Matsumoto, Kozo

Pezzolesi, Marcus G.

Sasase, Tomohiko

Yamada, Takahisa

Yokoi, Norihide

Journal of Diabetes Research

PubMed

Harvard University - DASH

 Animal Models of Diabetes and Metabolic Disease  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Sasase, Tomohiko, Marcus G. Pezzolesi, Norihide Yokoi,Takahisa Yamada, and Kozo Matsumoto. 2013. “Animal Modelsof Diabetes and Metabolic Disease.” Journal of DiabetesResearch 2013 (1): 281928. doi:10.1155/2013/281928.http://dx.doi.org/10.1155/2013/281928.Published Version doi:10.1155/2013/281928Accessed February 19, 2015 1:58:29 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11717507Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAHindawi Publishing CorporationJournal of Diabetes ResearchVolume 2013, Article ID 281928, 2 pageshttp://dx.doi.org/10.1155/2013/281928EditorialAnimal Models of Diabetes and Metabolic DiseaseTomohiko Sasase,1 Marcus G. Pezzolesi,2 Norihide Yokoi,3Takahisa Yamada,4 and Kozo Matsumoto51 Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc.,Osaka 569-1125, Japan2Section on Genetics and Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA3Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology,Kobe University Graduate School of Medicine, Kobe 650-0017, Japan4Laboratory of Animal Genetics, Division of Life and Food Sciences, Graduate School of Science and Technology,Niigata University, Niigata 950-2181, Japan5D e p a r t m e n to fL a b o r a t o r yA n i m a lS c i e n c e ,F a c u l t yo fL i f eS c i e n c e s ,K y o t oS a n g y oU n i v e r s i t y ,K y o t o6 0 3 - 8 5 5 5 ,J a p a nCorrespondence should be addressed to Tomohiko Sasase; tomohiko.sasase@jt.comReceived 3 April 2013; Accepted 3 April 2013Copyright © 2013 Tomohiko Sasase et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.Metabolic diseases, including diabetes (and its complica-tions), obesity, dyslipidemia, and hypertension, are commondiseases and frequently occur in combination. To study thesediseases,manyhereditaryanimalmodelshavebeenreported,such as ob/ob mouse, db/db mouse, KK-Ay mouse, Goto-Kakizaki (GK) rat, Zucker diabetic fatty (ZDF) rat, Otsuka-Long-Evans-Tokushima-fatty (OLETF) rat, SpontaneouslyDiabetic Torii (SDT) rat, spontaneously hypertensive rat(SHR), Watanabe Heritable hyperlipidemic (WHHL) rabbit,and Postprandial hypertriglyceridemia (PHT) rabbit. Chem-ical (e.g., streptozotocin (STZ), alloxan) and diet-induced(e.g., high sucrose, high fat, high cholesterol) experimentalanimal models have been in general use for a long time,and genetically modified animals have also been used widelyin recent decades. Although molecular biological techniqueshave become more important for clarifying the mechanismsof the diseases, the importance of animal models has notchanged. Animal models are needed to reveal the under-lying pathophysiology of metabolic diseases; this approachprovides information that is the key to the development ofnew therapies and drugs to treat and manage these diseases.In this special issue, we aim to provide information onrecent beneficial experimental animal models in this fieldand present up-to-date information on the pathophysiology,therapeutic drugs, and diagnosis of metabolic diseases usingv al u a b l ea n i m alm od e l s .W ebe l i ev eth a tth e1 4a rti c l e si nth i sspecial issue satisfy these aims.Type 2 diabetes (T2D) is a complex, multifactorial dis-ease. Both genetic and environmental factors are known tocontribute to its development; however, the precise patho-genesis of T2D remains largely unclear. In the presentspecial issue, various spontaneous T2D rodent models aresummarized in “Spontaneous type 2 diabetic rodent models”by Y.W. Wang et al.Several new animal models are introduced in this specialissue. Three papers introduce new diabetic animal models,SDT rat and its derivative SDT fatty rat. The SDT rat, anonobeseT2Dmodel,showsseverehyperglycemiaaccompa-niedwithhypoinsulinemia.Inthereviewarticle“TheSponta-neously Diabetic Torii rat: an animal model of nonobese type 2diabetes with severe diabetic complications” by T. Sasase et al.,characteristics of diabetic complications in SDT rats, such asdiabeticretinopathy,diabeticperipheralneuropathy,diabeticneuropathy, and osteoporosis, are described. Among thesediabetic complications, ocular complications are notably aunique characteristic of this animalmodel. Using this model,A. Ota et al. evaluated ranirestat, a novel aldose reductaseinhibitorthatiscurrentlyinphaseIIIclinicaltrial,ondiabeticcomplications, and report their findings in “Effects of long-term treatment with ranirestat, a potent aldose reductase2 Journal of Diabetes Researchinhibitor, on diabetic cataract and neuropathy in Sponta-neously Diabetic Torii rats.” The SDT fatty rat is an obese T2Dmodel established by introducing the fa allele of Zucker fattyrat into the SDT rat genome. In the review article “MetabolicdisordersanddiabeticcomplicationsinSpontaneouslyDiabeticTorii 𝐿𝑒𝑝𝑟𝑓𝑎 rat: a new obese type 2 diabetic model,” Y.Kemmochi et al. review the pathophysiological features ofthis animal model.In “A novel rat model of type 2 diabetes: the Zuckerfatty diabetes mellitus ZFDM rat,” N. Yokoi et al. reportthe establishment and characteristics of ZFDM rat. Thisnew T2D model is derived from the ZF rat, presents withhyperglycemia, and is phenotypically distinct from normo-glycemic ZF rats. Loss of islet architecture and fibrosis arealso observed in the ZFDM rat. This model is useful forinvestigating young- to middle-aged adult-onset T2D.T. Okamura et al. report the establishment and charac-teristics of Long-Evans Agouti (LEA) rat derived from Long-Evans (LE) strain, in “Phenotypic characterization of LEArat: a new rat model of nonobese type 2 diabetes.” The LEArat displays moderate hyperglycemia and glucose intolerancealong with impaired insulin secretion that is caused byprogressive fibrosis in pancreatic islets. This model is usefulin investigations on the progression of T2D with age.Three articles describe genetic factors of spontaneousT2D models, in detail. In “Genetic dissection of complexgenet icf act o ri n vo l vedi nNID D Mo fO LE TFr a t, ”T. Yamada etal.review1 4QTLs(Nidd1–14/of)identifiedinOLETFratthatare responsible for noninsulin dependent diabetes mellitus(NIDDM). Their work showed that NIDDM in the OLETFrat is a highly heterogeneous and complex genetic disorder.In “Single diabetic QTL derived from OLETF rat is a sufficientagent for severe diabetic phenotype in combination with leptin-signaling deficiency,” H. Kose et al. map hyperglycemia QTLsintheOLETFratandshowthatNidd2/of ishighlyresponsiveto obesity. In addition, Nidd2/of and another hyperglycemiaQTL, Nidd1/of, appear to act in combination to lead to thedevelopmentofdiabetes.Theirnewcongenicstrain,carryingasingleQTL,maybehelpfulinidentifyingthecausativegeneand should aid future investigations on understanding themechanism by which obesity interacts with QTLs to regulatediabetic traits.In the article “Dose effect and mode of inheritance ofdiabetogenic gene on mouse chromosome 11,” N. Babaya etal. revealed that the introgression of chromosome 11 ofT2D Nagoya-Shibata-Yasuda (NSY) strain onto nondiabeticC3H caused marked changes in glucose tolerance and STZsusceptibility, even in heterozygous state. However, hyper-glycemia and STZ sensitivity in heterozygous C3H-11NSYmouse was not as severe as in the homozygous mouse. Theconsomic strains constructed in their studies will facilitatefinemappingandidentificationofresponsiblegenesforT2D-related phenotypes.Islet transplantation is an effective treatment for severediabetes. N. Sakata et al. review three types of animalmodels (STZ-induced diabetes, pancreatomized diabetes,and spontaneous diabetes) used for preclinical islet trans-plantation research in “Animal models of diabetes mellitus forislet transplantation.” As highlighted in this review, selectingt h ea p p r o p r i a t em o d e l sb a s e do nt h es t u d y ’ so b j e c t i v ei sparamounttoproperlyinterpretastudy’sfindingsandcriticalto advance this area of research.Cardiovascular disorders (CVDs) are the leading causeof death in humans. In “Cardiovascular changes in animalmodels of metabolic syndrome” by A. M. Lehnen et al.,c a r d i o v a s c u l a rfi n d i n g si na n i m a lm o d e l sw i t ho b e s i t y ,d y s -lipidemia,diabetes,orhypertensionaresummarized.Theuseof different experimental models is important in order tobetter understand the mechanisms involved in CVDs causedby metabolic disease.Because the mortality due to CVD is greater in type 1diabetic (T1D) patients than in the general population, C. H.Hung et al. aimed to investigate the severity of cardiopul-monary dysfunction caused by lipopolysaccharide (LPS)in T1D rats in “Cardiopulmonary profile in streptozotocin-induced type 1 diabetic rats during systemic endotoxemia.” Inthis study, despite higher TNF-𝗼 l e v e li ns e r u ma n db r o n -choalveolar lavage fluid between nondiabetic and STZ T1Drats, there was only a modest difference of cardiopulmonarydysfunction between the two groups.T1D is an autoimmune disease that is characterized bythe selective destruction of pancreatic 𝗽 cells. Both envi-ronmental and genetic factors are known to contribute tothe progression of this autoimmunity. In the review article“Rodent models for investigating the dysregulation of immuneresponses in type 1 diabetes” by F. C. Chou et al., non-obesediabetic(NOD)mouseandotherspontaneousdiabetesmodels are introduced. In addition, this review discussesgenetically manipulated NOD mice that overexpress protec-tive genes in islet, T-cell receptors, islet-specific neoantigens,or humanized MHC.Lastly, in their review article entitled “𝐹𝑜𝑥𝑝3+ regulatoryT cells in mouse models of type 1 diabetes,” C. Petzold et al.focus on a murine model of T1D that expresses the Foxp3+transcriptionfactorinCD4+ CD25+ regulatoryT(Treg)cells.In this review, spontaneous and genetically engineered NODmice for studying the role of Foxp3+ Treg cells in 𝗽 cellautoimmunity are overviewed.Tomohiko SasaseMarcus G. PezzolesiNorihide YokoiTakahisa YamadaKozo Matsumoto

Animal Models of Diabetes and Metabolic Disease

Tomohiko Sasase

Marcus G. Pezzolesi

Norihide Yokoi

Takahisa Yamada

Kozo Matsumoto

Crossref

Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2013, Article ID 281928, 2 pageshttp://dx.doi.org/10.1155/2013/281928EditorialAnimal Models of Diabetes and Metabolic DiseaseTomohiko Sasase,1 Marcus G. Pezzolesi,2 Norihide Yokoi,3Takahisa Yamada,4 and Kozo Matsumoto51 Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc.,Osaka 569-1125, Japan2 Section on Genetics and Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA3Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology,Kobe University Graduate School of Medicine, Kobe 650-0017, Japan4 Laboratory of Animal Genetics, Division of Life and Food Sciences, Graduate School of Science and Technology,Niigata University, Niigata 950-2181, Japan5Department of Laboratory Animal Science, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, JapanCorrespondence should be addressed to Tomohiko Sasase; tomohiko.sasase@jt.comReceived 3 April 2013; Accepted 3 April 2013Copyright © 2013 Tomohiko Sasase et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.Metabolic diseases, including diabetes (and its complica-tions), obesity, dyslipidemia, and hypertension, are commondiseases and frequently occur in combination. To study thesediseases, many hereditary animalmodels have been reported,such as ob/ob mouse, db/db mouse, KK-Ay mouse, Goto-Kakizaki (GK) rat, Zucker diabetic fatty (ZDF) rat, Otsuka-Long-Evans-Tokushima-fatty (OLETF) rat, SpontaneouslyDiabetic Torii (SDT) rat, spontaneously hypertensive rat(SHR), Watanabe Heritable hyperlipidemic (WHHL) rabbit,and Postprandial hypertriglyceridemia (PHT) rabbit. Chem-ical (e.g., streptozotocin (STZ), alloxan) and diet-induced(e.g., high sucrose, high fat, high cholesterol) experimentalanimal models have been in general use for a long time,and genetically modified animals have also been used widelyin recent decades. Although molecular biological techniqueshave become more important for clarifying the mechanismsof the diseases, the importance of animal models has notchanged. Animal models are needed to reveal the under-lying pathophysiology of metabolic diseases; this approachprovides information that is the key to the development ofnew therapies and drugs to treat and manage these diseases.In this special issue, we aim to provide information onrecent beneficial experimental animal models in this fieldand present up-to-date information on the pathophysiology,therapeutic drugs, and diagnosis of metabolic diseases usingvaluable animal models. We believe that the 14 articles in thisspecial issue satisfy these aims.Type 2 diabetes (T2D) is a complex, multifactorial dis-ease. Both genetic and environmental factors are known tocontribute to its development; however, the precise patho-genesis of T2D remains largely unclear. In the presentspecial issue, various spontaneous T2D rodent models aresummarized in “Spontaneous type 2 diabetic rodent models”by Y.W. Wang et al.Several new animal models are introduced in this specialissue. Three papers introduce new diabetic animal models,SDT rat and its derivative SDT fatty rat. The SDT rat, anonobese T2Dmodel, shows severe hyperglycemia accompa-nied with hypoinsulinemia. In the review article “The Sponta-neously Diabetic Torii rat: an animal model of nonobese type 2diabetes with severe diabetic complications” by T. Sasase et al.,characteristics of diabetic complications in SDT rats, such asdiabetic retinopathy, diabetic peripheral neuropathy, diabeticneuropathy, and osteoporosis, are described. Among thesediabetic complications, ocular complications are notably aunique characteristic of this animal model. Using this model,A. Ota et al. evaluated ranirestat, a novel aldose reductaseinhibitor that is currently in phase III clinical trial, on diabeticcomplications, and report their findings in “Effects of long-term treatment with ranirestat, a potent aldose reductase2 Journal of Diabetes Researchinhibitor, on diabetic cataract and neuropathy in Sponta-neously Diabetic Torii rats.”The SDT fatty rat is an obese T2Dmodel established by introducing the fa allele of Zucker fattyrat into the SDT rat genome. In the review article “Metabolicdisorders and diabetic complications in Spontaneously DiabeticTorii 𝐿𝑒𝑝𝑟𝑓𝑎 rat: a new obese type 2 diabetic model,” Y.Kemmochi et al. review the pathophysiological features ofthis animal model.In “A novel rat model of type 2 diabetes: the Zuckerfatty diabetes mellitus ZFDM rat,” N. Yokoi et al. reportthe establishment and characteristics of ZFDM rat. Thisnew T2D model is derived from the ZF rat, presents withhyperglycemia, and is phenotypically distinct from normo-glycemic ZF rats. Loss of islet architecture and fibrosis arealso observed in the ZFDM rat. This model is useful forinvestigating young- to middle-aged adult-onset T2D.T. Okamura et al. report the establishment and charac-teristics of Long-Evans Agouti (LEA) rat derived from Long-Evans (LE) strain, in “Phenotypic characterization of LEArat: a new rat model of nonobese type 2 diabetes.” The LEArat displays moderate hyperglycemia and glucose intolerancealong with impaired insulin secretion that is caused byprogressive fibrosis in pancreatic islets. This model is usefulin investigations on the progression of T2D with age.Three articles describe genetic factors of spontaneousT2D models, in detail. In “Genetic dissection of complexgenetic factor involved in NIDDM of OLETF rat,” T. Yamada etal. review 14 QTLs (Nidd1–14/of ) identified in OLETF rat thatare responsible for noninsulin dependent diabetes mellitus(NIDDM). Their work showed that NIDDM in the OLETFrat is a highly heterogeneous and complex genetic disorder.In “Single diabetic QTL derived from OLETF rat is a sufficientagent for severe diabetic phenotype in combination with leptin-signaling deficiency,” H. Kose et al. map hyperglycemia QTLsin the OLETF rat and show thatNidd2/of is highly responsiveto obesity. In addition, Nidd2/of and another hyperglycemiaQTL, Nidd1/of, appear to act in combination to lead to thedevelopment of diabetes.Their new congenic strain, carryinga single QTL, may be helpful in identifying the causative geneand should aid future investigations on understanding themechanism by which obesity interacts with QTLs to regulatediabetic traits.In the article “Dose effect and mode of inheritance ofdiabetogenic gene on mouse chromosome 11,” N. Babaya etal. revealed that the introgression of chromosome 11 ofT2D Nagoya-Shibata-Yasuda (NSY) strain onto nondiabeticC3H caused marked changes in glucose tolerance and STZsusceptibility, even in heterozygous state. However, hyper-glycemia and STZ sensitivity in heterozygous C3H-11NSYmouse was not as severe as in the homozygous mouse. Theconsomic strains constructed in their studies will facilitatefinemapping and identification of responsible genes for T2D-related phenotypes.Islet transplantation is an effective treatment for severediabetes. N. Sakata et al. review three types of animalmodels (STZ-induced diabetes, pancreatomized diabetes,and spontaneous diabetes) used for preclinical islet trans-plantation research in “Animal models of diabetes mellitus forislet transplantation.” As highlighted in this review, selectingthe appropriate models based on the study’s objective isparamount to properly interpret a study’s findings and criticalto advance this area of research.Cardiovascular disorders (CVDs) are the leading causeof death in humans. In “Cardiovascular changes in animalmodels of metabolic syndrome” by A. M. Lehnen et al.,cardiovascular findings in animal models with obesity, dys-lipidemia, diabetes, or hypertension are summarized.The useof different experimental models is important in order tobetter understand the mechanisms involved in CVDs causedby metabolic disease.Because the mortality due to CVD is greater in type 1diabetic (T1D) patients than in the general population, C. H.Hung et al. aimed to investigate the severity of cardiopul-monary dysfunction caused by lipopolysaccharide (LPS)in T1D rats in “Cardiopulmonary profile in streptozotocin-induced type 1 diabetic rats during systemic endotoxemia.” Inthis study, despite higher TNF-𝛼 level in serum and bron-choalveolar lavage fluid between nondiabetic and STZ T1Drats, there was only a modest difference of cardiopulmonarydysfunction between the two groups.T1D is an autoimmune disease that is characterized bythe selective destruction of pancreatic 𝛽 cells. Both envi-ronmental and genetic factors are known to contribute tothe progression of this autoimmunity. In the review article“Rodent models for investigating the dysregulation of immuneresponses in type 1 diabetes” by F. C. Chou et al., non-obese diabetic (NOD)mouse and other spontaneous diabetesmodels are introduced. In addition, this review discussesgenetically manipulated NOD mice that overexpress protec-tive genes in islet, T-cell receptors, islet-specific neoantigens,or humanized MHC.Lastly, in their review article entitled “𝐹𝑜𝑥𝑝3+ regulatoryT cells in mouse models of type 1 diabetes,” C. Petzold et al.focus on a murine model of T1D that expresses the Foxp3+transcription factor in CD4+ CD25+ regulatory T (Treg) cells.In this review, spontaneous and genetically engineered NODmice for studying the role of Foxp3+ Treg cells in 𝛽 cellautoimmunity are overviewed.Tomohiko SasaseMarcus G. PezzolesiNorihide YokoiTakahisa YamadaKozo MatsumotoSubmit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Directory of Open Access Journals

http://dash.harvard.edu/bitstream/handle/1/11717507/3708415.pdf?sequence=1

Animal Models of Diabetes and Metabolic Disease

Abstract

Similar works

Full text

Available Versions

Harvard University - DASH

Crossref

Directory of Open Access Journals