La diabetes mellitus tipo 2 modifica la densidad celular en el cerebro de la rata

Carol Victoria Mérida-Portilla, Karen Paola Ramos-Riera, Ángel Alberto Puig-Lagunes, Luis Beltrán-Parrazal, Consuelo Morgado-Valle, María Leonor López-Meraz

Resumen


La diabetes mellitus (DM) es un trastorno metabólico con alta incidencia mundial que puede afectar la función cerebral. El objetivo de este estudio fue generar DM tipo 2 (DM2) en ratas recién nacidas tratadas con estreptozocina (STZ) y caracterizar su efecto en la densidad celular cerebral. Ratas macho de la cepa Wistar de 3 días de edad se inyectaron subcutáneamente con 100 mg/Kg de STZ; las ratas control se inyectaron con una solución amortiguadora de citratos (vehículo). El peso corporal y la glucemia se monitorearon durante los días postnatales 30, 60 y 90. El porcentaje de la hemoglobina glicada y el conteo de células en el hipocampo, la amígadala, el tálamo y la corteza piriforme (utilizando la tinción de hematoxilina y eosina) se evaluaron en el día postnatal 90. Los resultados mostraron que la glucemia de las ratas STZ incrementó paulatinamente y alcanzó valores mayores a los 200 mg/dL en el día postnatal 90, tiempo en el que también se identificó un mayor porcentaje de hemoglobina glicada. Los conteos celulares mostraron un menor número de células en el núcleo talámico dorsomedial de las ratas STZ en comparación con las ratas control; el resto de las regiones cerebrales evaluadas no mostraron cambios. En conclusión, la DM2 generada por la aplicación de STZ en la etapa neonatal promueve pérdida celular en el tálamo.


Abstract

Diabetes mellitus (DM) is a metabolic disorder with a high worldwide incidence that affects brain function. This study aimed to induce type 2 DM (DM2) by applying streptozocin (STZ) in newborn rats to evaluate its effects on brain cell density. Three-day-old Wistar male rats were injected subcutaneously with 100 mg/kg of STZ; matched control rats were injected with citrate buffer. Bodyweight and blood glucose were monitored at 30, 60, and 90 days of age; glycated hemoglobin and cell counting in the hippocampus, amygdala, piriform cortex, and thalamus (by using the hematoxylin and eosin staining) were performed at postnatal day 90. The results showed that the blood glucose of STZ rats gradually increased and reached values higher than 200 mg/dL at postnatal day 90; the percentage of glycated hemoglobin also augmented at that time. STZ rats showed fewer cells in the dorsomedial thalamic nucleus when compared to the control group; no additional changes were observed in other brain regions. In conclusion, DM2 produced by neonatal application of STZ promotes cell loss in the rat thalamus.

Keywords: Streptozotocin; diabetes mellitus; brain; newborn; rats.



Palabras clave


Estreptozocina; diabetes mellitus; cerebro; recién nacido; ratas.

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Referencias


Organización Mundial de la Salud. Diabetes. [Fecha de consulta 1 de marzo del 2022]. Disponible en: https://www.who.int/es/news-room/fact-sheets/detail/diabetes

American Diabetes Association. Introduction: Standards of Medical Care in Diabetes. Diabetes Care. 2019 42: (Supplement 1): S1-S2.

Organización Panamericana de Diabetes. Diabetes. [Fecha de consulta: 1 de marzo del 2022]. Disponible en: https://www.paho.org/hq/index.php?option=com_content&view=category&id=4475&layout=blog&Itemid=40610〈=es&limitstart=15#:~:text=La%20diabetes%20tipo%202%20es,cal%C3%B3rico%20de%20bajo%20valor%20nutricional

Hamed SA. Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications. Expert Rev Clin Pharmacol 2017 10(4):409-428.

Cho SE, Roy B, Freeby M, Mullur R, Woo MA, Kumar R. Prefrontal cortex brain damage and glycemic control in patients with type 2 diabetes. J Diabetes 2020 12(6):465-473.

Lenzen S. The mechanisms of alloxan and streptozotocin induced diabetes. Diabetologia 2008 51(2):216–226.

Tjälve H, Wilander E, Johansson EB. Distribution of labelled streptozotocin in mice: uptake and retention in pancreatic islets. J Endocrinol 1976 69(3):455-6.

Huang CW, Cheng JT, Tsai JJ, Wu SN, Huang CC. Diabetic hyperglycemia aggravates seizures and status epilepticus-induced hippocampal damage. Neurotox Res 2009 15(1):71-81.

Merzouk H, Madani S, Sari DC, Prost J, Bouchenak M, Belleville J. Time course of changes in serum glucose, insulin, lipids and tissue lipase activities in macrosomic offspring of rats with streptozotocin-induced diabetes. Clin Sci 2000 98(1):21–30.

Damasceno DC, Sinzato YK, Bueno A, Netto AO, Dallaqua B, Gallego FQ, et al. Mild Diabetes Models and Their Maternal-Fetal Repercussions. J Diabetes Res 2013 1-9.

Bequer L, Gómez T, Molina J. L, López F, Gómez CL, Clapés S. Inducción de hiperglucemias moderadas en ratas wistar por inoculación neonatal de estreptozotocina. ¿Inyección subcutánea o intraperitoneal?. Rev. Argent. Endocrinol Met 2014 51(4):178-184.

Bequer L, Gómez T, Molina J L, Artiles D, Bermúdez R, Clapés S. Acción de la estreptozotocina en un modelo experimental de inducción neonatal de la diabetes. Biomédica 2016 36:230-238.

Takada J, Machado M, Peres S, Brito L C, Borges Silva C, Costa C, et al. Neonatal streptozotocin induced diabetes mellitus: a model of insulin resistance associated with loss of adipose mass. Metabolism 2007 56(7):977–984.

Bolkent S, Akev N, Can A, Yanardag R, Okyar A. Immunohistochemical studies on the effect of Aloe vera on the pancreatic β-cells in neonatal streptozotocin-induced type-II diabetic rats. Egyptian Journal of Biology 2005 7:14-19.

Ghule AE, Jadhav SS, Bodhankar S. Trigonelline ameliorates diabetic hypertensive nephropathy by suppression of oxidative stress in kidney and reduction in renal cell apoptosis and fibrosis in streptozotocin induced neonatal diabetic (nSTZ) rats. Int Immunopharmacology 2012 14(4):740–748.

Figueroa C, Pérez IH, Mejía R. Caracterización de un modelo de diabetes tipo 2 en ratasWistar hembra. Rev MVZ Córdoba 2013 18(Supl): 3699-3707.

Bačová Z, Najvirtová M, Križanová O, Hudecová S, Zórad Š, Štrbák V, et al. Effect of Neonatal Streptozotocin and Thyrotropin-Releasing Hormone Treatments on Insulin Secretion in Adult Rats. Gen. Physiol Biophys 2005 24(2): 181-197.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research, PLOS Biol 2010 8(6): e1000412.

Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Elsevier. China. 2007 pp 106.

Sankar R, Shin DH, Wasterlain CG. Serum neuron-specific enolase is a marker for neuronal damage following status epilepticus in the rat. Epilepsy Res 1997 28(2):129-136.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: An open-source platform for biological-image analysis. Nat Methods 2012 9(7):676-682.

Yang S, Wang S, Yang B, Zheng J, Cai Y, Yang Z. Weight loss before a diagnosis of type 2 diabetes mellitus is a risk factor for diabetes complications. Medicine (Baltimore) 2016 95(49):e5618.

Arulmozhi DK, Veeranjaneyulu A, Bodhankar SL. Neonatal streptozotocin-induced rat model of type 2 diabetes mellitus: A glance. Indian J Pharmacol 2004 36:217-21.

Weir GC, Leahy JL, Bonner W. Experimental Reduction of B-Cell Mass: Implications for the Pathogenesis of Diabetes. Diabetes Metab Rev 1986 2(1-2):125-161.

Bonnier-Weir S, Trent DE, Honey RN, Weir GC. Response to neonatal islets to streptozotocin: Limited  cell regeneration and hyperglycemia. Diabetes 1981 30(1):64-69.

Bonnier-Weir S, Trent D F, Zmachinski C J, Clore E T, Weir G C. Limited  cell regeneration in a  cell deficient rat model: studies with dexamethasone. Metabolism 1981 30(9):914-918.

Portha B, Picolon L, Rosselin G. Chemical diabetes in the adult rat as the spontaneous evolution of neonatal diabetes. Diabetologia 1979 17(6):371-377.

Blondel O, Bailbe D, Portha B. Insulin Resistance in Rats With Non-Insulin-Dependent Diabetes Induced by Neonatal (5 Days) Streptozotocin: Evidence for Reversal Following Phlorizin Treatment. Metabolism 1990 39(8): 787-793.

Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011 54(10):2506-2514.

McCaffery JM, Jablonski KA, Franks PW, Dagogo J, Wing RR, Knowler WC et al. TCF7L2 polymorphism, weight loss and proinsulin: insulin ratio in the diabetes prevention program. PLoS One 2011 6(7): e21518.

Tanner R. The 3Rs: What are Medical Scientists Doing about Animal Testing? Front. Young Minds 2018 6:44.

Santos TO, Mazucanti CH, Xavier GF, Torrão AS. Early and late neurodegeneration and memory disruption after intracerebroventricular streptozotocin. Physiol Behav 2012 107(3):401-13.

Grieb P. Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism. Mol Neurobiol 2016 53(3):1741-1752.

Tourrel C, Bailbe D, Meile M, Kergoat M, Bernard Portha B. Glucagon-Like Peptide-1 and Exendin-4 Stimulate Cell Neogenesis in Streptozotocin-Treated Newborn Rats Resulting in Persistently Improved Glucose Homeostasis at Adult Age. Diabetes 2001 50: 1562-70.

Sartoretto JL, Melo GA, Carvalho MH, Nigro D, Passaglia RT, Scavone C, Cuman RK, Fortes ZB. Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression. Life Sci 2005 77(21):2676-89.

Sinzato Y, Ortiz PH, De Campos K, Inhasz KAC, Cunha RMV, Damasceno DC. Neonatally-induced diabetes: lipid profile outcomes and oxidative stress status In adult rats. Rev Assoc Med Bras 2009 55(4): 384-8.

Madhoosudan AP, Suryanarayana P, Kumar Putcha U, Srinivas M, Bhanuprakash RG. Evaluation of Neonatal Streptozotocin Induced Diabetic Rat Model for the Development of Cataract. Oxid Med and Cell Longev 2014 2014:463264.

Roy B, Ehlert L, Mullur R, Freeby MJ, Woo MA, Kumar R, Choi S. Regional Brain Gray Matter Changes in Patients with Type 2 Diabetes Mellitus. Sci Rep 2020 10(1):9925.

Chen YC, Xia W, Qian C, Ding J, Ju S, Teng GJ. Thalamic resting-state functional connectivity: disruption in patients with type 2 diabetes. Metab Brain Dis 2015 30(5):1227-36.

Guerrero-Berroa E, Schmeidler J, Beeri MS. Neuropathology of type 2 diabetes: a short review on insulin-related mechanisms. Eur Neuropsychopharmacol 2014 24(12):1961-6.

Verdile G, Fuller SJ, Martins RN. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis 2015 84:22-38.

Bathina S, Srinivas N, Das UN. Streptozotocin produces oxidative stress, inflammation and decreases BDNF concentrations to induce apoptosis of RIN5F cells and type 2 diabetes mellitus in Wistar rats. Biochem Biophys Res Commun 2017 486(2):406-413.




DOI: https://doi.org/10.25009/eb.v13i31.2595

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