**3. Other rodent models used in research in diabetes**

Rodent animal models for investigation of T1DM are streptozotocin- or alloxan-induced animals, nonobese diabetic (NOD) mouse, and bio-breeding (BB) rat [84]. NOD mice and BB rats are rodent animal model with spontaneous development of T1DM [85]. Rodent models for T2DM include except ZDF rats also Goto-Kakizaki (GK) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats,

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*Zucker Diabetic Fatty Rats for Research in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.88161*

handling and manipulation with them is comfortable.

with hypoinsulinemia [88].

**4. Conclusion**

and treatment [96].

appropriate model for common human T2DM.

spontaneously diabetic Tori (SDT) rats, Kuo Kondo (KK) mice, ob/ob+/+ mice, and db/db+/+ mice [84]. GK rats are nonobese Wistar substrain which develops T2DM early [86]. Male OLETS rats suffer from diabetes at 18–25 weeks of age. The symptoms include polyphagia, mild obesity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance in 16 weeks of age [87]. Tori SDT rat is inbred strain of Sprague-Dawley rat. Male individuals have high glucose levels by 20 weeks, pancreatic islet histopathology, hemorrhage in pancreatic islets, and inflammatory cell infiltration with fibroblasts, prior to diabetes glucose intolerance

KK mice are a polygenic model of obesity and T2DM. They are characterized by insulin resistance, hyperinsulinemia, and hyperphagia [89]. The ob/ob+/+ mice carry a mutation in the leptin gene, manifested as obesity, hyperglycemia, impaired glucose intolerance, and hyperinsulinemia [90]. The db/db+/+ mice have a leptin receptor mutation, are spontaneously hyperphagic, and suffer from obesity, hyperglycemia, hyperinsulinemia, and insulin resistance within the first month of life [91]. The advantages of ZDF rats in diabetes research are mainly due to the fact that it is a spontaneous model for T2DM research. It shows characteristics such as hyperglycemia, obesity, hyperphagia, polyuria, insulin disorders, and dyslipidemia due to the mutation in the leptin receptor gene and provides an appropriate model for common human T2DM. Moreover, these rats are calm and dispassionate; the

The ZDF strain is of increasing preclinical interest due to its pathophysiological similarities to human T2DM [92, 93]. They are generally used in studies of diabetes with obesity and cardiovascular complications because of dyslipidemia background [44]. Defective insulin release in ZDF rats could be partially restored by glucagon-like peptide (GLP-1). The action of GLP-1 therapy is mediated through Ca2+-independent signaling pathway in pancreatic islets [44]. The use of rosiglitazone protected ZDF rats against the loss of β-cell mass through sustaining cell proliferation, and blocking increased β cells' death [94]. Metformin prevented hyperglycemia in ZDF rats aged between 6 and 12 weeks. This compound significantly reduced free fatty acid level and triglycerides. It delayed the onset of DM which is linked to the improvement in β cell functions, on a par with the lipotoxicity hypothesis for adipogenic diabetes [95]. Some experimental interventions provided on ZDF rats are shown in **Table 2**. In general, animal model for DM research is required and needed to uncover and understand the pathophysiology of disease. This is the key to the development of new therapies

Today, the number of patients suffering from DM is increasing. The most common form of DM is T2DM. It is a genetic disease demonstrating insulin insufficiency. Therefore the research on this disease is deepening and required. Due to its complex, complicated, multifactorial heterogeneous disease resulting from both environmental factors and genetic responsiveness, accurate animal model that can mirror human T2DM symptoms and complication is required. Presently, the spontaneous T2DM rodent model for research in DM and obesity is ZDF rats. This strain shows characteristics such as obesity, hyperglycemia, insulin disorders, and dyslipidemia due to the mutation in the leptin receptor gene and provides an

*Zucker Diabetic Fatty Rats for Research in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.88161*

*Animal Models in Medicine and Biology*

and plasma osmolality [72].

effector mediators [76].

could be also a potential marker of angiopathy.

**3. Other rodent models used in research in diabetes**

Rodent animal models for investigation of T1DM are streptozotocin- or alloxan-induced animals, nonobese diabetic (NOD) mouse, and bio-breeding (BB) rat [84]. NOD mice and BB rats are rodent animal model with spontaneous development of T1DM [85]. Rodent models for T2DM include except ZDF rats also Goto-Kakizaki (GK) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats,

**2.1 Hematological parameters of ZDF rats**

In general, diabetic patients have increased values of some hematological parameters as platelet count, mean platelet volume (MPV), and platelet distribution width (PDWc). Platelet activation can result in the generation of vascular disease [67]. Hematological parameters can be altered as a result of infection that occurs during DM [65]. In the human study, the total granulocyte count was increased in diabetic patients. It was confirmed that granulocyte count is associated with T2DM [68]. In our experiment significant increase in granulocyte count was also observed in diabetic ZDF rats in comparison with the control animals [54]. It was also published that increased count of one part of granulocytes (neutrophils) correlated with the rising risk of vascular disease in T1DM [69] with consequences as diabetic angiopathy [70]. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were decreased in the diabetic ZDF rats when compared to the lean control [54]. Similar results are published by Mahmoud [71] in white albino rats with experimentally induced DM and Oyedemi et al. [65] in streptozotocin-induced diabetic Wistar rats. Generally, the decrease of these hematological parameters during the diabetes could be an indicator of abnormal hemoglobin synthesis, failure of blood osmoregulation,

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia accelerated in diabetic state [73]. They are source of inflammatory mediators [74]. We observed increased values of platelets in diabetic ZDF rats against the lean control [54]. Through inflammatory process during the DM, the platelets are highly activated. Activated platelets presumably support neutrophil activation and recruitment through expressing selectins, inflammatory cytokines, and chemokines [75]. It was proven that platelets and neutrophils regulate and affect each other's functions by platelet-leukocyte contact and releasing soluble

The marker of platelet function and activation is hematological parameter— MPV [77]. Increased MPV can be an independent risk factor for arterial thrombotic events such as myocardial infarction and cerebral thromboembolism [78]. Usually diabetic patients have increased MPV values [79] correlated with a large thrombocyte size that are more reactive and aggregable [77] which can upset hemostatic system during the diabetic state [80]. In diabetes the risk of retinopathy onset increases with higher MPV [79, 81]. In our study diabetic ZDF rats had increased MPV values in comparison with the healthy lean control [54]. In diabetic patients there is usually higher value of PDWc—the hematological parameter that presents an indicator of variation in platelets' size and activity [79, 82]. In our previous research [83], we observed that the rise in the secondary symptoms of T2DM complications caused by high-energy diet was accompanied with disturbed hematological parameters. It

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spontaneously diabetic Tori (SDT) rats, Kuo Kondo (KK) mice, ob/ob+/+ mice, and db/db+/+ mice [84]. GK rats are nonobese Wistar substrain which develops T2DM early [86]. Male OLETS rats suffer from diabetes at 18–25 weeks of age. The symptoms include polyphagia, mild obesity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance in 16 weeks of age [87]. Tori SDT rat is inbred strain of Sprague-Dawley rat. Male individuals have high glucose levels by 20 weeks, pancreatic islet histopathology, hemorrhage in pancreatic islets, and inflammatory cell infiltration with fibroblasts, prior to diabetes glucose intolerance with hypoinsulinemia [88].

KK mice are a polygenic model of obesity and T2DM. They are characterized by insulin resistance, hyperinsulinemia, and hyperphagia [89]. The ob/ob+/+ mice carry a mutation in the leptin gene, manifested as obesity, hyperglycemia, impaired glucose intolerance, and hyperinsulinemia [90]. The db/db+/+ mice have a leptin receptor mutation, are spontaneously hyperphagic, and suffer from obesity, hyperglycemia, hyperinsulinemia, and insulin resistance within the first month of life [91]. The advantages of ZDF rats in diabetes research are mainly due to the fact that it is a spontaneous model for T2DM research. It shows characteristics such as hyperglycemia, obesity, hyperphagia, polyuria, insulin disorders, and dyslipidemia due to the mutation in the leptin receptor gene and provides an appropriate model for common human T2DM. Moreover, these rats are calm and dispassionate; the handling and manipulation with them is comfortable.
