Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study.
1. Introduction
Islet transplantation is a cell replacement therapy for severe diabetes mellitus (DM), including type 1 DM, that has a long history. In 1967, Lacy and Kostianovsky established a method for isolating islets from rat pancreas using collagenase [1]. Their group also first succeeded in islet intraportal transplantation and reversed diabetes in a rat model [2]. In the clinical setting, the first successful trial of human islet allotransplantation was performed at the University of Pittsburgh in 1990, and five patients achieved an insulin-free condition after islet transplantation [3]. Shapiro and colleagues could significantly improve the outcome of islet transplantation using the “Edmonton Protocol” based on multiple transplantations with a steroid-free immunosuppressive regimen in 2000 [4]. Recent data of clinical islet transplantation revealed that 50% of the patients achieved insulin independence for 5 years [5]. This represents great progress since the rate of being insulin-free was only 10% in the late 1990s [6]. Many studies have been done to improve the success of islet transplantation and will continue to be done in the future.
Animal models of DM have contributed much to islet research and to evaluations of isolated human islets for clinical islet transplantation. Good control of blood glucose is the major goal in islet research. Assessments of drugs for improving islet function and immunosuppressants for protecting transplanted islets from the immune system are good examples of progress toward this goal. We introduce some animal models of DM in this paper, and clarify why and how the models should be used, based on our experience and publications by others.
2. Animal Models of DM for Islet Research2.1. History of Animal Models of DM
Animal experiments have a long history in the field of diabetic research, including islet research. Animal models of DM are classified as spontaneous or secondary (drug-induced, pancreatectomized, and biomolecular method). The earliest animal model of DM was a pancreatomized dog that was used to evaluate the intestine function in the 1880s, and many pancreatomized animal models (rabbit and dog) have been used for diabetic studies including the purification of insulin [7].
While the pancreatomized model was established approximately 100 years ago, drug-induced models also have a long history. Alloxan is a pyrimidine derivative that was synthesized by Wöhler in 1838 [8], and it was considered a representative drug for diabetes by inducing necrosis of the endocrine beta cells in 1940s [9, 10]. The first report of streptozotocin (STZ: N-nitroso derivative of glucosamine), a most convenient drug for inducing diabetes, was published in 1963 [11]. STZ was used as chemotherapeutic agent for cancer based on its inhibition of DNA synthesis and, like alloxan, has been used for making animal models of DM [12].
Spontaneous diabetic animal models were first described in the 1970s. A nonobese diabetic (NOD) mouse, known as a type 1 DM model, was established by Makino’s group from female mice derived from a JcI-ICR strain that developed cataracts [13]. The biobreeding (BB) rat, which was established by the Bio Breeding Laboratory and described in 1974 [14], is also an animal model of type 1 DM. Islets of these models suffered from autoimmune attack by T cells, B cells, macrophages, and natural killer cells, inducing insulitis and finally leading to islet loss [15–19]. This mechanism reflects the onset of type 1 DM, and these models have been utilized for many studies about this disease. Drug-induced diabetic models are similar to spontaneous type 1 DM models in terms of the loss of islets and deficiency of internal insulin, but the mechanism is different: the involvement of autoimmunity is a feature of the latter type.
On the other hand, there are many animal models of type 2 DM including ob/ob mice in 1949 [20], db/db mice in 1974 [21], fa/fa (Zunkar) rats in 1989 [22], Goto-Kakizaki rats in 1976 [23], and Otsuka Long-Evans Tokushima fatty (OLETF) rats in 1992 [24]. Many of them are animal models of obesity, and they contribute to clarifying the correlationship between obesity and type 2 DM. ob/ob mice and fa/fa rats have hyperinsulinemia with insulin resistance when they gain weight [7], reflecting the condition of obesity in human. Recently, it was clarified that a deficiency of or resistance to leptin, a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, caused the development of obesity in ob/ob mice (this is a model of ob gene deficient) [25], fa/fa rats, and db/db mice (which are leptin-resistant models due to a mutation of the leptin receptor) [26, 27].
Transgenic animal models have been used in diabetic research since the 1990s, and such models have revealed the roles of many genes that are related to DM including type 1 and 2 DM. Insulin receptor gene knockout mice have severe hyperglycemia and neonatal death by ketoacidosis [28]. Moreover, insulin receptor substrate (IRS), which is known to be an important ligand in the insulin response, has a different function according to the type of animal. For example, IRS1 gene knockout mice have mild insulin resistance with normoglycemia [29], while IRS2 gene knockout mice suffer from severe hyperglycemia with insulin resistance and reduction of the β cell mass [30, 31]. These findings make understandable the fact that some type 2 DM patients have normoglycemia or mild hyperglycemia, while others have severe hyperglycemia.
Many animal models of DM have been developed and are chosen depending on the purpose of the study (Table 1). In islet transplantation research, STZ-induced diabetic animals are mainly used, while spontaneous and pancreatomized models are also available.
Animal models of DM.
Characters
Name
Species
Type 1 DM
Spontaneous model
NOD
Mouse
BB
Rat
Type 2 DM
ob/ob
Mouse
db/db
Mouse
Obesity model
fa/fa
Rat
Goto Kakizaki
Rat
OLETF
Rat
Type 1 and 2 DM
Drug-induced model
Alloxan
*
STZ
*
Pancreatic DM
Pancreatomized model
Pancreatectomy
**
Others
Insulin knockout
Mouse
Transgenic animal model
IRS1 knockout
Mouse
IRS2 knockout
Mouse
*All experimental animals are available.
**All experimental animals are available but larger animals tend to be used.
2.2. STZ-Induced Diabetic Model for Islet Transplantation2.2.1. Background
STZ, a white powder with a molecular weight of 265.221 g/moL, is a glucosamine-nitrosourea compound. STZ causes toxicity to cells by impairing DNA and by other mechanisms. One is the activation of poly-ADP ribosylation, which is likely more important for the induction of DM than the DNA damage [32]. STZ is similar to glucose insofar as it is transported into β cells by the glucose transport protein GLUT2, but is not recognized by the other glucose transporters. Thus, β cells have relatively high levels of GLUT2 [33, 34]. This explains the specific toxicity of STZ for β cells. In the early 1970s, Lacy and his collaborators first performed experimental islet transplantation to rats with STZ-induced DM [35, 36]. STZ was applied not only to rats but also many other kinds of mammals including mouse [37], monkey [38], and dog [39]. Since then, STZ-induced diabetic models have been available for islet research.
2.2.2. Dose and Method of Inducing DM
The dose of STZ is varied according to the animal species and strain (Table 2) [40–87]. For example, mice required higher doses of STZ for inducing DM compared with other animals. While in ICR mice DM can be induced with comparatively lower doses (90–150 mg/kg), C57BL/6 mice need approximately 200 mg/kg dose of STZ [40, 42–48]. Immunodeficient mice tend to need less dose of STZ than other wild-type strains. For example, NOD-SCID mice are induced DM with 120–140 mg/kg dose of STZ [88–90]. STZ injection is done with two methods: a single injection and low dose multiple injection. Continuous low dose injection has been used in many studies, especially these employing rodents [49–57]. The merit of single injection is its convenience (only 1 injection), but the diabetic model induced by this method is unstable in terms of the diabetic condition, and sudden death is caused in approximately 10%–20% of the animals due to the elevation of blood glucose and the toxicity of STZ. On the other hand, the low dose multiple injection method can achieve hyperglycemia with no or few dead cases [91]. It is considered that the low dose multiple injection model is superior to single injection model in terms of safety. Intraperitoneal (i.p.) injection tends to be employed for rodents while intravenous (i.v.) injection used for larger animals, because i.p. is easier than i.v. in rodents while i.v. has the merit of direct injection of STZ without loss of STZ in comparison with i.p. Therefore i.v. injection can induce diabetes at a lower dose of i.p. because more time is required to absorb STZ with i.p., and some of the STZ is inactivated before absorption. The dose of STZ for i.v. is approximately 90% of that for i.p. in previous publications (Table 1). Citrate buffer at pH 4.5 has been used as a solvent in many studies because STZ remains stable at low pH (Table 2), but there is no problem with using normal saline if STZ is used immediately after dissolving.
Dose of STZ.
Animal species
Animal strains
Dose of STZ (mg/kg body weight)
Time of injection
Solvent
Method of injection
References
ICR
90–150
1
Citrate buffer, pH 4.5
i.p
[40, 43, 45, 48]
70
3
Citrate buffer, pH 4.5
i.p
[58]
130–225
1
Citrate buffer, pH 4.5
i.p
[42, 44, 46, 47]
Mice
C57BL/6
75–100
3
i.v
[59, 60]
40–65
5
Citrate buffer, pH 4.5
i.p
[49–54]
BALB/c
150
1
Citrate buffer, pH 4.5
i.p
[61]
50
5
i.p
[62]
60–85
1
Citrate buffer, pH 4.5
i.p
[60, 63–65]
Sprague-Dawley
55–60
1
i.v
[66, 67]
50
6
Citrate buffer, pH 4.5
i.v
[68]
Rat
50–70
1
Citrate buffer, pH 4.5 or Normal saline
i.p
[69–74]
Wistar
40
5
Citrate buffer, pH 4.5
i.p
[75]
50–65
1
Citrate buffer, pH 4.5
i.v
[55–57]
Dog
Beagle
30–50
1
i.v
[76–78]
Velvet Monkey
Chlorocebus aethiops
45–55
1
Normal saline
i.v
[79, 80]
Cynomolgus Monkey
Macaca fascicularis
68–150
1
Citrate buffer, pH 4.5
i.v
[41, 81, 82]
Yucatan
125
1
i.v
[83]
Yorkshire
50
1
Citrate buffer, pH 4.5
i.v
[84]
Pig
Landrace
125
1
i.v
[85]
Dutch Landrace X Yorkshire X Finnish Landrace
120
1
i.v
[86]
domestic
90
1
Normal saline
i.v
[87]
2.2.3. Our Method of DM Induction Using STZ and Discussion of STZ-Induced DM Model for Islet Transplantation
STZ (Sigma-Aldrich Co. LLC., St. Louis, MO, USA) must be stored in a freezer (under −20°C condition) because of its instability. To prevent inactivation, we divide 20 mg of STZ into 1.5 mL centrifuge tubes before using. Some of the divided STZ (3-4 mice per tube), 1 mL syringe with 29-gauge needle, an ice box with crushed ice, the solvent (citrate buffer solution, 0.09 M, pH4.8 (Sigma-Aldrich) or normal saline), and 18-gauge needles are prepared for the treatment (Figure 1(a)). The STZ tubes should be placed on ice until dissolution. At first, the mice are marked on the tail and measured for body weight, and then the final volume of STZ solution is decided. We induce DM with STZ at 200 mg/kg body weight. 20 mg of STZ is dissolved with 1 mL of solvent (the concentration is 20 mg/mL). We crushed the larger clusters of STZ with a 18-gauge needle and then dissolved it by shaking gently (Figures 1(b)–1(e)). To induce DM for a mouse with 20 g of body weight, for example, 200 μL of STZ solution is necessary. STZ solution should be used as soon as possible after dissolving, because the diabetogenic activity of STZ is decreased in the solvent [92]. Injection should be done within 10 minutes after the dissolution. In the case of i.p., the STZ solution is injected via the lower abdomen with care taken to prevent organ injury (Figure 1(f)). In the case of i.v., STZ solution is injected via a tail vein. Tail veins are located at the dorsal and left and right sides of the tail. After dilating the tail vein by warming, the 29-gauge needle is inserted in the upper 1/2~1/3 of the tail and the STZ solution is injected slowly (Figures 2(a) and 2(b)). After finishing the injection, the needle is removed while pressing part of the puncture with thumb to prevent leakage of the STZ solution (Figure 2(c)). After the injection of STZ, we check blood glucose every day, and mice with over 350 mg/dL of blood glucose at two consecutive measurements are considered DM mice suitable for islet transplantation. Our data revealed that the effect of 160 mg/kg of STZ injection via i.v. was equal to that of 200 mg/kg of STZ injection via i.p. in blood glucose level (Figure 3). The rates of achieving hyperglycemia (over 350 mg/dL) in BALB/c mice were 58.8% (33.3%–70%, n=36) by i.p. method and 81.8% (80%–83.3%, n=22) by i.v. method. In our opinion, diabetic models for islet transplantation studies should have severe hyperglycemia because mice with mild hyperglycemia (under 300 mg/dL) can show normoglycemia depending on the measurement time, and it can be difficult to determine whether the normoglycemia is due to the original pancreatic endocrine function of the recipient mice or due to the islet transplantation. Fasting is not necessary, but the measurements for blood glucose should be done at the same time to prevent the influence of ingestion. We measure the blood glucose from 6 to 10 AM. The afternoon is excluded because the blood glucose in the afternoon tends to be higher than in the morning. We defined normoglycemia as under 200 mg/dL blood glucose because it is the upper range of blood glucose in normal (untreated) mice.
STZ injection via intraperitoneum. (a) Preparation. 1.5 mL centrifuge tube with STZ, 29-gauge needle, 1 mL syringe, ice box with crushed ice, citrate buffer solution, and an 18-gauge needle are used. (b)–(e) Dissolving STZ. (b) Citrate buffer solution is poured into STZ. (c) Crushing the larger clusters of STZ with an 18-gauge needle. (d) and (e) Dissolving by shaking gently. (f) STZ solution is injected via the lower abdomen with care not to injure organs.
STZ intravenous injection. (a) Dilating tail vein by warming (using light in this case). (b) Injecting solution via the tail vein. A 29-gauge needle is inserted at the upper 1/2~1/3 of the tail. STZ solution is injected slowly. (c) After finishing injection, the needle is removed while pressing a part of puncture with the thumb to prevent leakage of the STZ solution.
Blood glucose levels after STZ injection in BALB/c mice. The effect of 160 mg/kg of STZ injection via i.v. was equally to that of 200 mg/kg of STZ injection via i.p. in blood glucose level.
2.3. Pancreatomized Diabetic Model for Islet Transplantation
Pancreatomized animals are one of the oldest models for DM. This model was considered to be and used as a type 1 DM model because of the elimination of the pancreatic β cells. The difference between this model and type 1 DM is the stability of the blood glucose: the type 1 DM model has a deficiency of insulin release but preservation of other hormonal functions that act to increase the blood glucose (i.e., glucagon). Pancreatomized diabetic animals have been used as islet autotransplantation models. Minnesota group performed pancreatectomy and islet autotransplantation in pigs in 1976 [93]. This group also performed islet autotransplantation of pancreatomized dogs and succeeded in achieving normoglycemia at the same time [39]. After their success, many experimental models of total pancreatectomy with islet autotransplantation using dogs were published in the 1970s and proved the effectiveness of the treatment [94–96]. These findings contributed to clinical trials of total pancreatectomy with islet autotransplantation for chronic pancreatitis [97]. Large pancreatomized animal models have also been used for the evaluation of cryopreserved islets [98–101] and optimal transplant sites [102–107]. Large pancreatomized diabetic animal models have been used not only for islet autotransplantation studies but also for allotransplant studies. Many groups examined the usefulness of immunosuppressants including cyclosporine using islet allotransplanted dog [108–110] and pig models [111]. Pancreatomized diabetic large animals were also used for studies about bioartificial pancreas (i.e., islet encapsulation technology using high molecular compound to prevent from immune attack) in allo- and xenotransplantation [112–118]. Large pancreatomized animal models for islet transplantation, including pig, dog, and monkey, are considered preclinical models and tend to be selected for evaluating some treatments in the clinical setting.
One of the recent uses of pancreatomized models is to assess β cell regeneration after pancreatectomy. Pancreatectomy over 70% induces some pancreatic regeneration-related factors like pancreatic and duodenal homeobox 1 (PDX1) and neurogenin-3 (Ngn3), which contribute to the regeneration of β cells in rodent models [119–121]. Recently, Jung and colleagues revealed that the regeneration of β cells could be detected in the remnant pancreas of BALB/c mice with 70% pancreatectomy, and the effect of regeneration was more prominent in pancreatomized mice with islet autotransplantation [122]. It is interesting that islet masses in remnant pancreas were increased with greater expression of Ngn3 and BrdU (a proliferation marker) and lower expression of TUNEL (an apoptosis marker) in pancreatomized mice with islet autotransplantation compared to pancreatomized mice without transplantation. They concluded that insulin released from transplanted islets has a role in the induction of islet proliferation and antiapoptotic effects on remnant islets. Pancreatomized animal is an old diabetic model, but is still important and useful for preclinical trials on islets transplantation and for understanding the mechanism of DM, including islet regeneration.
2.4. Spontaneous Type 1 Diabetic Models for Islet Transplantation
Spontaneous type 1 diabetic animals are useful models to understand the mechanism of type 1 DM because this model has autoimmunity, which causes islet injury like that found in type 1 DM patients. In general, it is difficult to study this disease in human and also difficult to analyze the findings in patients who received islet transplantation because of ethical considerations [123]. This is also a reliable model for analyzing the induction of transplantation tolerance [124] and the special problems of tolerance induction by autoimmunity [125]. The represented spontaneous diabetic models are BB rat and NOD mouse.
The mechanism of inducing DM in NOD mice is insulitis, which is inducted at 4 to 5 weeks after birth, and results in approximately 90% of females and 60% of males developing DM when they are 7 months old [123]. The autoimmunity of NOD mice is characterized by many abnormalities in the immune system including defects in regulatory T cells, which also appears in human in type 1 DM [123]. Regulatory T cells have a role of maintaining immune tolerance. Thus, it is considered that a defect in regulatory T cells causes them to be resistant to tolerance in islet transplantation [126]. As a model of type 1 DM, NOD mice have been used for the assessments of many immunosuppressants.
The first successful regime of immunosuppressants for islet transplantation was a combination of an anti-interleukin (IL)-2 monoclonal antibody daclizumab for the induction, the calcineurin inhibitor tacrolimus, and the mammalian target of rapamycin (mTOR) inhibitor sirolimus for the maintenance referred to as the Edmonton protocol in 2000 [4]. The utility of the regime was proved by the Miami group with an animal study using NOD mice [127]. This group performed islet allotransplantation using diabetic NOD mice and confirmed that a combination of tacrolimus and sirolimus could prolong the graft survival (over 100 days in 28.6% of recipient mice) and a combination of the three agents could achieve even better graft survival (over 100 days in 75%). The Minnesota group examined the effectiveness of antithymocyte globulin (ATG) and the antitumor necrosis factor (TNF)-α receptor inhibitor etanercept for the induction as a novel regime for single donor transplantation and achieved 62.5% insulin-free in 1 year after transplantation [128]. Recently, they assessed a novel immunosuppressant regime using FcR nonbinding anti-CD3 antibody or T cell-depleting antibodies and a TNF-α inhibitor by comparing the recipients enrolled in the Collaborative Islet Transplant Registry and revealed that the combination could result in an insulin-free rate of 5 years (approximately 50%) [129]. These novel immunosuppressants were also evaluated using NOD mice by many groups. Vergani and colleagues compared between treatment of ATG and cytotoxic T-lymphocyte antigen 4 and antibodies (CTLA4-Ig) and no immunosuppressants in the transplantation of BALB/c mice islets to NOD mice and revealed prolonged graft survival [130]. Anti-CD 3 monoclonal antibody has been shown to be effective in suppressing autoimmunity. Baeke and colleagues revealed that a combination of anti-CD3 monoclonal antibody, ciclosporin A, and vitamin D prolonged the graft survival in islet allotransplanted diabetic NOD mice by reducing CD4+ T cells and increasing FOXP3+CD4+ regulatory T cells [131]. Additionally, Mamchak and colleagues proved that anti-CD3 monoclonal antibody treatment with oral insulin intake improved the blood glucose level of diabetic NOD mice by increasing regulatory T cells and decreasing CD4+CD25+ T cells, indicating a suppression of autoimmunity [132].
To succeed in clinical islet transplantation, it is necessary to control both allo- and autoimmunity. NOD mice are suitable for evaluating the influences of both types of immunity in islet transplantation.
3. Conclusion
In summary, many diabetic animal models have been used for assessing the effects of therapeutic interventions on the outcome of islet transplantation. All the animals that we mentioned were models with a deficiency in islet function, but the mechanisms by which they induce DM are significantly different, and, thus, it is important to select the model according to the aim of the study.
Conflict of Interests
Conflict of interests does not exist in any companies.
Acknowledgment
The authors thank Professor Masafumi Goto and his collaborators for technical support in inducing DM with intravenous injection of STZ. This study is supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports Science and Technology of Japan (B: 22390253 S. Egawa), Challenging Exploratory Research: 24659582 and C: 22591513 (N. Sakata), the Takeda Science Foundation, the Gonryo Medical Foundation, the Suzuken Memorial Foundation (N. Sakata), and Network Medicine Global-COE Program from the Ministry of Education, Culture, Sports Science and Technology of Japan (M. Unno).
LacyP. E.KostianovskyM.Method for the isolation of intact islets of Langerhans from the rat pancreas196716135392-s2.0-0014042613KempC. B.KnightM. J.ScharpD. W.LacyP. E.BallingerW. F.Transplantation of isolated pancreatic islets into the portal vein of diabetic rats197324454164472-s2.0-0015804157TzakisA. G.RicordiC.AlejandroR.ZengY.FungJ. J.TodoS.DemetrisA. J.MintzD. H.StarzlT. E.Pancreatic islet transplantation after upper abdominal exenteration and liver replacement199033687124024052-s2.0-0025076398ShapiroA. M. J.LakeyJ. R. T.RyanE. A.KorbuttG. S.TothE.WarnockG. L.KnetemanN. M.RajotteR. V.Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen200034342302382-s2.0-003472125510.1056/NEJM200007273430401McCallM.James ShapiroA. M.Update on islet transplantation20122a007823BrendelM. H. B.SchulzA.BretzelR.1999Giessen, GermanyUniversity of GiessenReesD. A.AlcoladoJ. C.Animal models of diabetes mellitus20052243593702-s2.0-1714440420310.1111/j.1464-5491.2005.01499.xWöhlerF. L. J.Untersuchungen über die Natur der Harnsäure183826241340DunnJ. S.McletchieN. G. B.Experimental alloxan diabetes in the rat194324262653843872-s2.0-50349108317DunnJ. S. S. H.McLetchieN. G. B.Necrosis of islets of Langerhans produced experimentally1943244484487RakietenN.RakietenM. L.NadkarniM. V.Studies on the diabetogenic action of streptozotocin (NSC-37917)19632991982-s2.0-73649197648LenzenS.The mechanisms of alloxan- and streptozotocin-induced diabetes20085122162262-s2.0-3754902924210.1007/s00125-007-0886-7MakinoS.KunimotoK.MuraokaY.Breeding of a non-obese, diabetic strain of mice19802911132-s2.0-0018841766NakhoodaA. F.LikeA. A.ChappelC. I.MurrayF. T.MarlissE. B.The spontaneously diabetic Wistar rat. Metabolic and morphologic studies19772621001122-s2.0-0017353944BoneA. J.HitchcockP. R.GwilliamD. J.CunninghamJ. M.BarleyJ.Insulitis and mechanisms of disease resistance: studies in an animal model of insulin dependent diabetes mellitus199977157612-s2.0-0033047574YoonJ. W.JunH. S.SantamariaP.Cellular and molecular mechanisms for the initiation and progression of β cell destruction resulting from the collaboration between macrophages and T cells19982721091222-s2.0-0031968921RabinovitchA.Suarez-PinzonW.El-SheikhA.SorensenO.PowerR. F.Cytokine gene expression in pancreatic islet-infiltrating leukocytes of BB rats: expression of Th1 cytokines correlates with β-cell destructive insulitis and IDDM19964567497542-s2.0-0029922661LohrM.MarkholstH.DyrbergT.KloppelG.OberholzerM.LernmarkA.Insulitis and diabetes are preceded by a decrease in β cell volume in diabetes-prone BB rats198941951002-s2.0-0024354052LallyF. J.RatcliffH.BoneA. J.Apoptosis and disease progression in the spontaneously diabetic BB/S rat20014433203242-s2.0-003507982310.1007/s001250051621IngallsA. M.DickieM. M.SnellG. D.Obese, a new mutation in the house mouse195041123173182-s2.0-0000736325BoquistL.HellmanB.LernmarkA.TaljedalI. B.Influence of the mutation “diabetes” on insulin release and islet morphology in mice of different genetic backgrounds197462177892-s2.0-0016204314KurtzT. W.MorrisR. C.PershadsinghH. A.The Zucker fatty rat as a genetic model of obesity and hypertension19891368969012-s2.0-0024405776GotoY.KakizakiM.MasakiN.Production of spontaneous diabetic rats by repetition of selective breeding1976119185902-s2.0-0017066391KawanoK.HirashimaT.MoriS.SaitohY.KurosumiM.NatoriT.Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain19924111142214282-s2.0-0026722931ZhangY.ProencaR.MaffeiM.BaroneM.LeopoldL.FriedmanJ. M.Positional cloning of the mouse obese gene and its human homologue199437265054254322-s2.0-002813908910.1038/372425a0LeeG. H.ProencaR.MontezJ. M.CarrollK. M.DarvishzadehJ. G.LeeJ. I.FriedmanJ. M.Abnormal splicing of the leptin receptor in diabetic mice199637965666326352-s2.0-003003927210.1038/379632a0PhillipsM. S.LiuQ.HammondH. A.DuganV.HeyP. J.CaskeyC. J.HessJ. F.Leptin receptor missense mutation in the fatty Zucker rat199613118192-s2.0-0030137757JoshiR. L.LamotheB.CordonnierN.MesbahK.MonthiouxE.JamiJ.BucchiniD.Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality1996157154215472-s2.0-0029879127TamemotoH.KadowakiT.TobeK.YagiT.SakuraH.HayakawaT.TerauchiY.UekiK.KaburagiY.SatohS.SekiharaH.YoshiokaS.HorikoshiH.FurutaY.IkawaY.KasugaM.YazakiY.AizawaS.Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1199437265021821862-s2.0-002803289410.1038/372182a0WithersD. J.GutierrezJ. S.ToweryH.BurksD. J.RenJ. M.PrevisS.ZhangY.BernalD.PonsS.ShulmanG. I.Bonner-WeirS.WhiteM. F.Disruption of IRS-2 causes type 2 diabetes in mice199839166709009042-s2.0-003256793710.1038/36116KubotaN.TobeK.TerauchiY.EtoK.YamauchiT.SuzukiR.TsubamotoY.KomedaK.NakanoR.MikiH.SatohS.SekiharaH.SciacchitanoS.LesniakM.AizawaS.NagaiR.KimuraS.AkanumaY.TaylorS. I.KadowakiT.Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia20004911188018892-s2.0-0033755408SzkudelskiT.The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas20015065375462-s2.0-0035691617WangZ.GleichmannH.GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice199847150562-s2.0-0031963919SchnedlW. J.FerberS.JohnsonJ. H.NewgardC. B.STZ transport and cytotoxicity: specific enhancement in GLUT2-expressing cells19944311132613332-s2.0-0028604486BallingerW. F.LacyP. E.Transplantation of intact pancreatic islets in rats19727221751862-s2.0-0015386234BallingerW. F.LacyP. E.ScharpD. W.KempC. B.KnightM.Isografts and allografts of pancreatic islets in rats19736043132-s2.0-0015609254KrampR. C.CongdonC. C.SmithL. H.Isogeneic or allogeneic transplantation of duct ligated pancreas in streptozotocin diabetic mice1975532492582-s2.0-0016715314ScharpD. W.MurphyJ. J.NewtonW. T.BallingerW. F.LacyP. E.Transplantation of islets of Langerhans in diabetic rhesus monkeys19757711001052-s2.0-0016668114MatasA. J.SutherlandD. E. R.SteffesM. W.NajarianJ. S.Short term culture of adult pancreatic fragments for purification and transplantation of islets of Langerhans19768021831912-s2.0-0017185740TaharaA.KurosakiE.YokonoM.Antidiabetic effects of SGLT2-selective inhibitor Ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice20121203644LiuC.KoeberleinB.FeldmanM. D.Accumulation of intrahepatic islet amyloid in a nonhuman primate transplant model201215316731683YangB.LiM.ShiZ. G.FengQ. Z.Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice2012128621627KimH. K.Ecklonia cava inhibits glucose absorption and stimulates insulin secretion in streptozotocin-induced diabetic mice20122012743929410.1155/2012/439294ZhangY.BoneR. N.CuiW.Regeneration of pancreatic non-beta endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin20127e36675KimM. J.KimH. K.Insulinotrophic and hypolipidemic effects of Ecklonia cava in streptozotocin-induced diabetic mice20125374379WangC. D.TengB. S.HeY. M.Effect of a novel proteoglycan PTP1B inhibitor from Ganoderma lucidum on the amelioration of hyperglycaemia and dyslipidaemia in db/db mice201210820142025WangT.FuF.HanB.ZhangL.ZhangX.Danshensu ameliorates the cognitive decline in streptozotocin-induced diabetic mice by attenuating advanced glycation end product-mediated neuroinflammation20122457986Matsuyama-YokonoA.TaharaA.NakanoR.SomeyaY.NagaseI.HayakawaM.ShibasakiM.ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity2008761981072-s2.0-4504908696810.1016/j.bcp.2008.03.021LiuY.QuY.WangR.The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury2012303E841E852TieL.AnY.HanJ.Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes2013248896LoefflerI.LiebischM.WolfG.Collagen VIII influences epithelial phenotypic changes in experimental diabetic nephropathy2012303F733F745OuH. Y.WuH. T.HungH. C.YangY. C.WuJ. S.ChangC. J.Endoplasmic reticulum stress induces the expression of fetuin-A to develop insulin resistance201215329742984TieL.YangH. Q.AnY.Ganoderma lucidum polysaccharide accelerates refractory wound healing by inhibition of mitochondrial oxidative stress in type 1 diabetes201229583594ZhuW.LiW.SilversteinR. L.Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36201211961366144ChengY. Z.ChenL. J.LeeW. J.ChenM. F.Jung LinH.ChengJ. T.Increase of myocardial performance by Rhodiola-ethanol extract in diabetic rats2012144234239ZhongX.WangL.WangY.Exogenous hydrogen sulfide attenuates diabetic myocardial injury through cardiac mitochondrial protection20123711-2187198ChengM. F.ChenL. J.ChengJ. T.Decrease of Klotho in the kidney of streptozotocin-induced diabetic rats2010201072-s2.0-7795536205110.1155/2010/513853513853OchmanA. R.LipinskiC. A.HandlerJ. A.ReaumeA. G.SaporitoM. S.The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes20123422332LeeY.BerglundE. D.WangM. Y.Metabolic manifestations of insulin deficiency do not occur without glucagon action20121091497214976BlaesN.PecherC.MehrenbergerM.Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor2012303F293F303UlugolA.OltuluC.GunduzO.5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice2012102344348LiY. Y.LiuH. H.ChenH. L.LiY. P.Adipose-derived mesenchymal stem cells ameliorate STZ-induced pancreas damage in type 1 diabetes20122297103VermaA. K.SinghH.SatyanarayanaM.Flavone-based novel antidiabetic and antidyslipidemic agents20125545514567TirganN.KulpG. A.GuptaP.Nicotine exposure exacerbates development of cataracts in a type 1 diabetic rat model20122012734932010.1155/2012/349320TalbotS.De Brito GariepyH.Saint-DenisJ.CoutureR.Activation of kinin B1 receptor evokes hyperthermia through a vagal sensory mechanism in the rat20129, article 214PihlL.PerssonP.FaschingA.HansellP.DiBonaG. F.PalmF.Insulin induces the correlation between renal blood flow and glomerular filtration rate in diabetes: implications for mechanisms causing hyperfiltration20123033947ZhangR.ThorD.HanX.AndersonL.RahimianR.Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: a shift in the relative importance of EDRFs20123031011831198Delli PizziS.MadonnaR.CauloM.RomaniG. L.De CaterinaR.TartaroA.MR angiography, MR imaging and proton MR spectroscopy in-vivo assessment of skeletal muscle ischemia in Diabetic rats20127e44752PeresG. B.JulianoM. A.SimoesM. J.MichelacciY. M.Lysosomal enzymes are decreased in the kidney of diabetic rats201318328595PremalathaR.JubendradassR.RaniS. J.SrikumarK.MathurP. P.A phytooxysterol, 28-homobrassinolide modulates rat testicular steroidogenesis in normal and Diabetic ratsReproductive Sciences. In pressKhaliqF.ParveenA.SinghS.HussainM. E.FahimM.Terminalia arjuna improves cardiovascular autonomic neuropathy in streptozotocin-induced Diabetic ratsCardiovascular Toxicology. In pressLiuW.ZhangY.LiuS.The expression of intermediate filament protein nestin and its association with cyclin-dependent kinase 5 in the glomeruli of rats with diabetic nephropathyThe American Journal of the Medical Sciences. In pressSalumE.KampusP.ZilmerM.Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes201211, article 58YoshikumiY.OhnoH.SuzukiJ.IsshikiM.MorishitaY.OhnishiH.YasudaH.OmataM.FujitaT.MashimaH.Up-regulation of JAM-1 in AR42J cells treated with activin A and betacellulin and the diabetic regenerating islets20085547577652-s2.0-5144910607510.1507/endocrj.K08E-017ArambasicJ.MihailovicM.UskokovicA.Alpha-lipoic acid upregulates antioxidant enzyme gene expression and enzymatic activity in diabetic rat kidneys through an O-GlcNAc-dependent mechanismEuropean Journal of Nutrition. In pressAlkharfyK. M.Influence of overt diabetes mellitus on cyclosporine pharmacokinetics in a canine model20092009610.1155/2009/3637873637872-s2.0-73949100114MatsuoS.HayashiS.WatanabeT.AdachiK.MiyoshiA.KatoA.SuzukiM.Emphysematous cystitis in a chemically-induced diabetic dog20092242892922-s2.0-7574912098910.1293/tox.22.289ZhuS.LuY.ZhuJ.XuJ.HuangH.ZhuM.ChenY.ZhouY.FanX.WangZ.Effects of intrahepatic bone-derived mesenchymal stem cells autotransplantation on the diabetic Beagle dogs201116822132232-s2.0-7995583804910.1016/j.jss.2009.10.008KavanaghK.FlynnD. M.NelsonC.ZhangL.WagnerJ. D.Characterization and validation of a streptozotocin-induced diabetes model in the vervet monkey20116332963032-s2.0-7995460346710.1016/j.vascn.2011.02.003SaishoY.ManessoE.ButlerA. E.GalassoR.KavanaghK.FlynnM.ZhangL.ClarkP.GurloT.ToffoloG. M.CobelliC.WagnerJ. D.ButlerP. C.Ongoing β-cell turnover in adult nonhuman primates is not adaptively increased in streptozotocin-induced diabetes20116038488562-s2.0-7995236983610.2337/db09-1368ZouC.WangS.HuangF.ZhangY. A.Advanced glycation end products and ultrastructural changes in corneas of long-term streptozotocin-induced diabetic monkeys20123114551459ZouC.WangJ.WangS.Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin201255210218SheehyA.HsuS.BouchardA.Comparative vascular responses three months after paclitaxel and everolimus-eluting stent implantation in streptozotocin-induced diabetic porcine coronary arteries201211, article 75JuranekJ. K.AleshinA.RattiganE. M.Morphological changes and immunohistochemical expression of RAGE and its ligands in the sciatic nerve of hyperglycemic pig (sus scrofa)201020104759JamiesonR. W.ZilvettiM.RoyD.HughesD.MorovatA.CoussiosC. C.FriendP. J.Hepatic steatosis and normothermic perfusion-preliminary experiments in a porcine model20119232892952-s2.0-7996106206810.1097/TP.0b013e318223d817KoopmansS. J.VandermeulenJ.WijdenesJ.CorbijnH.DekkerR.The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs2011121, article 252-s2.0-7995619043810.1186/1471-2091-12-25von WilmowskyC.StockmannP.HarschI.AmannK.MetzlerP.LutzR.MoestT.NeukamF. W.SchlegelK. A.Diabetes mellitus negatively affects peri-implant bone formation in the diabetic domestic pig20113887717792-s2.0-7996037241710.1111/j.1600-051X.2011.01746.xBangaA.AkinciE.GrederL. V.DuttonJ. R.SlackJ. M.In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts20121091533615341BoseB.ShenoyP. S.KondaS.WangikarP.Human embryonic stem cell differentiation into insulin secreting beta-cells for diabetes20123610131020HanJ.McLaneB.KimE. H.YoonJ. W.JunH. S.Remission of diabetes by insulin gene therapy using a hepatocyte-specific and glucose-responsive synthetic promoter20111934704782-s2.0-7995218340910.1038/mt.2010.255Ventura-SobrevillaJ.Boone-VillaV. D.AguilarC. N.Effect of varying dose and administration of streptozotocin on blood sugar in male CD1 mice20115459AxlerD. A.Stability of the diabetogenic activity of streptozotocin19821021571582-s2.0-0020048107LampeE. W.SutherlandD. E.NajariamH. S.Autotransplantation of porcine islets of langerhans Langerhans19767921381432-s2.0-0017261333KolbE.RuckertR.LargiaderF.Intraportal and intrasplenic autotransplantation of pancreatic islets in the dog1977964194262-s2.0-0017566843KretschmerG. J.SutherlandD. E. R.MatasA. J.CainT. L.NajarianJ. S.Autotransplantation of pancreatic islets without separation of exocrine and endocrine tissue in totally pancreatectomized dogs197782174812-s2.0-0017684365KretschmerG. J.SutherlandD. E. R.MatasA. J.SteffesM. W.NajarianJ. S.The dispersed pancreas: transplantation without islet purification in totally pancreatectomized dogs19771354955022-s2.0-0017655001NajarianJ. S.SutherlandD. E. R.BaumgartnerD.Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis198019245265422-s2.0-0019214009AldersonD.WalshT. N.FarndonJ. R.Islet cell transplantation in diabetic dogs: studies of graft function and storage198471107567602-s2.0-0021178329KnetemanN. M.RajotteR. V.WarnockG. L.Long-term normoglycemia in pancreatectomized dogs transplanted with frozen/thawed pancreatic islets19862332142212-s2.0-0022725665WalshT. N.FitzpatrickJ. M.AldersonD.AlbertiK. G. M. M.FarndonJ. R.Diurnal insulin and glucose profiles following transplantation of fresh and cryopreserved canine pancreatic islets19897612128712902-s2.0-002478979010.1002/bjs.1800761221EvansM. G.WarnockG. L.KnetemanN. M.RajotteR. V.Reversal of diabetes in dogs by transplantation of pure cryopreserved islets19905022022062-s2.0-0025078535LevyM. M.KetchumR. J.TomaszewskiJ. E.NajiA.BarkerC. F.BraymanK. L.Intrathymic islet transplantation in the canine: I. Histological and functional evidence of autologous intrathymic islet engraftment and survival in pancreatectomized recipients20027368428522-s2.0-0037181408ChristofferssonG.HenriksnäsJ.JohanssonL.RolnyC.AhlströmH.Caballero-CorbalanJ.SegersvärdR.PermertJ.KorsgrenO.CarlssonP. O.PhillipsonM.Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets20105910256925782-s2.0-7795759067610.2337/db10-0205MadureiraM. L. C.Adult pancreatic tissue fate after pancreatic fragment autotransplantation into the spleen of the pancreatectomized dog19941822592652-s2.0-0028327096AoZ.MatayoshiK.LakeyJ. R. T.RajotteR. V.WarnockG. L.Survival and function of purified islets in the omental pouch site of outbred dogs19935635245292-s2.0-0027522205MotojimaK.KoharaN.MaedaJ.YamaguchiM.KanematsuT.A comparison of endocrine and exocrine function after pancreatic fragment autotransplantation into splenic pulp, portal vein, and hepatic parenchyma19925335275322-s2.0-0026563715RajabA.BussJ.DiakoffE.HadleyG. A.OseiK.FergusonR. M.Comparison of the portal vein and kidney subcapsule as sites for primate islet autotransplantation2008179101510232-s2.0-6254908434810.3727/096368908786991533KnetemanN. M.AldersonD.ScharpD. W.Long-term normoglycemia in pancreatectomized dogs following pancreatic islet allotransplantation and cyclosporine immunosuppression19874455955992-s2.0-0023493483KoyamaI.WilliamsM.CameronJ. L.ZuidemaG. D.Experimental pancreatic allotransplantation in large animals. The role of donor kidney and cyclosporine in modifying rejection19864243333362-s2.0-0022980178AlejandroR.CutfieldR.ShienvoldF. L.LatifZ.MintzD. H.Successful long-term survival of pancreatic islet allografts in spontaneous or pancreatectomy-induced diabetes in dogs. Cyclosporine-induced immune unresponsiveness19853488258282-s2.0-0021835888KumagaiN.LaMattinaJ. C.KamanoC.VagefiP. A.BarthR. N.O'NeilJ. J.YamamotoS.MoranS. G.UtsugiR.SachsD. H.YamadaK.Vascularized islet cell transplantation in miniature swine: islet-kidney allografts correct the diabetic hyperglycemia induced by total pancreatectomy20025111322032282-s2.0-0036829044KinT.IwataH.AomatsuY.OhyamaT.KanehiroH.HisanagaM.NakajimaY.Xenotransplantation of pig islets in diabetic dogs with use of a microcapsule composed of agarose and polystyrene sulfonic acid mixed gel2002251941002-s2.0-003599027110.1097/00006676-200207000-00020TashiroH.IwataH.WarnockG. L.TakagiT.MachidaH.IkadaY.TsujiT.Characterization and transplantation of agarose microencapsulated canine islets of Langerhans19972333392-s2.0-0031292416MakiT.OtsuI.O'NeilJ. J.DunleavyK.MullonC. J. P.SolomonB. A.MonacoA. P.Treatment of diabetes by xenogeneic islets without immunosuppression: use of a vascularized bioartificial pancreas19964533423472-s2.0-0030046957LanzaR. P.BorlandK. M.LodgeP.CarrettaM.SullivanS. J.MullerT. E.SolomonB. A.MakiT.MonacoA. P.ChickW. L.Treatment of severely diabetic pancreatectomized dogs using a diffusion- based hybrid pancreas19924178868892-s2.0-0026718763MonacoA. P.MakiT.OzatoH.CarrettaM.SullivanS. J.BorlandK. M.MahoneyM. D.ChickW. L.MullerT. E.WolfrumJ.SolomonB.Transplantation of islet allografts and xenografts in totally pancreatectomized diabetic dogs using the Hybrid Artificial Pancreas199121433393622-s2.0-002639665610.1097/00000658-199109000-00016WangT.AdcockJ.KühtreiberW.QiangD.SallengK. J.TrenaryI.WilliamsP.Successful allotransplantation of encapsulated islets in pancreatectomized canines for diabetic management without the use of immunosuppression20088533313372-s2.0-4004911137610.1097/TP.0b013e3181629c25Grundfest-BroniatowskiS. F.TelliogluG.RosenthalK. S.KangJ.ErdodiG.YalcinB.CakmakM.DrazbaJ.BennettA.LuL.KennedyJ. P.A new bioartificial pancreas utilizing amphiphilic membranes for the immunoisolation of porcine islets a pilot study in the canine20095544004052-s2.0-6884910766910.1097/MAT.0b013e3181a8debaFigeacF.IliasA.BailbeD.PorthaB.MovassatJ.Local in vivo GSK3beta knockdown promotes pancreatic beta cell and acinar cell regeneration in 90% pancreatectomized rat20122019441952AnsarullahBharuchaB.UmaraniM.Oreocnide integrifolia flavonoids augment reprogramming for islet neogenesis and beta-cell regeneration in pancreatectomized BALB/c mice201220121326046710.1155/2012/260467WangY.WangH.LiuY.LiC.QiP.BaoJ.Antihyperglycemic effect of ginsenoside Rh2 by inducing islet beta-cell regeneration in mice2012443340JungH. S.AhnY. R.OhS. H.KimY. S.NoH.LeeM. K.KimK. W.Enhancement of β-cell regeneration by islet transplantation after partial pancreatectomy in mice20098833543592-s2.0-6944910596110.1097/TP.0b013e3181b07a02PearsonT.MarkeesT. G.SerrezeD. V.PierceM. A.WickerL. S.PetersonL. B.ShultzL. D.MordesJ. P.RossiniA. A.GreinerD. L.Islet cell autoimmunity and transplantation tolerance: two distinct mechanisms?200310051481562-s2.0-1114435786710.1196/annals.1288.016RossiniA. A.MordesJ. P.MarkeesT. G.PhillipsN. E.GordonE. J.GreinerD. L.Induction of islet transplantation tolerance using donor specific transfusion and anti-CD154 monoclonal antibody1999311-26296322-s2.0-003306244710.1016/S0041-1345(98)01589-9MarkeesT. G.SerrezeD. V.PhillipsN. E.SorliC. H.GordonE. J.ShultzL. D.NoelleR. J.WodaB. A.GreinerD. L.MordesJ. P.RossiniA. A.NOD mice have a generalized defect in their response to transplantation tolerance induction19994859679742-s2.0-003291023110.2337/diabetes.48.5.967HaraM.KingsleyC. I.NiimiM.ReadS.TurveyS. E.BushellA. R.MorrisP. J.PowrieF.WoodK. J.IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo20011666378937962-s2.0-0035869432MolanoR. D.PileggiA.BerneyT.PoggioliR.ZahrE.OliverR.MalekT. R.RicordiC.InverardiL.Long-term islet allograft survival in nonobese diabetic mice treated with tacrolimus, rapamycin, and anti-interleukin-2 antibody20037511181218192-s2.0-003770857710.1097/01.TP.0000064622.54799.0EHeringB. J.KandaswamyR.AnsiteJ. D.EckmanP. M.NakanoM.SawadaT.MatsumotoI.IhmS. H.ZhangH. J.ParkeyJ.HunterD. W.SutherlandD. E. R.Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes200529378308352-s2.0-1384426575210.1001/jama.293.7.830BellinM. D.BartonF. B.HeitmanA.Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes20121215761583VerganiA.D'AddioF.JurewiczM.PetrelliA.WatanabeT.LiuK.LawK.SchuetzC.CarvelloM.OrsenigoE.DengS.RodigS. J.AnsariJ. M.StaudacherC.AbdiR.WilliamsJ.MarkmannJ.AtkinsonM.SayeghM. H.FiorinaP.A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice2010599225322642-s2.0-7795637769810.2337/db09-1264BaekeF.Van BelleT. L.TakiishiT.Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes20125527232732MamchakA. A.ManenkovaY.LeconetW.Preexisting autoantibodies predict efficacy of oral insulin to cure autoimmune diabetes in combination with anti-CD320126114901499