFARMASIAN INDONESIA, [S.l.], v. 12, n. 2, p. 279-284, sep. 2014. ISSN 2614-6495. Available at: <>. Date accessed: 31 may 2023.