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Current Diabetes Reviews


ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Review Article

Streptozotocin-Induced Diabetes Mellitus in Neonatal Rats: An Insight into its Applications to Induce Diabetic Complications

Author(s): Mirza Anwar Baig and Shital Sharad Panchal*

Volume 16, Issue 1, 2020

Page: [26 - 39] Pages: 14

DOI: 10.2174/1573399815666190411115829

Price: $65


Background: Diabetic complications are the major contributor in the mortality of diabetic patients despite controlling blood glucose level. In the journey of new drug discovery, animal models have to play a major role. A large number of chemical-induced and genetically modified animal models have been investigated to induce diabetic complications but none of them was found to be mimicking the pathophysiology of the human. Therefore, the search and identification of the appropriate animal model become essential.

Objective: In the present review, we have made an attempt to understand the pathophysiology of diabetic complication in the neonatal streptozotocin-diabetic rat model and tried to identify the targets for therapeutic agents. The review will help the researchers to explore the animal model to induce diabetic complications, to identify targets and further to find lead molecules for treatment or prevention of diabetic complications.

Methods: We have compiled the available research work from 1974 by using prominent databases, organized the available information and analyzed the data to improve the understanding of the pathophysiology of streptozotocin-induced diabetic complications in neonates of rats.

Results: The neonatal streptozotocin-diabetic rat model is frequently used and well-established animal model for type 2 diabetes mellitus. We have found that this model has been used to study the pathogenesis of various micro and macrovascular diabetic complications and also investigated for its effects on the liver, thymus gland, and brain. The underlying pathophysiology for complications had a resemblance to the human.

Conclusion: The neonatal streptozotocin-diabetic rat model may demonstrate symptomatic diabetic complications due to persistent hyperglycemia at the age of approximately 18-24 weeks. Critical interpretations of available research work showed that the researcher can explore split dose STZ (90- 100mg/kg b.w) model to induce Type 2 DM in neonates of rats at 2nd or 3rd postnatal day.

Keywords: Streptozotocin, neonatal rats, diabetic complications, animal model, pathophysiology, insulin.

Mathis D, Vence L, Benoist C. Beta-Cell death during progression to diabetes. Nature 2001; 414: 792-8.
International Diabetes Federation. IDF Diabetes Atlas- 8th Edition. Diabetes Atlas http://www. (2017). Accessed on: 15/01/2019.
Abdul G, Reddy KS, Singhi M. Burden on non-communicable disease in South Asia. BMJ 2004; 328: 807-10.
Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 4-14.
American Diabetes Association clinical practice recommendations. Diabetes Care 1997; 20(1): S1-S70.
Venugopal V, Ramesh M, and Manjunath NKS. Ethnic disparity and increased prevalence of type 2 diabetes among south asians: aetiology and future implications for diabetes prevention and management. Curr Diabetes Rev 2018; 14: 518-22.
Nouwen A, Nefs G, Caramlau I, et al. Prevalence of depression in individuals with impaired glucose metabolism or undiagnosed diabetes: a systematic review and meta-analysis of the European Depression in Diabetes (EDID) Research Consortium. Diabetes Care 2011; 34: 752-62.
Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes systematic overview of prospective observational studies. Diabetologia 2005; 48: 2460-9.
Adeniyi AF, Adeleye JO, Adeniyi CY. Diabetes, sexual dysfunction and therapeutic exercise: a 20 year review. Curr Diabetes Rev 2011; 6: 201-6.
Dodda D, Ciddi V. Plants used in the management of diabetic complications. Indian J Pharm Sci 2014; 76(2): 97-106.
Munehiro K, Zhaoyun Z, Akira M, George LK. Molecular mechanisms of diabetic vascular complications. J Diabetes Investig 2010; 1(3): 77-89.
Maria GB. Hexosamines, insulin resistance and the complications of diabetes: current status. Am J Physiol Endocrinol Metab 2006; 290(1): E1-8.
Pedro G, George LK. Activation of protein kinase c isoforms & its impact on diabetic complications. Circ Res 2010; 106(8): 1319-31.
Varun PS, Anjana B, Nirmal S, Amteshwar SJ. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014; 18: 1-14.
Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 2005; 52(4): 313-20.
Portha B, Levacher C, Picon L, Rosselin G. Diabetogenic effect of streptozotocin in the rat during the perinatal period. Diabetes 1974; 23: 889-95.
Weir GC, Clore ET, Zmachinski CJ, Bonner-Weir S. Islet secretion in a new experimental model for non-insulin-dependent. Diabetes 1981; 30: 590-5.
Bonner WS, Trent DF, Honey RN, Weir GC. Responses of neonatal rat islets to streptozotocin limited B-cell regeneration and hyperglycemia. Diabetes 1981; 30(1): 64-9.
Portha B, Blondel O, Serradas P, et al. The rat models of non-insulin dependant diabetes induced by neonatal streptozotocin. Diabetes Metab 1989; 15: 161-75.
Dutrillaux MC, Portha B, Roze C, Hollande E. Ultrastructural study of pancreatic β-cell regeneration in newborn rats after destruction by streptozotocin. Virchows Arch B Cell Pathol Incl Mol Pathol 1982; 39: 173-85.
Giroix MH, Portha B, Kergoat M, Bailbe D, Picon L. Glucose insensitivity and aminoacid hypersensitivity of insulin release in rats with non-insulin dependent diabetes: A study with the perfused pancreas. Diabetes 1983; 32: 445-51.
Weir GC, Leahy JL, Bonner-Weir S. Experimental reduction of the β-cell mass: Implications for the pathogenesis of diabetes. Diabetes Metab Rev 1986; 2: 125-61.
Adolfo AC, Eddy MZ, Ana SC, Cristina RM, Helmut W. Chronic hypoglycemic effect of Malmea depressa root on n5-streptozotocin diabetic rats. J Ethnopharmacol 2008; 116: 358-62.
Mohamed B, Fatima ZM, Abderrahim Z, Mohamed A, Abdelkhaleq L, Hassane M. Antidiabetic effect of some medicinal plants of Oriental Morocco in neonatal non-insulin-dependent diabetes mellitus rats. Hum Exp Toxicol 2010; 29(10): 865-71.
Yan W, Xin X, Zhendong J, et al. Anti-diabetic effects of pentamethylquercetin in neonatally streptozotocin-induced diabetic rats. Eur J Pharmacol 2011; 668: 347-53.
Silmara B, Bruno AR, Juliana O, Jurandir FC, Silvana MCA, Ciomar ABA. Hydroethanolic extract of Smallanthus sonchifolius leaves improves hyperglycemia of streptozotocin induced neonatal diabetic rats. Asian Pac J Trop Med 2016; 9(5): 432-6.
Jesus C, Veronica S, Maria LVP, et al. Glucagon-like peptide 1 content of intestinal tract in adult rats injected with streptozotocin either during neonatal period or 7d before sacrifice. Endocrine 2002; 19(3): 279-86.
Creutzfeld W, Frerichs H, Sickinger K. Liver diseases and diabetes mellitus. Prog Liver Dis 1970; 3: 371-407.
Datusalia AK, Dora CP, Sharma S. Acute and chronic hypoglycemic activity of sida tiagii fruits in n5-streptozotocin diabetic rats. Acta Pol Pharm 2012; 69(4): 699-706.
Shinde UA, Goyal RK. Effect of chromium picolinate on histopathological alterations in STZ and neonatal STZ diabetic rats. J Cell Mol Med 2003; 7(3): 322-9.
Leelavinothan P, Natarajan A. Effect of N-benzoyl-D-phenylalanine on lipid profile in liver of neonatal streptozotocin diabetic rats. Fundam Clin Pharmacol 2005; 19: 563-8.
Jacek R. Hepatocyte proliferation in health and liver failure. Med Sci Monit 2002; 8(2): RA32-8.
Floettmann E, Gregory L, Teague J, et al. prolonged inhibition of glycogen phosphorylase in livers of Zucker diabetic fatty rats models human glycogen storage disease. Toxicol Pathol 2010; 38: 393-401.
Masanori I, Kiyohide N, Seizo S, Masanori K, Masatoshi F. Liver, kidney and icelet cell tumour in spontaneously hypertensive and normotensive rats treated with neonatally streptozotocin. Tohoku J Exp Liver Med 1989; 159: 83-90.
Abdollahi M, Zuki ABZ, Goh YM, Rezaeizadeh A, Noordin MM. The effects of Momordica charantia on the liver in streptozotocin-induced diabetes in neonatal rats. Afr J Biotechnol 2010; 9(31): 5004-12.
Catena C. GianLuca C, Stefania F, Leonardo AS. insulin resistance in the early stages of renal failure: implications for cardiovascular risk. Curr Diabetes Rev 2012; 8: 268-73.
Anjaneyulu M, Chopra K. Quercetin, an anti-oxidant bioflavanoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol 2004; 31: 244-8.
Sonia G, Srinivasan BP, Atul SA. Aliskiren improves insulin resistance and ameliorates diabetic renal vascular complications in STZ-induced diabetic rats. J Renin Angiotensin Aldosterone Syst 2012; 14(1): 3-13.
Aksun SA, Ozmen D, Ozmen B, et al. Beta 2-microglobulin and cystatin C in type 2 diabetes: assessment of diabetic nephropahty. Exp Clin Endocrinol Diabetes 2004; 112(4): 195-200.
Sonta T, Inoguchi T, Matsumoto S, et al. In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker. Biochem Biophys Res Commun 2005; 330: 415-22.
Fiorentino AD, Cianchetti S, Celi A, et al. Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS. J Renin Angiotensin Aldosterone Syst 2010; 11: 243-7.
Maeda K, Okubo K, Shimomura I. et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 Adipose Most abundant Gene transcript. Biochem Biophys Res Commun 1996; 221(2): 286-9.
Nakamaki S, Satoh H, Kudoh A, Hayashi Y, Hirai H, Watanabe T. Adiponectin reduces proteinuria in streptozotocin-induced diabetic Wistar rats. Exp Biol Med 2011; 236: 614-20.
Fisher JW. Erythropoietin: physiology and pharmacology update. Exp Biol Med 2003; 228: 1-14.
Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol 2007; 27(2): 195-207.
Vleming LJ, Baelde JJ, Westendorp RG, Daha MR, Van Es LA, Bruijn JA. Progression of chronic renal disease in humans is associated with the deposition of basement membrane component an decorin in the interstitial extracellular matrix. Clin Nephrol 1995; 44(4): 211-9.
Morcos M, Sayed AA, Bierhaus A, Yard B, Waldherr R, Merz W. Activation of tubular epithelial cells in diabetic nephropathy. Diabetes 2002; 51(12): 3532-44.
Puente ADELA, Goya L, Ramos S, Martín MA, Alvarez C. Effects of experimental diabetes on renal IGF/IGFBP system during neonatal period in the rat. Am J Physiol Renal Physiol 2000; 279: F1067-76.
anaina MZ, Helen M, Isabella CSD, Anne KS, Camila PS, and Joice MC. Depression associated with diabetes: from pathophysiology to treatment. Curr Diabetes Rev 2016; 12: 165-78.
Marta CSB, Monserrat GC, and Nídia NDARB. Functional aspects in ageing adults with diabetic neuropathy. A review. Curr Diabetes Rev 2016; 12: 114-9.
Kandhare AD, Raygude KS, Kumar VS, Rajmane AR, Visnagri A, Ghule AE. Ameliorative effects quercetinagainst impaired motor nerve function, inflammatory mediators and apoptosis in neonatal. Biomed Aging Pathol 2012; 2: 173-86.
Paulino BI, Victor H, Emanuel L, et al. Evaluation of neonatal streptozotocin model of diabetes in rats: evidence for a model of neuropathic pain. Pharmacol Rep 2017; 2: 294-303.
Rosa AP, Jacques CED, De Souza LO, et al. Neonatal hyperglycemia induces oxidative stress in the rat brain:the role of pentose phosphate pathway enzymes and NADPH oxidase. Mol Cell Biochem 2015; 403(1-2): 159-67.
Ahmed N, Tarannum S. Acetylcholinesterase activity in the brain of alloxan diabetic albino rats: Presence of an inhibitor of this enzyme activity in the cerebral extract. Int J Diabetes Dev Ctries 2009; 29(4): 174-7.
Ghareeb DA, Hussen HM. Vanadium improves brain acetylcholinesterase activity on early stage alloxan-diabetic rats. Neurosci Lett 2008; 436(1): 44-7.
Dash NK, Azam M, Gupta G, Baquer NZ. Effect of hyperglycemia on acetylcholinesterase and catecholamine levels in rat brain and heart. Biochem Int 1991; 23(2): 261-9.
Schmatz R, Mazzanti CM, Spanevello R, et al. Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol 2009; 610(1-3): 42-8.
Maciel RM, Carvalho FB, Olabiyi AA, et al. Neuroprotective effects of quercetin on memory and anxiogenic-like behavior in diabetic rats: Role of ectonucleotidases and acetylcholinesterase activities. Biomed Pharmacother 2016; 84: 559-68.
Ramkumar KM, Latha M, Ashokkumar N, Pari L, Ananthan R. Modulation of impaired cholinesterase activity in experimental diabetes: effect of Gymnema montanum leaf extract. J Basic Clin Physiol Pharmacol 2005; 16(1): 17-35.
Welsh B, Wecker L. Effects of streptozotocin-induced diabetes on acetylcholine metabolism in rat brain. Neurochem Res 1991; 16(4): 453-60.
Natarajan A, Leelavinothan P, Kunga MR. N-benzoyl-d-phenylalanine attenuates brain acetylcholinesterase in neonatal streptozotocin-diabetic rats. Basic Clin Pharmacol Toxicol 2006; 99: 246-50.
Shpakov AO, Derkach KV, Chistyakova OV, Moiseyuk IV, Sukhov IB, Bondareva VM. Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary,and uterus of rats with prolonged neonatal model of diabetes mellitus. Zh Evol Biokhim Fiziol 2013; 49(2): 153-64.
Caio CS, Jhonatan CM, Marcel PR, Roberto KNC, Elisabeth AA. Antidepressant-like effect of insulin in streptozotocin-induced type 2 diabetes mellitus rats. Basic Clin Pharmacol Toxicol 2016; 119: 243-8.
Peter JK, Johnson TM. Evidence based eye care. Wolters Kluwar Health Philadelphia 2007.
Tapp RJ, Shaw JE, Harper CA, et al. The prevalence of and factors associated with diabetic retinopathy in Australian population. Diabetes Care 2003; 26(6): 1731-7.
Agata K, Paulina K, Michal K, Beata S, Anna G. The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis. Arch Immunol Ther Exp 2015; 63: 41-52.
Lam HC, Lee JK, Lu CC, Chu CH, Chaung MJ, Wang MC. Role of endothelin in diabetic retinopathy. Curr Vasc Pharmacol 2003; 1(3): 243-50.
Kermorvant-Duchemin E, Pinel AC, Lavalette S, et al. Neonatal hyperglycemia inhibits angiogenesis and induces inflammation and neuronal degeneration in the retina. PLoS One 2013; 8(11): 1-10.
Madhoosudan AP, Palla S, Uday KP, Myadara S, Bhanuprakash GR. Evaluation of neonatal streptozotocin induced diabetic rat model for the development of cataract. Oxid Med Cell Longev 2014. Article ID 463264:1-10
Mancini JE, Gustavo O, Juan OC, Juan EG. Retinal upregulation of inflammatory and proangiogenic markers in a model of neonatal diabetic rats fed on a high-fat-diet. BMC Ophthalmol 2013; 13: 1-12.
Joao SF, Camila CK, Carolina TC, et al. Present insights on cardiomyopathy in diabetic patients. Curr Diabetes Rev 2016; 12: 384-95.
Rabindra ND. Relationship between diabetes mellitus and coronary heart disease. Curr Diabetes Rev 2016; 12: 285-95.
Christina V, Dimitrios P, Nicholars T. Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies. Vasc Health Risk Manag 2010; 6: 883-903.
Yuri KS, Paula HOL. Kleber E de Campos, Ana CIK, Marilza VCR, Débora CD. Neonatally-induced diabetes: lipid profile outcomes and oxidative stress status in adult rats. Rev Assoc Med Bras 2009; 55(4): 384-8.
Milan FR, Hiromi EA, Oliveira MA, et al. Influence of insulin on the microvascular response to inflammatory mediators in neonatal streptozotocin diabetic rats. Inflamm Res 2005; 54: 173-9.
Sartoretto JL, Melo GA, Carvalho MH, et al. Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression. Life Sci 2005; 77: 2676-89.
Said B, Zineb H, Abderrahim Z, et al. Antidiabetic and antihypertensive effect of Virgin Argan Oil in model of neonatal streptozotocin-induced diabetic and L-nitroarginine methylester (L-NAME) hypertensive rats. J Complement Integr Med 2013; 10(1): 1-8.
Mohamed B, Wafaa B, Said B, et al. Antidiabetic and antihypertensive effect of a polyphenol-rich fraction of Thymelaea hirsuta L. in a model of neonatal streptozotocin-diabetic and N G -nitro-L-arginine methyl ester-hypertensive rats. J Diabetes 2012; 4: 307-13.
Shali C. Terry Evans, Kallol M, Morris K, Subrta C. Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors. J Mol Cell Cardiol 2000; 32(9): 1621-9.
Mohammed S, Inamdar MN, and Razdan R. Cardiovascular risk factors involved in Type 2diabetes rat models: A long term preliminary screening. IJPLS 2012; 3(11): 2126-34.
Mohammed IS, Inamdar MN. Effect of gliclazide on cardiovascular risk factors involved in split-dose streptozotocin induced neonatal rat model: a chronic study. Int J Basic Clin Pharmacol 2012; 1(3): 196-201.
Maratha PA, Parekar RR, Shinde SP, et al. A split dose regimen of streptozotocin to induce diabetes in a neonatal rat model. Indian J Pharmacol 2006; 6(38): 432-3.
Howard EW, Subbiah MTR. Streptozotocin-induced diabetes in the neonatal rat: effect on plasma lipids and aortic prostaglandin synthesis in adult life. Biochem Med 1984; 31: 174-84.
Enzlin P, Mathieu C, Van Den Bruel A, et al. Prevalence and predicotrs of sexual dysfunction in patients with type 1 diabetes. Diabetes Care 2003; 26(2): 409-14.
Ejiofor TU, Rosemary T. Androgen deficiency in aging male questionnaire for the clinical detection of testosterone deficiency in a population of black sub-saharan african men with type 2 diabetes mellitus: is it a reliable tool? Curr Diabetes Rev 2018; 14: 280-5.
Forouzan E, Zahra K, Bentolhoda T, Adele B, Mohammad K. Sexual dysfunction in women with type 2 diabetes mellitus. Iran J Med Sci 2015; 40(3): 206-13.
Abu ARM. AL Hajeri RM, Khader YS, Shegem NS, Ajlouni KM. Sexual dysfunction in jordanian diabetic women. Diabetes Care 2008; 31: 1580-1.
Shpakov AO, Derkach KV, Bondareva VM. Changes in hormone sensitivity of the adenylate cyclase signaling system in the testicular tissue of rats with neonatal streptozotocin-induced diabetes. Bull Exp Biol Med 2009; 148(3): 394-8.
Rato L, Alves MG, Dias TR, Cavaco JE, Pedro FO. Testicular metabolic reprogramming in neonatal streptozotocin-induced type 2 diabetic rats impairs glycolytic flux and promotes glycogen synthesis. J Diabetes Res 2015. Article ID 973142, 1-13
Ana CIK, Barbara W, Yuri KS, et al. Neonatally induced mild diabetes: influence on development, behavior and reproductive function of female wistar rats. Diabetol Metab Syndr 16 5(1): 61.
Derkach KV, Moyseyuk IV, Chistyakova OV, Shpakov AO. Androgen Deficiency in Male Rats with Prolonged Neonatal Streptozotocin Diabetes. Bull Exp Biol Med 2013; 155(3): 339-42.
Didem Y, Nur B, Ozge U, Philip JK, Suresh CS, and Serap G. The effect of intracavernosal avanafil, a newer phosphodiesterase-5 inhibitor, on neonatal type 2 diabetic rats with erectile dsfunction. Urology 2014; 83(2): 508.e7-e12.
Scarano WR, Messias AG, Oliva SU, Klinefelter GR, Kempinas WG. Sexual behaviour, sperm quantity and quality after short term streptozotocin induced hyperglycemia in rats. Int J Androl 2006; 29(4): 482-8.
Meurer KA, Cox NM, Matamoros IA, Tubbs RC. Decreased follicular steroids and insulin-like growth factor-I and increased atresia in diabetic gilts during follicular growth stimulated with PMSG. J Reprod Fertil 1991; 91: 187-96.
Kuznetsova LA, Chistyakova OV, Bondareva VM, Sharova TS, Pertseva MN. Disturbance of regulation of NO synthase activity by peptides of insulin family in rat skeletal muscles in streptozotocin model of neonatal type 2 diabetes mellitus. Dokl Biochem Biophys 2010; 432: 123-5.
Kaya DF, Süsleyici DB, Oztürk M. Protective effects of a calcium channel blocker on apoptosis in thymus of neonatal STZ-diabetic rats. Acta Histochem 2005; 107: 207-14.
Julie T, Magaly AM, Sidney BP, et al. Neonatal streptozotocin-induced diabetes mellitus: a model of insulin resistance associated with loss of adipose mass. Metab Clin Exp 2007; 56: 977-84.
SC Cavalher M, Cuman RKN, Sartoretto JL, et al. The allergic inflammatory reaction in neonatal streptozotocin induced diabetic rats: evidence of insulin resistance and microvascular dysfunction. Inflamm Res 2008; 57: 535-41.
Koyuturk M, Sacan O, Karabulut S, et al. The role of ghrelin on apoptosis, cell proliferation and oxidant-antioxidant system in the liver of neonatal diabetic rats. Cell Biol Int 2015; 39: 834-41.
Tabuchi M, Ozaki M, Tamura A, et al. Antidiabetic effect of lactobacillus gg in streptozotocin-induced diabetic rats. Biosci Biotechnol Biochem 2003; 67(6): 1421-4.

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