Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2016 (2016), Article ID 9051426, 12 pages
Review Article

Experimental Diabetes Mellitus in Different Animal Models

1Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Kozep Fasor 52, 6726 Szeged, Hungary
2Department of Laboratory Science and Technology, Faculty of Health Sciences, American University of Science and Technology, Alfred Naccache Avenue, Beirut 1100, Lebanon
3Sport Science Program, Qatar University, Doha, Qatar

Received 16 May 2016; Revised 27 June 2016; Accepted 28 June 2016

Academic Editor: Hiroshi Okamoto

Copyright © 2016 Amin Al-awar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans.

1. Background

Diabetes mellitus is well known as a chronic metabolic disease that is characterized by a relative or absolute lack of insulin, resulting in hyperglycemia. A variety of complications arises from chronic hyperglycemia such as neuropathy, nephropathy, and retinopathy and increased risk of cardiovascular disease [1]. The two most common types of diabetes mellitus are type 1 diabetes (T1D) and type 2 diabetes (T2D). Type 1 diabetes is generally thought to be precipitated by an immune-associated, if not directly immune-mediated, destruction of insulin-producing pancreatic β cells [2, 3]. Therefore, it is considered as an autoimmune disease, and its occurrence is most common in children and young adults [4]. The management of the disease via blood glucose monitoring and exogenous insulin administration is arduous and costly, which in parallel with the meticulous efforts to regulate blood glucose can result in hyper- and hypoglycemic events associated with systemic comorbidities [5, 6]. Type 2 diabetes (T2D) is associated with insulin resistance and a lack of adequate compensation by the beta cells which lead to a relative insulin deficiency [7]. Therefore, both types of endocrine disorders represent quite complex diseases with the involvement of different bodily systems. On this basis, animal models should be carefully selected for diabetes investigations depending on what aspects of the disease are being studied. Furthermore, animal models play a vital role in the understanding of diabetes pathogenesis as they allow the combination of genetic and functional characterization of the syndrome [8]. Attaining deficiency in insulin production in type 1 diabetes mellitus can occur by a variety of different mechanisms ranging from chemical ablation of the beta cells to breeding rodents that spontaneously develop autoimmune diabetes. Since the animals used to study type 1 diabetes are highly inbred with a limited number of pathways to T1D, the relevance to human T1D has been questioned [9]. In type 2 diabetes (T2D) mellitus, numerous animal models have been developed for understanding the pathophysiology of diabetes and its complications [10]. These animal models tend to include models of insulin resistance and/or models of beta cell failure. On the other hand, several T2D animal models are obese, reflecting the human condition where obesity is closely linked to T2D development. Most of these models tend to have abnormalities in a single gene or multiple genes related to obesity, glucose intolerance, and/or insulin resistance leading to high blood glucose levels [11]. The outgrowth and progression of diabetic complications are affected by various factors including obesity, insulin resistance, hyperglycemia, and hyperlipidemia [10] (Figure 1).

Figure 1: Summary of animal models of diabetes mellitus.

2. Zucker Diabetic Fatty (ZDF) Rats

The discovery of this type of rats occurred in 1961 after a cross of Merck (M-strain) and Sherman rats. They are characterized by a mutated leptin receptor that induces hyperphagia and the rats become obese by 4 weeks of age [12]. These rats are hyperinsulinemic, hyperlipidemic, and hypertensive as well and show impaired glucose tolerance [13]. The homozygous mutation (fa/fa) of the leptin hormone receptor results in the development of type 2 diabetes in male rats when they are fed a high-energy rodent diet. These rats develop advanced insulin resistance and glucose intolerance between 3 and 8 weeks of age and turn overtly diabetic between 8 and 10 weeks of age with glucose levels in the feeding state typically 500 mg/dL by 10 to 11 weeks of age. Evidence suggests that there is a good consistency between the increase in islet DNA content and serum insulin levels indicating that islet hyperplasia plays a role in the development of hyperinsulinemia in Zucker Diabetic Fatty (ZDF) rats [14].

Triglycerides and cholesterol levels in obese rats are higher than those observed in lean rats. The lipotoxicity is attributed to the products of excessive non-β-oxidative metabolism of fatty acid excess in skeletal muscle and pancreatic islets [1517]. The common complications of obesity, insulin resistance, cardiovascular disease, and diabetes are believed to be caused by high levels of these metabolic products through disrupting cell function and ultimately by promoting programmed cell death “lipoapoptosis” [16, 17]. In addition, it was reported that very high lipid levels can be induced in obese Zucker Diabetic Fatty (ZDF) rats, using high saturated fat and sucrose-containing diets. The infertility of obese males is considered an important issue that hampers research in these rats and which has been addressed by the use of testosterone propionate (TP) [18]. Depending on the amount and duration of TP administration, male obesity increases the probability of ejaculation and sexual activity. Furthermore, ZDF rats do not develop hypertension or cardiovascular disease spontaneously [19].

The inbred Zucker Diabetic Fatty (ZDF) rats substrain with a diabetogenic phenotype is derived by the induction of a mutation in this strain. This derived strain of rats are less obese than the Zucker Fatty (ZF) rats but have more severe insulin resistance which they are unable to compensate for due to the increase in apoptosis levels in beta cells [20]. This is characterized by initial hyperinsulinemia at eight weeks of age followed by decreased insulin levels [21]. It was mentioned that females do not develop overt diabetes [13]. According to these facts, the evolution of diabetes in male leptin receptor-deficient ZDF rats (ZDF/CrlCrlj) has become a popular model for preclinical studies of type 2 diabetes due to the fact that these rats exhibit disrupted islet architecture, B cell degranulation, and increased B cell death [19].

3. BB Rats

This type of rat was derived from outbred Wistar rats. Firstly, spontaneous autoimmune diabetes was identified in 1974 in a Canadian colony and then led to the creation of two founder colonies from which all substrains have been derived including one of inbred Biobreeding Diabetes-Prone/Worcester (BBDP/Wor) and one of outbred Biobreeding Diabetes-Prone (BBDP) rats [22]. It was reported that immunologically and genetically distinct BB rat substrains were derived from several tertiary Biobreeding (BB) rat colonies [23] including Biobreeding/Ottawa Karlsburg (BB/OK) (BB/Pfd) and Biobreeding Spontaneously Hypertensive Rats (BB.SHR) [2427]. Additionally, BB rats resistant to diabetes have been bred to act as controls.

After puberty, Biobreeding (BB) rats develop diabetes with a similar incidence between males and females with about 90% of rats developing diabetes between eight and sixteen weeks of age. The diabetic phenotype is quite severe and is characterized by development of hyperglycemia, hypoinsulinemia weight loss, and ketonuria requiring insulin therapy for survival. The latter clinical and metabolic symptoms are preceded by histological abnormalities in the islets of pancreas. It was concluded that the earliest detectable anomaly is the enhanced expression of interferon-α (IFN-α) and major histocompatibility complex (MHC) class I molecules in islet cells, which occur soon after weaning followed by progressive infiltration of islets by macrophages, natural killer (NK) cells, dendritic cells, T cells and to a lesser extent B cells [2830].

Though these animals have insulitis with the presence of T cells, B cells, macrophages, and natural killer (NK) cells, they are lymphopenic with a severe reduction in CD4+ T cells and a near absence of CD8+ T cells. Lymphopenia is not a characteristic of type 1 diabetes (T1D) neither in humans nor in Nonobese Diabetic (NOD) mice. Recently, a novel member of the GTPase family was described as rIAN5 in the BB rat, and its mutation, which was identified in the Gimap5 (Ian5) gene (RNO4), results in T cell lymphopenia causing diabetes in this model [31, 32]. Consequently, it is perceived as a disadvantage in using Biobreeding (BB) rats as a model of human type 1 diabetes [22]. T lymphopenia is present at birth and its severity explains why this animal is immune-deficient. Although the serum of BB rats contains normal levels of circulating immunoglobulins and autoantibodies of various specificities, their capability to generate germinal centers following immunization with T-dependent antigens is compromised and the ability of T cells to generate allospecific cytotoxic T cells and to proliferate robustly in response to alloantigens in vitro is severely reduced [3336]. Otherwise, the advantages of this model have been insufficient in elucidating type 1 diabetes (T1D) on the genetic level [37]. In some intervention studies and studies of diabetic neuropathy, BB rats have been used as well [3840]. Both sexes of inbred Biobreeding Diabetes-Prone/Worcester (BBDP/Wor) rats and outbred Biobreeding Diabetes-Prone (BBDP) rats develop pancreatic insulitis that is rapidly followed by selective destruction of beta cells and frank diabetes between 50 and 90 days of age. The natural course of insulitis in the spontaneously diabetic BB rat was noted to be different from that of the Nonobese Diabetic (NOD) mouse. In Biobreeding (BB) rats, insulitis is morphologically similar to what is observed in human T1D and features a predominance of Th1-type lymphocytes [41, 42]. Profound T cell lymphopenia is shown clearly to be the most obvious and problematic immunopathology in all diabetic Biobreeding (BB) rats [4345]. The rats also appear to be severely deficient in ART2+ T cells, where ART2 is a rat maturational T cell alloantigen with nicotinamide adenine dinucleotide glycol-hydrolase activity that appears to identify cells with immune-regulatory properties [46]. The conditions that lead to beta cell autoreactivity in the spontaneously diabetic BB rat are still not resolved yet, but the mechanism likely involves the presentation of autoantigen by RT1u molecules, while the identity of the primary autoantigen is unknown. The transfusion of CD4+ ART2+ T cells to overcome the effects of lymphopenia is considered to be one of the unique preventative strategies against the spontaneous diabetic BB rat model [47] with no documented human equivalent of the ART2+ T cell. The treatment of diabetic BB rats has been achieved with islet transplantation plus either immunosuppression [48] or costimulatory blockade [49].

4. LEW 1AR1/-iddm Rats

4.1. (ZDF-Leprfa/Crl)

This rat model of type 1 diabetes (T1D) arose spontaneously in a colony of congenic Lewis rats characterized by a defined MHC haplotype Lewis.1AR1 (LEW.1AR1) rat. It is a unique model for studying human T1D in which rats were being bred in Hannover Medical School (Ztm) at the Institute of Laboratory Animal Science and obtained as a result of a spontaneous mutation in the LEW.1AR1 strain. It was obvious that these rats develop diabetes between 60 and 90 days of age and are characterized by rapid progression of insulitis leading to extensive β cell destruction [50, 51]. These rats are distinct from the well-characterized Nonobese Diabetic (NOD) model of T1D as, unlike Biobreeding Diabetes-Prone (BBDP) rats, diabetes develops with equal frequency in both male and female animals [52]. Studies clearly showed that the incidence of diabetes in these animals is increased from 20% to 60% with further inbreeding with equal incidence in both genders [50, 51]; moreover, the animals also display a prediabetic state that lasts for approximately a week with islet infiltration [51]. The Lewis-insulin dependent diabetes mellitus (LEW-iddm) rats are able to survive well after diabetes is overtly shown and, consequently, they can be used as a model to study diabetic complications [53]. These animals are ketonuric, but they are not lymphopenic expressing normal numbers of ART2+ T cells. Furthermore, β cells of the islets of Langerhans of affected animals are infiltrated with B and T lymphocytes, macrophages, and natural killer (NK) cells and it appears that the beta cells die via apoptosis [22]. They show apoptotic beta cell destruction induced by proinflammatory cytokines that are released from islet-infiltrating immune cells [51]. In Lewis.1AR1-insulin dependent diabetes mellitus (LEW.1AR1-iddm) rat, the diabetic syndrome displays an autosomal recessive mode of inheritance with an incomplete penetrance of the mutant phenotype of about 60% [50, 51]. The genome-wide linkage analysis using a (BN6LEW.1AR1-iddm) × LEW.1AR1-iddm] N2 (N2 BN) population facilitated the discovery of three T1DM susceptibility loci in this rat model [54]. One of these loci mapped to RNO20p12 within the MHC region provides T1D mellitus susceptibility also in humans (IDDM1) and the NOD mouse (idd1) and the BB rat and the Komeda diabetes-prone (KDP) rat models insulin dependent diabetes mellitus1 (Iddm1) [8]. In this case, the MHC haplotype plays a pivotal role in permitting T1DM development [55]. It was possible to confer protection against diabetes through adoptive transfer of immune cells from the Lewis.1AR1 (LEW.1AR1) background strain into prediabetic LEW.1AR1-iddm rats. Thus, LEW.1AR1 rats are protected against beta cell autoreactive immune cells by the regulatory elements of the immune system [56]. In addition to the diabetes-related MHC class II (Iddm1) susceptibility locus, insulin dependent diabetes mellitus8 (Iddm8) was identified recently as the site of mutation(s) contributing to disease susceptibility in the LEW.1AR1 strain [57].

Moreover, in addition to autoimmune diabetes, Lewis.1AR1-insulin dependent diabetes mellitus (LEW.1AR1-iddm) rats manifest a second phenotype described as a “variable CD3+ T cell frequency” which could also be mapped within the Iddm8 region [8]. So, the mutation in the Iddm8 region confers susceptibility to diabetes as well as to the variable CD3+ T cell frequency in blood. A previous study done by Arndt et al. shows that the spontaneous mutation in the LEW.1AR1-iddm rat was also identified in the Dock8 gene, and this mutation was also shown to be accompanied by autoimmune diabetes development and a variable CD3+ T cell frequency in peripheral blood. It is well known that other mutations in the Dock family can also lead to an imbalance in the immune system in humans [5860].

Effective prevention strategies from diabetes require a combination therapy to target the proinflammatory cytokines produced in the different immune cell types. Of crucial importance in this context is the proinflammatory cytokine tumor necrosis factor-α (TNF-α) that is expressed in all immune cell types infiltrating the pancreatic islets in patients with T1D as well as in the LEW.1AR1-iddm rat model [61, 62]. Fingolimod (FTY720) treatment has been performed to protect against islet infiltration in the prediabetic and early diabetic phase in type 1 diabetes, but only in animal models and not in humans [63, 64]. The clinical benefit of this immunomodulatory agent is the lack of severe adverse effects at a dose of 1 mg/kg body weight as applied in diabetes prevention studies in rodent models, including the LEW.1AR1-iddm (iddm) [65].

The MHC-II RT1-B/Du haplotype is indispensable for diabetes development in rats, and, in several studies, the congenic Lewis (LEW), Lewsi.1AR1 (LEW.1AR1), and Lewsi.1WR1 (LEW.1WR1) strains were selected to compare the frequencies of immune cell subpopulations in peripheral blood to those in LEW.1AR1-iddm rats. The LEW.1AR1 (RT1-Aa, RT1-B/Du, and RT1-Cu) and LEW.1WR1 (RT1-Au, RT1-B/Du, and RT1-Ca) strains express also the MHC-II RT1-B/Du haplotype, and, conversely, the original LEW (RT1-Al, RT1-B/Dl, and RT1-Cl) strain cannot develop diabetes because of the missing RT1-B/Du haplotype.

5. Goto-Kakizaki Rats

Developing mild hyperglycaemia at an early stage of life, the Goto-Kakizaki (GK) rat is considered a nonobese model. This type 2 diabetes (T2D) model originates from Wistar (W) rat established by repeated inbreeding with Wistar (W) rats at the upper limit of normal distribution for glucose tolerance [66, 67] with most likely glucose intolerance due to impaired β cell mass and function on the background of a polygenic inheritance. Chronic exposure to hyperglycemia (glucotoxicity) may further impair β cell function and insulin action and contribute to the development of hyperglycemia. However, insulin resistance contribution may likely be secondary in the development of hyperglycemia in this model. Goto-Kakizaki (GK) rat pancreatic islets may develop into the so-called starfish-shaped islets characterized by disrupted structure with clear fibrosis separating strands of endocrine cells making the islets resemble the appearance of a starfish. These changes are not present in the pancreas of young GK rats but increase in prevalence with aging [68]. In adult Goto-Kakizaki (GK) rats, total pancreatic β cell mass and pancreatic insulin stores are similarly decreased by 60% [69, 70]. This alteration in the β cell population cannot be attributed to increased β cell apoptosis but is rather related, at least in part, to marked decrease in β cell replication [71]. The onset of a profound alteration in glucose-stimulated insulin secretion by the GKβ cell, after weaning, correlates with the exposure to the diabetic environment. These changes in the islet function may result, at least in part, from a loss of differentiation of β cells chronically exposed to even mild chronic hyperglycemia and elevated plasma nonesterified fatty acids, a process referred to as “glucolipotoxicity.” According to a previous study conducted in our laboratory using GK rats as a diabetic model, measurement of oral glucose tolerance test (OGTT) revealed that blood glucose concentration peaked at 60 min after glucose administration and then began to decrease. Basal blood glucose level was significantly lower than that after the oral glucose tolerance test (OGTT) pointing to the impairment of carbohydrate homeostasis. Furthermore, the study revealed that hyperglycemia in GK rats can be moderated by exercise, where exercise promotes the prevention and treatment of type 2 diabetes (T2D) because of the increase in the capacity of the muscles to capture circulating glucose due to the decreased intramuscular fat reserves. Running Goto-Kakizaki (GK) rats displayed a significantly lower fasting blood glucose level after the 6-week training period. Initial basal glucose level (0 min) was  mM/L in the sedentary group and  mM/L in the voluntary running group. Exercise was associated with a significantly lower blood glucose level after 60 ( versus  mmol/L) and 120 ( versus  mmol/L) min of the OGTT test [72].

6. Chemically Induced Diabetes

Alloxan and streptozotocin (STZ) are considered the most potent diabetogenic chemicals used in diabetes research so far [73]. Both chemicals are employed as cytotoxic glucose analogues that tend to accumulate in pancreatic beta cells through glucose transporter 2 (GLUT2) [73].

STZ acts as a nitrosourea analogue, in which there is linkage between the N-methyl-N-nitrosourea (MNU) moiety and carbon-2 of hexose [73]. In general, the mode of action of toxicity of STZ depends on the DNA alkylating activity of its methyl-nitrosourea moiety [73]. The transfer of the methyl group from STZ to the DNA molecule causes damage along a defined chain of events [73] and leads to DNA fragmentation [73] (Figure 2).

Figure 2: The mechanism of action of streptozotocin (STZ) in β cells.

STZ-induced diabetes is of two types: the adult type and neonatal type. In case of the adult type streptozotocin- (STZ-) induced diabetes, rats weighing 140 to 300 g underwent a single streptozotocin (STZ) intraperitoneal injection (45–70 mg/kg) dissolved in 0.1 M citrate buffer (pH 4.5) after an overnight fast. Control rats of the same age received only an injection of citrate buffer.

A number of studies with STZ-induced diabetes mellitus reported that diabetes mellitus can improve the recovery of cardiac function after ischemia-reperfusion [74] along with decreasing the incidence of arrhythmias [75, 76]. It was previously contended that the contractile function of diabetic hearts following ischemia-reperfusion recovered to a greater extent than that of the control hearts. However, the magnitude of the preischemic basal contractile function was significantly reduced in the diabetic hearts [74]. Protein kinase C (PKC) inhibitors were found to restore the impaired cardiac function in diabetes before ischemia; however, PKC inhibitors completely abolished protection against postischemic injury in diabetic hearts [74]. This effect of protein kinase C inhibition in diabetes may be explained by the decreased phosphorylation of myocardial proteins (e.g., troponin) [74]. Chen et al. have found that severe hyperglycemia due to diabetes mellitus induced by STZ decreases the incidence of arrhythmias and increases coronary flow and expression of heat shock protein 90 (hsp90) [75]. Nonetheless, the study hypothesized that increased osmolarity due to severe hyperglycemia is in charge of the overexpression of heat shock protein 90 (hsp90), which in turn increases the production of endothelial nitric oxide (NO) [75]. Furthermore, it was well addressed that diabetic hearts are much more resistant to ischemia-induced arrhythmias compared to nondiabetic controls [76]. It was also noted that, 4 weeks following streptozotocin (STZ) treatment, hearts have improved functional recovery after ischemia-reperfusion in comparison to control hearts and this functional recovery was associated with the prevention of hexokinase solubilization during ischemia [77].

Conversely, several published studies indicated that diabetes mellitus induced by STZ did not decrease the infarct size [7882], with no reduction in the incidence of arrhythmias [83]. Some studies also reported that STZ-induced diabetes mellitus even increased the infarct size compared to normal rats [8486].

7. Diabetes and Cardioprotective Strategies

It is still not clear whether or not preconditioning can exert a cardioprotective effect in subjects with diabetes mellitus, and further studies are needed in this regard. Wu et al. found that pharmacological preconditioning with ginsenoside Rb1 in diabetic rats decreased infarct size, while phosphoinositide 3 (PI3) kinase inhibition with wortmannin reverted the cardioprotective effects of ginsenoside Rb1, which is an indication that pharmacological preconditioning with ginsenoside Rb1 involved PI3 kinase/Akt signaling in the diabetic hearts [85]. A study by Zhu et al. showed that the infarct size is decreased in diabetic rats subjected to ischemic preconditioning and noninvasive limb ischemic preconditioning, and this protective effect involved the increase in enzymatic activity of superoxide dismutase as well as increased glutathione peroxidase activity [87]. Pharmacological preconditioning with remifentanil decreased the infarct size both in normal and in diabetic rats and this protection involves antiapoptotic pathways of survival, including extracellular signal regulated kinases (ERK); however, pharmacological preconditioning was less efficient in the case of diabetic hearts [78]. Another study by Ravingerová et al. on isolated hearts taken from rats suffering from diabetes mellitus induced by a single streptozotocin (STZ) intravenous injection (45 mg/kg) showed that ischemic preconditioning induced an antiarrhythmic effect only during the chronic stage of diabetes, in contrary to the acute stage, where ischemic preconditioning did not decrease the incidence of ischemic arrhythmia.

Several other studies also revealed that diabetes impairs preconditioning. Similarly, a study by Ji et al. proved that diabetes impaired preconditioning [81]. Ischemic preconditioning was abolished in STZ-treated rats due to a failure to increase glucose uptake during reperfusion [81]. It was shown by Vinokur et al. that impaired iron homeostasis in diabetic heart can lead to failure of preconditioning to induce myocardial protection [82]. Sharma et al. found that diabetes mellitus impaired pharmacological preconditioning by adenosine; however, adenosine transport blockade by dipyridamole restored the protective effect [86]. Results of Ajmani et al. suggested that attenuation of cardioprotection in the diabetic heart may be due to the decrease in ischemic preconditioning-mediated release of nitric oxide (NO) in the diabetic myocardium, which may be a result of upregulating caveolin and the subsequent decrease of endothelial nitrogen oxide synthase (eNOS) activity [80]. According to Yadav et al., diabetes mellitus induced attenuation of cardioprotective effect of ischemic preconditioning through the activation of glycogen synthase kinase 3-beta (GSK-3β), due to the impaired protective upstream signaling pathways and (mPTP) opening during reperfusion [79]. On the other hand, Tosaki et al. reported that ischemic preconditioning did not confer antiarrhythmia and antimyocardial stunning effects in diabetic rats induced by intraperitoneal injection of STZ (65 mg/kg) [83].

Ischemic postconditioning, as another strategy in cardioprotection, is abolished by STZ-induced diabetes mellitus. According to Ren et al., it was found that ischemic postconditioning failed to ameliorate the cardiac function and most likely failed to reduce creatine kinase and cardiac troponin I release in isolated perfused heart from diabetic rats. Moreover, it was also revealed in this study that the decrease in transient receptor potential cation channel subfamily V member 1 (TRPV1) and the increase in the expression of calcitonin gene related peptide (CGRP) and Substance P (SP) in diabetic hearts caused the loss of the cardioprotective activity of ischemic postconditioning associated with a failure to increase calcitonin gene related peptide (CGRP) and Substance P (SP) release [88]. Sevoflurane postconditioning was abolished by chemically induced diabetes in a rat model and this detrimental effect involved the impairment of phosphorylation of glycogen synthase kinase 3-beta (GSK-3β) and its upstream pathways, such as PI3 kinase/Akt and extracellular signal regulated kinases (ERK) in diabetes [89]. Najafi et al. indicated that ischemic postconditioning did not exert a protective effect in diabetic hearts [90]. Concurrent inhibition of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mPTP) may lead to a restoration of the protective effect of ischemic postconditioning in these diseased hearts [90].

In case of neonatal type of STZ treatment, 2–4-day-old neonatal Wistar (W) rats are injected intraperitoneally with 65–100 mg/kg of STZ or its vehicle (ice-cold citrate buffer) to induce diabetes. Neonatal rats are kept with their mother during the lactation period until week 4. For lactating mothers, standard rat chow and tap water were supplied ad libitum [91]. Type 2 diabetes (T2D) induced by neonatal STZ treatment can protect the heart against ischemia-reperfusion [92]. Moreover, preconditioning can furthermore protect the diabetic heart [92]. Based on a previous study, the recovery of cardiac function after ischemia-reperfusion and infarct size was improved in diabetic rats [93].

It is well known that alloxan possesses two pathological effects: it can selectively inhibit glucose-induced insulin secretion through the inhibition of glucokinase, the glucose sensor of the beta cell, and it creates a state of insulin dependent diabetes by inducing reactive oxygen species (ROS) formation causing a selective necrosis of beta cells [73] (Figure 3).

Figure 3: The main pathological effects of alloxan.

Alloxan was also shown to induce diabetes in fasting male Wistar (W) rats weighing 200–250 g that were given subcutaneously 125 mg/kg alloxan [94]. Galagudza et al. have found that diabetic rats for six weeks were more resistant to ischemic damage compared to the myocardium of healthy animals, and ischemic preconditioning in animals with diabetes mellitus was much less effective in limiting infarct size than in control animals [94]. However, diabetes mellitus induced by alloxan interferes with the protective effect of postconditioning in other species [9597].

8. Nonobese Diabetic Mouse

This type of mouse was first developed at Shionogi Research Laboratories in Osaka, Japan, in 1974 [98]. Insulitis appears at around 3rd or 4th week of their age. During this prediabetic stage, the islets of the pancreas become infiltrated by CD4+ and CD8+ lymphocytes, though natural killer (NK) and B cells are also present [99]. The infiltration of innate immune cells into the islets attracts adaptive CD4+ and CD8+ T cell subsets into the islets starting from approximately 4–6 weeks of age [100], which are both required for diabetes development. Insulitis leads to the destruction of beta cells, while the onset of overt diabetes usually appears when approximately 90% of the pancreatic insulin is lost at around 10–14 weeks, although diabetes can develop up to 30 weeks of age. These mice can lose weight rapidly when they become overtly diabetic and require insulin treatment.

Nonobese Diabetic (NOD) mouse is one of the most commonly used models to study type 1 diabetes (T1D). Unlike other models used in autoimmunity studies, this model can develop spontaneous disease similar to humans. Several advances in our understanding of the disease arose from using this model, including the identification of several autoantigens and biomarkers that are similar in humans and enabled the development of therapeutic targets [101]. Both in NOD mice and in humans, the most important genetic factor that contributes to T1D susceptibility is the major histocompatibility complex (MHC) known as insulin dependent susceptibility 1 (idd1) in mice and insulin dependent diabetes mellitus1 (IDDM1) in humans [102, 103]. In addition, more than 40 genetic loci discovered in both NOD mice and humans have been shown to play an important role in mediating T1D susceptibility, including genes related to immune system function and regulation as well as pancreatic beta cell function [104]. The pancreas of Nonobese Diabetic (NOD) mice is infiltrated by innate immune cells at an early period of 3 weeks of age. These cells include dendritic cells (DCs), macrophages and neutrophils [105107], prior to the infiltration of the lymphocytes. Identically, these cells are also found in the human islet infiltrate [108]. According to several studies, MHC class 2 proteins in NOD mice share structural similarities to those in humans, which may confer resistance or susceptibility to the disease in both NOD mice and humans [109]. The similarity in the genes of type 1 diabetes (T1D) between NOD mice and humans has been completely useful in dissecting some mechanisms and pathways behind T1D [110]. Therefore, these animals are believed to be a potentially suitable model for testing therapies in which modulation of the autoimmune response is being targeted. However, it should also be noted that there are a number of effective drugs in NOD mice, which were shown to be ineffective in humans [111]. One of the main issues is the time point of intervention and another difficulty in the translation of therapies tested in Nonobese Diabetic (NOD) mice is that whereas the pancreas of NOD can be removed for examination after a study, there is a deficiency of biomarkers in human peripheral blood that could be used as evidence to verify the success of the intervention [112]. There are problems as well in translating dosing from the Nonobese Diabetic (NOD) mouse to humans [112]. Diabetes development in the Nonobese Diabetic (NOD) mouse is associated negatively with microbial exposure. Therefore, mice should be protected in specific pathogen-free (SPF) conditions to maintain diabetes incidence. Because of the differences in gender, the unpredictability of the disease onset, and the requirement for SPF conditions, this mouse model is expensive to maintain as type 1 diabetes (T1D) model in comparison with the chemically induced diabetic model. Adoptive transfer was also proved to be useful, where this strategy is based on the injection of T cells from diabetic NOD mice into nondiabetic recipient mice, causing the recipient mouse to develop diabetes [113].

9. Akita Mice

The Akita mouse was initially developed in Akita, Japan, from a C57BL/6NSlc mouse due to a spontaneous mutation in insulin 2 gene leading to incorrect proinsulin processing. This mutation caused the aggregation of misfolded proteins and led, subsequently, to endoplasmic reticulum (ER) stress (Figure 4).

Figure 4: Akita mice.

Collectively, these alterations resulted in pronounced insulin dependent diabetes with an onset of 3 to 4 weeks of age. The resulting rodent model exhibits characteristic signs, including hyperglycemia, hypoinsulinemia, polyuria, and polydipsia. The absence of beta cell mass in this mouse model renders it a valid alternative to STZ-treated mice in transplantation studies. It has been well utilized as a model of type 1 diabetes (T1D) macrovascular disease and neuropathy [114116]. Likewise, this model is usually used to investigate potential alleviators of ER stress in the islets. In this regard, some of the pathological manifestations of type 2 diabetes (T2D) are also visible in the Akita mouse model [117]. Studies have reported that mice and humans lacking PERK, a critical component of the ER stress response, develop spontaneous diabetes mellitus at a very young age taking into consideration that β cells may be especially vulnerable to endoplasmic reticulum (ER) stress [118].

Akita mice carry the Ins2+/C96Y mutation, a single nucleotide substitution in the insulin 2 (Ins2) gene. This mutation causes incorrect folding of the insulin protein, pancreatic β cells toxic injury, and reduced insulin secretion propensity resulting in T1D [119, 120]. The Ins2C96Y mutation present in the Akita diabetic mouse prevents the formation of an essential disulfide bond between insulin 2 chains and prevents proper folding and processing of this protein. The misfolded proinsulin 2 is not secreted and is retained in the pancreatic β cell endoplasmic reticulum (ER) during its processing in the secretory pathway [121]. Mice carrying the Ins2C96Y mutation develop progressive diabetes mellitus, a phenotype that probably reflects a holistic effect rather than just the loss of correctly folded insulin production by the mutant Ins2 allele. In fact, rodents have two insulin genes (Ins1 and Ins2) and, interestingly, the loss of both Ins2 genes copies is fully compensated [122]. Even though newborn Ins2C96Y mutant mice have normal sized islets of Langerhans that produce an adequate complement of insulin-producing β cells, over time they undergo a progressive and marked loss of the β cell mass. Apoptosis-mediated loss of these cells correlates with the development of diabetes mellitus. A key finding was that this specific pathophysiological aspect of the Akita mouse can be reproduced in vitro by expressing high levels of Ins2C96Y, but not wild-type Ins2, in the β Min6 cell line [123]. This “Akita” polymorphism of insulin 2 gene () acts in a dominant-negative manner in Ins2akita/+ mice and leads to severe hyperglycemia persisting throughout the mouse life [124]. It is likely, therefore, that the expression of Ins2C96Y is toxic to islet cells and that the loss of β cell mass mediates hyperglycemia development in the Akita mouse. Studies have reported that Ins2 Akita mouse is a valid model of diabetic sympathetic autonomic neuropathy corresponding closely to the characteristic pathology of other rodent models and humans [125]. C57BL/6-Ins2+/C96Y mice also had higher levels of albuminuria and systematic renal pathological changes. Therefore, the C57BL/6-Ins2 Akita model presents a number of advantages over the chemically induced STZ model of diabetes and may serve as a platform for developing models of diabetic nephropathy [126]. Nonetheless, proteinuria is less developed in C57BL/6-Ins2+/C96Y mice and mesangial expansion is the only reported renal pathological change. In this regard, Ins2 Akita mice can serve as a model of diabetes ameliorating the deficiencies encountered in the STZ treatment in studies of islet transplantation [114]. It was argued as well that the mouse genetic background might exert an effect on the development of kidney injury in Akita mice [120]. One of the drawbacks that marred the utilization of this animal model is that the Akita mouse has not been validated by antineuropathic drugs [127]. These mice, for a reason yet to be identified, show mesangial immunoglobulin A (IgA) deposits [128]. This deposition is a major factor in the development of human mesangial proliferative glomerulopathy and, consequently, the lack of clear understanding of the underlying mechanism of the increase of mesangial matrix will make these observations of limited value. This is especially evident in the cases where the key endpoint is represented by alterations in mesangial volume and matrix accumulation [129].

10. Conclusions and Future Outstandings

Due to the increase in the prevalence of diabetes mellitus worldwide, the diabetic rat models are believed to play an important role in elucidating the pathogenesis of human diabetes and its complications, such as retinopathy, nephropathy, and neuropathy. Moreover, the diabetic rat models are essential for investigating and developing novel drugs for diabetes and its complications. All of the rat and mouse models available to date possess important limitations, despite all the advantages they offer. Thus, designing better models of diabetes mellitus (DM) that will allow identification of the underlying mechanisms or testing of therapeutic interventions, must continue. The best model of diabetes should have some major criteria such as the following: the model should have all major pathogenesis of diabetes with other minor pathogenesis that can be normally found in diabetic humans, the model should be sensitive to antidiabetic drugs, and the model needs to be suitable to study the pathogenesis of disease as well as for routine pharmacological screening of antidiabetic drugs. Furthermore, the diseased animal models have contributed to helping scientists and researchers to better understand the mechanisms of other diseases in preclinical studies that allowed the screening of drugs and pharmaceutical agents, but their value in predicting the effectiveness of treatment strategies in clinical trials has remained controversial. In this case, more future studies are needed to investigate the role of the diseases animals in combination with pharmacological therapy.

Competing Interests

The authors declare no competing or financial interests.

Authors’ Contributions

Amin Al-awar drafted the paper. Krisztina Kupai was responsible for study conception and design. Médea Veszelka was responsible for publication process. Gergő Szűcs was responsible for acquisition of data. Zouhair Attieh was responsible for abstract writing. Zsolt Murlasits participated in drafting the paper. Szilvia Török acquired the data. Anikó Pósa was responsible for critical revision. Csaba Varga revised the paper critically for important intellectual content.


This research was carried out in the frame of TÁMOP 4.2.4.A/2-11-1-2012-0001 “National Excellence Program—Elaborating and operating an inland student and researcher personal support system.” The project was subsidized by the European Union and cofinanced by the European Social Fund. Gergő Szűcs is supported by MTA Postdoctoral Research Programme, Hungarian Academy of Sciences.


  1. G. Danaei, M. M. Finucane, Y. Lu et al., “National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants,” The Lancet, vol. 378, no. 9785, pp. 31–40, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. J. A. Bluestone, K. Herold, and G. Eisenbarth, “Genetics, pathogenesis and clinical interventions in type 1 diabetes,” Nature, vol. 464, no. 7293, pp. 1293–1300, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. J. A. Todd, “Etiology of type 1 diabetes,” Immunity, vol. 32, no. 4, pp. 457–467, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. V. Hyttinen, J. Kaprio, L. Kinnunen, M. Koskenvuo, and J. Tuomilehto, “Genetic liability of type 1 diabetes and the onset age among 22, 650 young Finnish twin pairs: a nationwide follow-up study,” Diabetes, vol. 52, no. 4, pp. 1052–1055, 2003. View at Publisher · View at Google Scholar · View at Scopus
  5. B. Tao, M. Pietropaolo, M. Atkinson, D. Schatz, and D. Taylor, “Estimating the cost of type 1 diabetes in the U.S.: a propensity score matching method,” PLoS ONE, vol. 5, no. 7, Article ID e11501, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. M. Ben Nasr, F. D'Addio, V. Usuelli, S. Tezza, R. Abdi, and P. Fiorina, “The rise, fall, and resurgence of immunotherapy in type 1 diabetes,” Pharmacological Research, vol. 98, pp. 31–38, 2015. View at Publisher · View at Google Scholar · View at Scopus
  7. T. P. J. Solomon, S. N. Sistrun, R. K. Krishnan et al., “Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults,” Journal of Applied Physiology, vol. 104, no. 5, pp. 1313–1319, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Arndt, A. Jörns, H. Weiss et al., “A variable CD3+ T-cell frequency in peripheral blood lymphocytes associated with type 1 diabetes mellitus development in the LEW.1AR1-iddm rat,” PLoS ONE, vol. 8, no. 5, Article ID e64305, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. B. Phillips, M. Trucco, and N. Giannoukakis, “Current state of type 1 diabetes immunotherapy: incremental advances, huge leaps, or more of the same?” Clinical and Developmental Immunology, vol. 2011, Article ID 432016, 18 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  10. N. A. Calcutt, M. E. Cooper, T. S. Kern, and A. M. Schmidt, “Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials,” Nature Reviews Drug Discovery, vol. 8, no. 5, pp. 417–429, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. K. Kawano, S. Mori, T. Hirashima, Z.-W. Man, and T. Natori, “Examination of the pathogenesis of diabetic nephropathy in OLETF rats,” Journal of Veterinary Medical Science, vol. 61, no. 11, pp. 1219–1228, 1999. View at Publisher · View at Google Scholar · View at Scopus
  12. M. S. Phillips, Q. Liu, H. A. Hammond et al., “Leptin receptor missense mutation in the fatty Zucker rat,” Nature Genetics, vol. 13, no. 1, pp. 18–19, 1996. View at Publisher · View at Google Scholar · View at Scopus
  13. K. Srinivasan and P. Ramarao, “Animal models in type 2 diabetes research: an overview,” Indian Journal of Medical Research, vol. 125, no. 3, pp. 451–472, 2007. View at Google Scholar · View at Scopus
  14. Y. Tokuyama, J. Sturis, A. M. DePaoli et al., “Evolution of β-cell dysfunction in the male Zucker diabetic fatty rat,” Diabetes, vol. 44, no. 12, pp. 1447–1457, 1995. View at Publisher · View at Google Scholar · View at Scopus
  15. Y. Lee, H. Hirose, Y.-T. Zhou, V. Esser, J. D. McGarry, and R. H. Unger, “Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM,” Diabetes, vol. 46, no. 3, pp. 408–413, 1997. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Shimabukuro, M. Higa, Y.-T. Zhou, M.-Y. Wang, C. B. Newgard, and R. H. Unger, “Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression,” The Journal of Biological Chemistry, vol. 273, no. 49, pp. 32487–32490, 1998. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Shimabukuro, Y.-T. Zhou, M. Levi, and R. H. Unger, “Fatty acid-induced β cell apoptosis: a link between obesity and diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 5, pp. 2498–2502, 1998. View at Publisher · View at Google Scholar · View at Scopus
  18. R. B. Hemmes and R. Schoch, “High dosage testosterone propionate induces copulatory behavior in the obese male Zucker rat,” Physiology and Behavior, vol. 43, no. 3, pp. 321–324, 1988. View at Publisher · View at Google Scholar · View at Scopus
  19. J. B. Clark, C. J. Palmer, and W. N. Shaw, “The diabetic Zucker fatty rat,” Proceedings of the Society for Experimental Biology and Medicine, vol. 173, no. 1, pp. 68–75, 1983. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Pick, J. Clark, C. Kubstrup et al., “Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in the male Zucker diabetic fatty rat,” Diabetes, vol. 47, no. 3, pp. 358–364, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. T. Shibata, S. Takeuchi, S. Yokota, K. Kakimoto, F. Yonemori, and K. Wakitani, “Effects of peroxisome proliferator-activated receptor-α and -γ agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats,” British Journal of Pharmacology, vol. 130, no. 3, pp. 495–504, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. J. P. Mordes, R. Bortell, E. P. Blankenhorn, A. A. Rossini, and D. L. Greiner, “Rat models of type 1 diabetes: genetics, environment, and autoimmunity,” ILAR Journal, vol. 45, no. 3, pp. 278–291, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. J. B. Prins, L. Herberg, M. Den Bieman, and L. F. M. Van Zutphen, “Genetic variation within and between lines of diabetes-prone and non-diabetes-prone BB rats; allele distribution of 8 protein markers,” Laboratory Animals, vol. 25, no. 3, pp. 207–211, 1991. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Mathieu, B. Kuttler, M. Waer, R. Bouillon, and H. J. Hahn, “Spontaneous reestablishment of self-tolerance in BB/pfd rats,” Transplantation, vol. 58, no. 3, pp. 349–354, 1994. View at Publisher · View at Google Scholar · View at Scopus
  25. I. Klöting, J. van den Brandt, and B. Kuttler, “Genes of SHR rats protect spontaneously diabetic BB/OK rats from diabetes: lessons from congenic BB.SHR rat strains,” Biochemical and Biophysical Research Communications, vol. 283, no. 2, pp. 399–405, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Kovacs, J. van den Brandt, A. C. Bonne, L. F. van Zutphen, H. A. van Lith, and I. Kloting, “Congenic BB.SHR rat provides evidence for effects of a chromosome 4 segment (D4Mit6-Npy approximately 1 cm) on total serum and lipoprotein lipid concentration and composition after feeding a high-fat, high-cholesterol diet,” Metabolism, vol. 50, no. 4, pp. 458–462, 2001. View at Google Scholar
  27. D. Schröder, M. Ratke, U. C. Bauer, I. Klöting, B. Ziegler, and S. Schmidt, “Prophylactic insulin treatment of diabetes-prone BB/OK rats by application of a sustained release insulin implant,” Autoimmunity, vol. 35, no. 2, pp. 143–153, 2002. View at Publisher · View at Google Scholar · View at Scopus
  28. S. J. Ono, B. Issa-Chergui, E. Colle, R. D. Guttmann, T. A. Seemayer, and A. Fuks, “IDDM in BB rats. Enhanced MHC class I heavy-chain gene expression in pancreatic islets,” Diabetes, vol. 37, no. 10, pp. 1411–1418, 1988. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Hanenberg, V. Kolb-Bachofen, G. Kantwerk-Funke, and H. Kolb, “Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats,” Diabetologia, vol. 32, no. 2, pp. 126–134, 1989. View at Publisher · View at Google Scholar · View at Scopus
  30. X. Huang, B. Hultgren, N. Dybdal, and T. A. Stewart, “Islet expression of interferon-α precedes diabetes in both the BB rat and streptozotocin-treated mice,” Immunity, vol. 1, no. 6, pp. 469–478, 1994. View at Publisher · View at Google Scholar · View at Scopus
  31. A. J. MacMurray, D. H. Moralejo, A. E. Kwitek et al., “Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene,” Genome Research, vol. 12, no. 7, pp. 1029–1039, 2002. View at Publisher · View at Google Scholar · View at Scopus
  32. J. Krücken, R. M. U. Schroetel, I. U. Müller et al., “Comparative analysis of the human gimap gene cluster encoding a novel GTPase family,” Gene, vol. 341, no. 1-2, pp. 291–304, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. T. Dyrberg, A. F. Nakhooda, S. Baekkeskov, A. Lernmark, P. Poussier, and E. B. Marliss, “Islet cell surface antibodies and lymphocyte antibodies in the spontaneously diabetic BB Wistar rat,” Diabetes, vol. 31, no. 3, pp. 278–281, 1982. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Baekkeskov, T. Dyrberg, and A. Lernmark, “Autoantibodies to a 64-kilodalton islet cell protein precede the onset of spontaneous diabetes in the BB rat,” Science, vol. 224, no. 4655, pp. 1348–1350, 1984. View at Publisher · View at Google Scholar · View at Scopus
  35. B. A. Woda, A. A. Like, C. Padden, and M. L. McFadden, “Deficiency of phenotypic cytotoxic-suppressor T lymphocytes in the BB/W rat,” The Journal of Immunology, vol. 136, no. 3, pp. 856–859, 1986. View at Google Scholar · View at Scopus
  36. E. P. van Rees, H. A. M. Voorbij, and C. D. Dijkstra, “Neonatal development of lymphoid organs and specific immune responses in situ in diabetes-prone BB rats,” Immunology, vol. 65, no. 3, pp. 465–472, 1988. View at Google Scholar · View at Scopus
  37. R. H. Wallis, K. Wang, L. Marandi et al., “Type 1 diabetes in the BB rat: a polygenic disease,” Diabetes, vol. 58, no. 4, pp. 1007–1017, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. W. Zhang, H. Kamiya, K. Ekberg, J. Wahren, and A. A. F. Sima, “C-peptide improves neuropathy in type 1 diabetic BB/Wor-rats,” Diabetes/Metabolism Research and Reviews, vol. 23, no. 1, pp. 63–70, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. M.-L. Hartoft-Nielsen, A. K. Rasmussen, T. Bock, U. Feldt-Rasmussen, A. Kaas, and K. Buschard, “Iodine and tri-iodo-thyronine reduce the incidence of type 1 diabetes mellitus in the autoimmune prone BB rats,” Autoimmunity, vol. 42, no. 2, pp. 131–138, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. R. Holmberg, E. Refai, A. Höög et al., “Lowering apolipoprotein CIII delays onset of type 1 diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 26, pp. 10685–10689, 2011. View at Publisher · View at Google Scholar · View at Scopus
  41. H. Kolb, U. Wörz-Pagenstert, R. Kleemann, H. Rothe, P. Rowsell, and F. W. Scott, “Cytokine gene expression in the BB rat pancreas: natural course and impact of bacterial vaccines,” Diabetologia, vol. 39, no. 12, pp. 1448–1454, 1996. View at Publisher · View at Google Scholar · View at Scopus
  42. D. Zipris, D. L. Greiner, S. Malkani, B. Whalen, J. P. Mordes, and A. A. Rossini, “Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats,” The Journal of Immunology, vol. 156, no. 3, pp. 1315–1321, 1996. View at Google Scholar · View at Scopus
  43. R. Jackson, N. Rassi, T. Crump, B. Haynes, and G. S. Eisenbarth, “The BB diabetic rat. Profound T-cell lymphocytopenia,” Diabetes, vol. 30, no. 10, pp. 887–889, 1981. View at Publisher · View at Google Scholar · View at Scopus
  44. M. E. Elder and N. K. Maclaren, “Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat,” Journal of Immunology, vol. 130, no. 4, pp. 1723–1731, 1983. View at Google Scholar · View at Scopus
  45. J.-F. Yale, M. Grose, and E. B. Marliss, “Time course of the lymphopenia in BB rats. Relation to the onset of diabetes,” Diabetes, vol. 34, no. 10, pp. 955–959, 1985. View at Publisher · View at Google Scholar · View at Scopus
  46. R. Bortell, T. Kanaitsuka, L. A. Stevens et al., “The RT6 (Art2) family of ADP-ribosyltransferases in rat and mouse,” Molecular and Cellular Biochemistry, vol. 193, no. 1-2, pp. 61–68, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. D. Burstein, J. P. Mordes, D. L. Greiner et al., “Prevention of diabetes in BB/Wor rat by single transfusion of spleen cells. Parameters that affect degree of protection,” Diabetes, vol. 38, no. 1, pp. 24–30, 1989. View at Google Scholar · View at Scopus
  48. W. E. Dugoni and S. T. Bartlett, “Evidence that cyclosporine prevents rejection and recurrent diabetes in pancreatic transplants in the BB rat,” Transplantation, vol. 49, no. 5, pp. 845–848, 1990. View at Publisher · View at Google Scholar · View at Scopus
  49. K. L. Kover, Z. Geng, D. M. Hess, C. D. Benjamin, and W. V. Moore, “Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat,” Diabetes, vol. 49, no. 10, pp. 1666–1670, 2000. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Lenzen, M. Tiedge, M. Elsner et al., “The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus,” Diabetologia, vol. 44, no. 9, pp. 1189–1196, 2001. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Jörns, A. Günther, H.-J. Hedrich, D. Wedekind, M. Tiedge, and S. Lenzen, “Immune cell infiltration, cytokine expression, and β-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat,” Diabetes, vol. 54, no. 7, pp. 2041–2052, 2005. View at Publisher · View at Google Scholar · View at Scopus
  52. T. Arndt, A. Jörns, H.-J. Hedrich, S. Lenzen, and D. Wedekind, “Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddm rats over time compared to other congenic LEW strains,” Clinical and Experimental Immunology, vol. 177, no. 1, pp. 168–178, 2014. View at Publisher · View at Google Scholar · View at Scopus
  53. C. E. Mathews, “Utility of murine models for the study of spontaneous autoimmune type 1 diabetes,” Pediatric Diabetes, vol. 6, no. 3, pp. 165–177, 2005. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Weiss, A. Bleich, H.-J. Hedrich et al., “Genetic analysis of the LEW.1AR1-iddm rat: an animal model for spontaneous diabetes mellitus,” Mammalian Genome, vol. 16, no. 6, pp. 432–441, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. K. E. Ellerman and A. A. Like, “Susceptibility to diabetes is widely distributed in normal class II(u) haplotype rats,” Diabetologia, vol. 43, no. 7, pp. 890–898, 2000. View at Publisher · View at Google Scholar · View at Scopus
  56. D. Wedekind, H. Weiss, A. Jörns, S. Lenzen, M. Tiedge, and H.-J. Hedrich, “Effects of polyinosinic-polycytidylic acid and adoptive transfer of immune cells in the LEW.1AR1-iddm rat and in its coisogenic LEW.1AR1 background strain,” Autoimmunity, vol. 38, no. 4, pp. 265–275, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. H. Weiss, T. Arndt, A. Jörns et al., “The mutation of the LEW.1AR1-iddm rat maps to the telomeric end of rat chromosome 1,” Mammalian Genome, vol. 19, no. 4, pp. 292–297, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. J.-F. Côté and K. Vuori, “GEF what? Dock180 and related proteins help Rac to polarize cells in new ways,” Trends in Cell Biology, vol. 17, no. 8, pp. 383–393, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. H. C. Su, “Dedicator of cytokinesis 8 (DOCK8) deficiency,” Current Opinion in Allergy and Clinical Immunology, vol. 10, no. 6, pp. 515–520, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. T. Arndt, D. Wedekind, A. Jörns et al., “A novel Dock8 gene mutation confers diabetogenic susceptibility in the LEW.1AR1/Ztm-iddm rat, an animal model of human type 1 diabetes,” Diabetologia, vol. 58, no. 12, pp. 2800–2809, 2015. View at Publisher · View at Google Scholar · View at Scopus
  61. J. B. Matthews, T. P. Staeva, P. L. Bernstein, M. Peakman, and M. Von Herrath, “Developing combination immunotherapies for type 1 diabetes: Recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group,” Clinical and Experimental Immunology, vol. 160, no. 2, pp. 176–184, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Jörns, T. Arndt, A. M. Zu Vilsendorf et al., “Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes,” Diabetologia, vol. 57, no. 3, pp. 512–521, 2014. View at Publisher · View at Google Scholar · View at Scopus
  63. Z. Yang, M. Chen, L. B. Fialkow et al., “The immune modulator FYT720 prevents autoimmune diabetes in nonobese diabetic mice,” Clinical Immunology, vol. 107, no. 1, pp. 30–35, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. T. Maki, R. Gottschalk, N. Ogawa, and A. P. Monaco, “Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720,” Transplantation, vol. 79, no. 9, pp. 1051–1055, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. A. Jörns, K. J. Rath, T. Terbish et al., “Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation,” Endocrinology, vol. 151, no. 8, pp. 3555–3565, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Goto, M. Kakizaki, and N. Masaki, “Spontaneous diabetes produced by selective breeding of normal wistar rats,” Proceedings of the Japan Academy, vol. 51, no. 1, pp. 80–85, 1975. View at Google Scholar
  67. B. Portha, M.-H. Giroix, P. Serradas et al., “β-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony,” Diabetes, vol. 50, supplement 1, pp. S89–S93, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. C.-G. Östenson and S. Efendic, “Islet gene expression and function in type 2 diabetes; studies in the Goto-Kakizaki rat and humans,” Diabetes, Obesity and Metabolism, vol. 9, supplement 2, pp. 180–186, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Movassat, C. Saulnier, P. Serradas, and B. Portha, “Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat,” Diabetologia, vol. 40, no. 8, pp. 916–925, 1997. View at Publisher · View at Google Scholar · View at Scopus
  70. M.-H. Giroix, C. Saulnier, and B. Portha, “Decreased pancreatic islet response to L-leucine in the spontaneously diabetic GK rat: enzymatic, metabolic and secretory data,” Diabetologia, vol. 42, no. 8, pp. 965–977, 1999. View at Publisher · View at Google Scholar · View at Scopus
  71. F. Picarel-Blanchot, C. Berthelier, D. Bailbé, and B. Portha, “Impaired insulin secretion and excessive hepatic glucose production are both early events in the diabetic GK rat,” American Journal of Physiology—Endocrinology and Metabolism, vol. 271, no. 4, part 1, pp. E755–E762, 1996. View at Google Scholar · View at Scopus
  72. K. Kupai, R. Szabó, M. Veszelka et al., “Consequences of exercising on ischemia-reperfusion injury in type 2 diabetic Goto-Kakizaki rat hearts: role of the HO/NOS system,” Diabetology and Metabolic Syndrome, vol. 7, article 85, 2015. View at Publisher · View at Google Scholar · View at Scopus
  73. S. Lenzen, “The mechanisms of alloxan- and streptozotocin-induced diabetes,” Diabetologia, vol. 51, no. 2, pp. 216–226, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. C.-H. Moon, Y.-S. Jung, S. H. Lee, and E. J. Baik, “Protein kinase C inhibitors abolish the increased resistance of diabetic rat heart to ischemia-reperfusion injury,” Japanese Journal of Physiology, vol. 49, no. 5, pp. 409–415, 1999. View at Publisher · View at Google Scholar · View at Scopus
  75. H. Chen, W.-L. Shen, X.-H. Wang et al., “Paradoxically enhanced heart tolerance to ischaemia in type 1 diabetes and role of increased osmolarity,” Clinical and Experimental Pharmacology and Physiology, vol. 33, no. 10, pp. 910–916, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. T. Ravingerová, J. Matejíková, D. Pancza, and F. Kolář, “Reduced susceptibility to ischemia-induced arrhythmias in the preconditioned rat heart is independent of PI3-Kinase/Akt,” Physiological Research, vol. 58, no. 3, pp. 443–447, 2009. View at Google Scholar · View at Scopus
  77. E. Gurel, S. Ustunova, A. Kapucu et al., “Hexokinase cellular trafficking in ischemia-reperfusion and ischemic preconditioning is altered in type I diabetic heart,” Molecular Biology Reports, vol. 40, no. 7, pp. 4153–4160, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. H. S. Kim, J. E. Cho, K. C. Hwang, Y. H. Shim, J. H. Lee, and Y. L. Kwak, “Diabetes mellitus mitigates cardioprotective effects of remifentanil preconditioning in ischemia-reperfused rat heart in association with anti-apoptotic pathways of survival,” European Journal of Pharmacology, vol. 628, no. 1–3, pp. 132–139, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. H. N. Yadav, M. Singh, and P. L. Sharma, “Involvement of GSK-3β in attenuation of the cardioprotective effect of ischemic preconditioning in diabetic rat heart,” Molecular and Cellular Biochemistry, vol. 343, no. 1-2, pp. 75–81, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. P. Ajmani, H. N. Yadav, M. Singh, and P. L. Sharma, “Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart,” BMC Cardiovascular Disorders, vol. 11, article 43, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. L. Ji, X. Zhang, W. Liu et al., “AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury,” PLoS ONE, vol. 8, no. 7, Article ID e69910, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. V. Vinokur, E. Berenshtein, B. Bulvik, L. Grinberg, R. Eliashar, and M. Chevion, “The bitter fate of the sweet heart: impairment of iron homeostasis in diabetic heart leads to failure in myocardial protection by preconditioning,” PLoS ONE, vol. 8, no. 5, Article ID e62948, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. A. Tosaki, D. T. Engelman, R. M. Engelman, and D. K. Das, “The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts,” Cardiovascular Research, vol. 31, no. 4, pp. 526–536, 1996. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Thirunavukkarasu, S. V. Penumathsa, S. Koneru et al., “Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase,” Free Radical Biology and Medicine, vol. 43, no. 5, pp. 720–729, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. Y. Wu, Z.-Y. Xia, J. Dou et al., “Protective effect of ginsenoside Rb1 against myocardial ischemia/reperfusion injury in streptozotocin-induced diabetic rats,” Molecular Biology Reports, vol. 38, no. 7, pp. 4327–4335, 2011. View at Publisher · View at Google Scholar · View at Scopus
  86. N. K. Sharma, N. Mahadevan, and P. Balakumar, “Adenosine transport blockade restores attenuated cardioprotective effects of adenosine preconditioning in the isolated diabetic rat heart: potential crosstalk with opioid receptors,” Cardiovascular Toxicology, vol. 13, no. 1, pp. 22–32, 2013. View at Publisher · View at Google Scholar · View at Scopus
  87. X.-H. Zhu, H.-J. Yuan, Y.-N. Wu et al., “Non-invasive limb ischemic pre-conditioning reduces oxidative stress and attenuates myocardium ischemia-reperfusion injury in diabetic rats,” Free Radical Research, vol. 45, no. 2, pp. 201–210, 2011. View at Publisher · View at Google Scholar · View at Scopus
  88. J.-Y. Ren, J.-X. Song, M.-Y. Lu, and H. Chen, “Cardioprotection by ischemic postconditioning is lost in isolated perfused heart from diabetic rats: involvement of transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P,” Regulatory Peptides, vol. 169, no. 1–3, pp. 49–57, 2011. View at Publisher · View at Google Scholar · View at Scopus
  89. W. Tai, E. Shi, L. Yan, X. Jiang, H. Ma, and C. Ai, “Diabetes abolishes the cardioprotection induced by sevoflurane postconditioning in the rat heart in vivo: roles of glycogen synthase kinase-3β and its upstream pathways,” Journal of Surgical Research, vol. 178, no. 1, pp. 96–104, 2012. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Najafi, S. Farajnia, M. Mohammadi et al., “Inhibition of mitochondrial permeability transition pore restores the cardioprotection by postconditioning in diabetic hearts,” Journal of Diabetes & Metabolic Disorders, vol. 13, , article 106, 2014. View at Publisher · View at Google Scholar
  91. M. Sárközy, V. Fekete, G. Szucs et al., “Anti-diabetic effect of a preparation of vitamins, minerals and trace elements in diabetic rats: a gender difference,” BMC Endocrine Disorders, vol. 14, article 72, 2014. View at Publisher · View at Google Scholar · View at Scopus
  92. Y. Liu, J. D. Thornton, M. V. Cohen, J. M. Downey, and S. W. Schaffer, “Streptozotocin-induced non-insulin-dependent diabetes protects the heart from infarction,” Circulation, vol. 88, no. 3, pp. 1273–1278, 1993. View at Publisher · View at Google Scholar · View at Scopus
  93. E. Kravchuk, E. Grineva, A. Bairamov, M. Galagudza, and T. Vlasov, “The effect of metformin on the myocardial tolerance to ischemia-reperfusion injury in the rat model of diabetes mellitus type II,” Experimental Diabetes Research, vol. 2011, Article ID 907496, 5 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. M. M. Galagudza, M. K. Nekrasova, A. V. Syrenskii, and E. M. Nifontov, “Resistance of the myocardium to ischemia and the efficacy of ischemic preconditioning in experimental diabetes mellitus,” Neuroscience and Behavioral Physiology, vol. 37, no. 5, pp. 489–493, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. D. Ebel, J. Müllenheim, J. Fräßdorf et al., “Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo,” Pflugers Archiv European Journal of Physiology, vol. 446, no. 2, pp. 175–182, 2003. View at Publisher · View at Google Scholar · View at Scopus
  96. K. Hirose, Y. M. Tsutsumi, R. Tsutsumi et al., “Role of the o-linked β-N-acetylglucosamine in the cardioprotection induced by isoflurane,” Anesthesiology, vol. 115, no. 5, pp. 955–962, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. F. A. Babiker, J. van Golde, W. Y. Vanagt, and F. W. Prinzen, “Pacing postconditioning: impact of pacing algorithm, gender, and diabetes on its myocardial protective effects,” Journal of Cardiovascular Translational Research, vol. 5, no. 5, pp. 727–734, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. T. Hanafusa, J.-I. Miyagawa, H. Nakajima et al., “The NOD mouse,” Diabetes Research and Clinical Practice, vol. 24, pp. S307–S311, 1994. View at Publisher · View at Google Scholar · View at Scopus
  99. J.-W. Yoon and H.-S. Jun, “Viruses in type 1 diabetes: brief review,” ILAR Journal, vol. 45, no. 3, pp. 343–348, 2004. View at Publisher · View at Google Scholar · View at Scopus
  100. A. Miyazaki, T. Hanafusa, K. Yamada et al., “Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study,” Clinical and Experimental Immunology, vol. 60, no. 3, pp. 622–630, 1985. View at Google Scholar · View at Scopus
  101. J. A. Pearson, F. S. Wong, and L. Wen, “The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes,” Journal of Autoimmunity, vol. 66, pp. 76–88, 2016. View at Publisher · View at Google Scholar · View at Scopus
  102. D. P. Singal and M. A. Blajchman, “Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus,” Diabetes, vol. 22, no. 6, pp. 429–432, 1973. View at Publisher · View at Google Scholar · View at Scopus
  103. J. Nerup, P. Platz, O. O. Andersen et al., “HL-A antigens and diabetes mellitus,” The Lancet, vol. 304, no. 7885, pp. 864–866, 1974. View at Publisher · View at Google Scholar · View at Scopus
  104. J. A. Noble and H. A. Erlich, “Genetics of type 1 diabetes,” Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 1, Article ID a007732, 2012. View at Google Scholar · View at Scopus
  105. A. Jansen, F. Homo-Delarche, H. Hooijkaas, P. J. Leenen, M. Dardenne, and H. A. Drexhage, “Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and β-cell destruction in NOD mice,” Diabetes, vol. 43, no. 5, pp. 667–675, 1994. View at Publisher · View at Google Scholar · View at Scopus
  106. G. Bouma, J. M. C. Coppens, S. Mourits et al., “Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice,” European Journal of Immunology, vol. 35, no. 8, pp. 2386–2396, 2005. View at Publisher · View at Google Scholar · View at Scopus
  107. J. Diana, Y. Simoni, L. Furio et al., “Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes,” Nature Medicine, vol. 19, no. 1, pp. 65–73, 2013. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Willcox, S. J. Richardson, A. J. Bone, A. K. Foulis, and N. G. Morgan, “Analysis of islet inflammation in human type 1 diabetes,” Clinical and Experimental Immunology, vol. 155, no. 2, pp. 173–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  109. J. A. Todd and L. S. Wicker, “Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models,” Immunity, vol. 15, no. 3, pp. 387–395, 2001. View at Publisher · View at Google Scholar · View at Scopus
  110. Y. Yang and P. Santamaria, “Lessons on autoimmune diabetes from animal models,” Clinical Science, vol. 110, no. 6, pp. 627–639, 2006. View at Publisher · View at Google Scholar · View at Scopus
  111. M. von Herrath, C. Filippi, and K. Coppieters, “How viral infections enhance or prevent type 1 diabetes-from mouse to man,” Journal of Medical Virology, vol. 83, no. 9, p. 1672, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. M. von Herrath and G. T. Nepom, “Animal models of human type 1 diabetes,” Nature Immunology, vol. 10, no. 2, pp. 129–132, 2009. View at Publisher · View at Google Scholar · View at Scopus
  113. S. W. Christianson, L. D. Shultz, and E. H. Leiter, “Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice: relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors,” Diabetes, vol. 42, no. 1, pp. 44–55, 1993. View at Publisher · View at Google Scholar · View at Scopus
  114. C. E. Mathews, S. H. Langley, and E. H. Leiter, “New mouse model to study islet transplantation in insulin-dependent diabetes mellitus,” Transplantation, vol. 73, no. 8, pp. 1333–1336, 2002. View at Publisher · View at Google Scholar · View at Scopus
  115. V. R. Drel, P. Pacher, R. Stavniichuk et al., “Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice,” International Journal of Molecular Medicine, vol. 28, no. 4, pp. 629–635, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. C. Zhou, B. Pridgen, N. King, J. Xu, and J. L. Breslow, “Hyperglycemic Ins2AkitaLdlr-/- mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease,” Journal of Lipid Research, vol. 52, no. 8, pp. 1483–1493, 2011. View at Publisher · View at Google Scholar · View at Scopus
  117. H. Chen, C. Zheng, X. Zhang et al., “Apelin alleviates diabetes-associated endoplasmic reticulum stress in the pancreas of Akita mice,” Peptides, vol. 32, no. 8, pp. 1634–1639, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. N. Sonenberg and C. B. Newgard, “Protein synthesis. The perks of balancing glucose,” Science, vol. 293, no. 5531, pp. 818–819, 2001. View at Publisher · View at Google Scholar · View at Scopus
  119. M. D. Breyer, E. Böttinger, F. C. Brosius III et al., “Mouse models of diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 16, no. 1, pp. 27–45, 2005. View at Publisher · View at Google Scholar · View at Scopus
  120. S. B. Gurley, C. L. Mach, J. Stegbauer et al., “Influence of genetic background on albuminuria and kidney injury in Ins2+/C96Y(Akita) mice,” American Journal of Physiology, vol. 298, no. 3, pp. F788–F795, 2010. View at Publisher · View at Google Scholar · View at Scopus
  121. J. Wang, T. Takeuchi, S. Tanaka et al., “A mutation in the insulin 2 gene induces diabetes with severe pancreatic β-cell dysfunction in the Mody mouse,” Journal of Clinical Investigation, vol. 103, no. 1, pp. 27–37, 1999. View at Publisher · View at Google Scholar · View at Scopus
  122. L. Leroux, P. Desbois, L. Lamotte et al., “Compensatory responses in mice carrying a null mutation for Ins1 or Ins2,” Diabetes, vol. 50, supplement 1, pp. S150–S153, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. S. Oyadomari, A. Koizumi, K. Takeda et al., “Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes,” The Journal of Clinical Investigation, vol. 109, no. 4, pp. 525–532, 2002. View at Publisher · View at Google Scholar · View at Scopus
  124. N. H. Bishop, K. S. Beard, and R. G. Gill, “Resistance of spontaneously diabetic Ins2akita mice to allograft tolerance induced by anti-CD154 therapy,” Transplantation Proceedings, vol. 46, no. 6, pp. 2007–2009, 2014. View at Publisher · View at Google Scholar · View at Scopus
  125. R. E. Schmidt, K. G. Green, L. L. Snipes, and D. Feng, “Neuritic dystrophy and neuronopathy in Akita (Ins2Akita) diabetic mouse sympathetic ganglia,” Experimental Neurology, vol. 216, no. 1, pp. 207–218, 2009. View at Publisher · View at Google Scholar · View at Scopus
  126. S. B. Gurley, S. E. Clare, K. P. Snow, A. Hu, T. W. Meyer, and T. M. Coffman, “Impact of genetic background on nephropathy in diabetic mice,” American Journal of Physiology—Renal Physiology, vol. 290, no. 1, pp. F214–F222, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. M. S. Islam, “Animal models of diabetic neuropathy: progress since 1960s,” Journal of Diabetes Research, vol. 2013, Article ID 149452, 9 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  128. T. Haseyama, T. Fujita, F. Hirasawa et al., “Complications of IgA nephropathy in a non-insulin-dependent diabetes model, the Akita mouse,” Tohoku Journal of Experimental Medicine, vol. 198, no. 4, pp. 233–244, 2002. View at Publisher · View at Google Scholar · View at Scopus
  129. C. E. Alpers and K. L. Hudkins, “Mouse models of diabetic nephropathy,” Current Opinion in Nephrology and Hypertension, vol. 20, no. 3, pp. 278–284, 2011. View at Publisher · View at Google Scholar · View at Scopus