neurotoxicity and mechanisms of induced hyperexcitability

B) Spontaneous modelsGoto Kakizaki RatThe Goto Kakizaki (GK) rat is skinny, diabetic rat developedin Japan in 1975 from Wistar species (6). Bothinsulin resistance and impaired insulin secretion are presentin this model (32). GK rats have a decreased numbersof beta cells at birth, which is probably the consequenceof their apoptosis during embryonic development (16-18day). However, GK rats are still normoglycemic and withoutmarked changes in islet morphology at birth (33). Thecharacteristics of diabetes type 2 in this model are mildhyperglycemia (9 mmol/l) in the fourth week and the increaseof basal insulin secretion and insulin resistance followedby a decrease in glucose tolerance (34). GK rats areresistant to food intake restrictions (35).Starting from the 8 th week, insulin islets show signs of fibrosiswith a marked elevation of hyperglycemia (36). In addition,the expression of CD38 and GLUT2 proteins is reducedin GK islets (37-38). Microscopically, numerous macrophages(major histocompatibility complex class II + and CD68 + ) andgranulocytes were found in and around pancreatic islets (39).Elevated islet IL-1β activity in GK rat promotes cytokine andchemokine expression, leading to the recruitment of innateimmune cells (40). Treatment of GK rats with IL-1 receptorantagonists decreases hyperglycemia, reduces the proinsulin/insulin ratio and improves insulin sensitivity (40).The most important factor for the disorder of insulin secretionis the dysfunction of glucose metabolism connectedwith a deficiency of enzymes that control oxidative glycolysis(6). The GK rat develops some features that can be comparedwith the complications of diabetes seen in humans (1).Zucker Fatty and Zucker Fatty Diabetic RatThe Zucker Fatty (ZF) rat has a defect of a gene thatcodes for leptin receptors (fa/fa), resulting in the developmentof obesity and hypertension with associated renaland cardiovascular disease (6). The Zucker Fatty DiabeticRat (ZDF) has the identical genetic mutation and, additionally,a mutation which leads to the spontaneous developmentof hyperglycemia in males during the 7 th -10 thweek (41). The females become hyperglycemic only afterhigh-fat diet, and it is supposed that this additional mutationis expressed in beta cells (42).Leptin suppresses insulin secretion and controls foodintake. The fa/fa mutation of the leptin receptor results ininsulin resistance with severe glucose intolerance (6). ZFand ZDF rats are hyperphagic due to the reduction in leptinsignalling that results in obesity (6). These animals, inadulthood, become extremely dislipemic with increasedconcentration of free fatty acids, cholesterol, and triglyceridesin plasma with a consequent development of diabetesmellitus complications (cardiovascular, renal, and peripheralneuropathy) (6, 43-44).Pancreatic islets in adults show increased beta cell activity,with marked characteristics of a prediabetic state (6).After the onset of diabetes, pancreatic islets become irregularas a result of hyperplasia, hypertrophy and infiltrationof inflammatory cells (45). An almost complete absence ofbeta cells was detected by the 14 th week of age (45).Reduced expression of mGDP and pyruvate carboxylaseactivity was noticed in this model (46).Otsuka Long Evans Tokushima Fatty RatThe Otsuka Long Evans Tokushima Fatty Rat (OLETF)is derived by inbreeding from the glucose-intolerant Long-Evans colony of rats (47). These animals develop hyperglycemiaslowly, by 40 weeks of age, with greater incidence inmales than in females (1). Adult animals are mildly obeseand hyperglycemic, with increased appetite and renalglomerulosclerosis. These changes are the result of a deletionof the gene for cholecystokinin 1 receptors. Diet andexercise prevent type 2 diabetes in this model (48).Histopathologic changes inside the islets during the 8 th -10 th week show an infiltration of inflammatory cells followedby tissue damage. Beta cell hyperplasia and proliferation occurbetween the 20 th and 40 th weeks, while atrophy and fibrosisof the islets start after the 40 th week (47). From the72 nd week, inflammatory cytokines (tumour necrosis factor-(TNF- ), interleukin-1β (IL-1β) and interleukin-6 (IL-6)) aredetectable by immunohistochemical method (49).Psammomys obesusThe Psammomys obesus is rat from North Americaand the Middle East. It usually feeds on a low-calorie dietand demonstrates the strong effect of a high-calorie diet bydeveloping hyperglycemia within 4-7 days (6).Pathogenesis of the disorders goes through four typicalstages: normoglycemia and normoinsulinemia, normoglycemiawith hyperinsulinemia (indicating insulinresistance), hyperglycemia with hyperinsulinemia, and hyperglycemiawith hypoinsulinemia (50). The last stage ischaracterized by marked apoptosis and a reduction of betacell mass (51). Returning to a low-calorie diet results in therecovery of beta cells, indicating that the irreversible loss ofbeta cell mass is a late event (52).TRANSGENIC AND KNOCKOUT MODELSOF DIABETES MELLITUSIn experimental diabetes, numerous transgenic andknockout models are being used. These models have beencreated by genetic manipulations using either transgeneinsertion and/or targeted gene-deletion approaches.Still, these techniques have some limitations. Somehomozygotes may die in the womb, which makes studiesin adults impossible. Several genes could function differentlyduring embryogenesis and in adulthood. Finally,some models’ gene expression is altered in soft tissues, andtherefore it is impossible to analyze their function in thedesired tissue. Tissue-specific knockout models for diabetes,in which the gene being studied is only knocked out inspecific tissues, were created to address this issue.32