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Porcine models for studying complications and organ crosstalk in diabetes mellitus

  • Simone Renner
  • Andreas Blutke
  • Sebastian Clauss
  • Cornelia A. Deeg
  • Elisabeth Kemter
  • Daphne Merkus
  • Rüdiger Wanke
  • Eckhard WolfEmail author
Review

Abstract

The worldwide prevalence of diabetes mellitus and obesity is rapidly increasing not only in adults but also in children and adolescents. Diabetes is associated with macrovascular complications increasing the risk for cardiovascular disease and stroke, as well as microvascular complications leading to diabetic nephropathy, retinopathy and neuropathy. Animal models are essential for studying disease mechanisms and for developing and testing diagnostic procedures and therapeutic strategies. Rodent models are most widely used but have limitations in translational research. Porcine models have the potential to bridge the gap between basic studies and clinical trials in human patients. This article provides an overview of concepts for the development of porcine models for diabetes and obesity research, with a focus on genetically engineered models. Diabetes-associated ocular, cardiovascular and renal alterations observed in diabetic pig models are summarized and their similarities with complications in diabetic patients are discussed. Systematic multi-organ biobanking of porcine models of diabetes and obesity and molecular profiling of representative tissue samples on different levels, e.g., on the transcriptome, proteome, or metabolome level, is proposed as a strategy for discovering tissue-specific pathomechanisms and their molecular key drivers using systems biology tools. This is exemplified by a recent study providing multi-omics insights into functional changes of the liver in a transgenic pig model for insulin-deficient diabetes mellitus. Collectively, these approaches will provide a better understanding of organ crosstalk in diabetes mellitus and eventually reveal new molecular targets for the prevention, early diagnosis and treatment of diabetes mellitus and its associated complications.

Keywords

Pig model Diabetes Complications Retinopathy Cardiomyopathy Nephropathy Organ crosstalk Biobank Multi-omics analysis Obesity 

Notes

Acknowledgments

The authors gratefully acknowledge Prof. Peter Cowan, Fellow of the Center for Advanced Studies (CAS) of LMU Munich, for careful editing of the manuscript.

Funding information

This work was supported by the German Center for Diabetes Research (DZD; 82DZD00802, 82DZD0043G, 82DZD0044G, 82DZD0015G to EW, SR and EK), the German Center for Cardiovascular Research (DZHK; 81X2600210, 81X2600204, 81X3600208, 81X2600249 to SC, 81Z0600207 to DM), the Deutsche Forschungsgemeinschaft (TRR127 to EW and EK and DFG DE 719/7-1/SPP2127 to CD), the European Union (iNanoBIT grant agreement no. 760986 to EK and EW), the Bayerische Forschungsstiftung (AZ-1247-16 VasOP to EK and EW), the LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to SC), the Förderprogramm für Forschung und Lehre (FöFöLe; 962 to SC), the Heinrich-and-Lotte-Mühlfenzl Stiftung (to SC), the ERA-NET on Cardiovascular Diseases (ERA-CVD; 01KL1910 to SC), the Netherlands Cardiovascular Research Initiative, an initiative with financial support from the Dutch Heart Foundation (CVON2014-11, RECONNECT to DM), and the Corona-Foundation (S199/10079/2019 to SC).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national and institutional guidelines for the care and use of animals were followed.

References

  1. Abbas AR, Baldwin D, Ma Y, Ouyang W, Gurney A, Martin F, Fong S, van Lookeren CM, Godowski P, Williams PM, Chan AC, Clark HF (2005) Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun 6:319–331PubMedCrossRefPubMedCentralGoogle Scholar
  2. Abbott A (2015) Inside the first pig biobank. Nature 519:397–398PubMedCrossRefPubMedCentralGoogle Scholar
  3. Acharya NK, Qi X, Goldwaser EL, Godsey GA, Wu H, Kosciuk MC, Freeman TA, Macphee CH, Wilensky RL, Venkataraman V, Nagele RG (2017) Retinal pathology is associated with increased blood–retina barrier permeability in a diabetic and hypercholesterolaemic pig model: beneficial effects of the LpPLA2 inhibitor Darapladib. Diabetes Vasc Dis Res 14:200–213CrossRefGoogle Scholar
  4. Afshin A, Reitsma MB, Murray CJL (2017) Health effects of overweight and obesity in 195 countries. N Engl J Med 377:1496–1497PubMedPubMedCentralGoogle Scholar
  5. Ahlqvist E, Storm P, Karajamaki A, Martinell M, Dorkhan M, Carlsson A, Vikman P, Prasad RB, Aly DM, Almgren P, Wessman Y, Shaat N, Spegel P, Mulder H, Lindholm E, Melander O, Hansson O, Malmqvist U, Lernmark A, Lahti K, Forsen T, Tuomi T, Rosengren AH, Groop L (2018) Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6:361–369PubMedCrossRefPubMedCentralGoogle Scholar
  6. Aizarani N, Saviano A, Sagar ML, Durand S, Herman JS, Pessaux P, Baumert TF, Grun D (2019) A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572:19–204PubMedPubMedCentralCrossRefGoogle Scholar
  7. Albl B, Haesner S, Braun-Reichhart C, Streckel E, Renner S, Seeliger F, Wolf E, Wanke R, Blutke A (2016) Tissue sampling guides for porcine biomedical models. Toxicol Pathol 44:414–420PubMedCrossRefPubMedCentralGoogle Scholar
  8. Alicic RZ, Rooney MT, Tuttle KR (2017) Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 12:2032–2045PubMedPubMedCentralCrossRefGoogle Scholar
  9. Al-Mashhadi RH, Sorensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, Thim T, Du Y, Li J, Liu Y, Moldt B, Schmidt M, Vajta G, Larsen T, Purup S, Bolund L, Nielsen LB, Callesen H, Falk E, Mikkelsen JG, Bentzon JF (2013) Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med 5:166ra161CrossRefGoogle Scholar
  10. Al-Mashhadi RH, Bjorklund MM, Mortensen MB, Christoffersen C, Larsen T, Falk E, Bentzon JF (2015) Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs. Diabetologia 58:1926–1936PubMedCrossRefPubMedCentralGoogle Scholar
  11. Alpers CE, Hudkins KL (2011) Mouse models of diabetic nephropathy. Curr Opin Nephrol Hypertens 20:278–284PubMedPubMedCentralCrossRefGoogle Scholar
  12. American Diabetes Association (2019) Standards of medical care in diabetes. Diabetes Care 42:S13–S28Google Scholar
  13. Amuzie C, Swart JR, Rogers CS, Vihtelic T, Denham S, Mais DE (2016) A translational model for diet-related atherosclerosis: effect of statins on hypercholesterolemia and atherosclerosis in a minipig. Toxicol Pathol 44:442–449PubMedCrossRefPubMedCentralGoogle Scholar
  14. Aune D, Feng T, Schlesinger S, Janszky I, Norat T, Riboli E (2018) Diabetes mellitus, blood glucose and the risk of atrial fibrillation: a systematic review and meta-analysis of cohort studies. J Diabetes Complicat 32:501–511PubMedCrossRefPubMedCentralGoogle Scholar
  15. Backman M, Flenkenthaler F, Blutke A, Dahlhoff M, Landstrom E, Renner S, Philippou-Massier J, Krebs S, Rathkolb B, Prehn C, Grzybek M, Coskun U, Rothe M, Adamski J, de Angelis MH, Wanke R, Frohlich T, Arnold GJ, Blum H, Wolf E (2019) Multi-omics insights into functional alterations of the liver in insulin-deficient diabetes mellitus. Mol Metab 26:30–44PubMedPubMedCentralCrossRefGoogle Scholar
  16. Badin JK, Kole A, Stivers B, Progar V, Pareddy A, Alloosh M, Sturek M (2018) Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome. J Transl Med 16:58PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bakhti M, Bottcher A, Lickert H (2019) Modelling the endocrine pancreas in health and disease. Nat Rev Endocrinol 15:155–171PubMedCrossRefPubMedCentralGoogle Scholar
  18. Barter PJ, Rye KA (2012) Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J Lipid Res 53:1755–1766PubMedPubMedCentralCrossRefGoogle Scholar
  19. Barter PJ, Hopkins GJ, Gorjatschko L, Jones ME (1982) A unified model of esterified cholesterol exchanges between human plasma lipoproteins. Atherosclerosis 44:27–40PubMedCrossRefPubMedCentralGoogle Scholar
  20. Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570–2581PubMedCrossRefPubMedCentralGoogle Scholar
  21. Bender SB, Tune JD, Borbouse L, Long X, Sturek M, Laughlin MH (2009) Altered mechanism of adenosine-induced coronary arteriolar dilation in early-stage metabolic syndrome. Exp Biol Med (Maywood) 234:683–692CrossRefGoogle Scholar
  22. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA (1994) Independent risk factors for atrial fibrillation in a population-based cohort The Framingham Heart Study. JAMA 271:840–844PubMedCrossRefPubMedCentralGoogle Scholar
  23. Berryman DE, List EO, Palmer AJ, Chung M-Y, Wright-Piekarski J, Lubbers E, O’Connor P, Okada S, Kopchick JJ (2010) Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci 65:31–40PubMedCrossRefPubMedCentralGoogle Scholar
  24. Betz B, Conway BR (2016) An Update on the use of animal models in diabetic nephropathy research. Curr Diab Rep 16:18PubMedPubMedCentralCrossRefGoogle Scholar
  25. Betz MJ, Enerback S (2018) Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nat Rev Endocrinol 14:77–87PubMedCrossRefPubMedCentralGoogle Scholar
  26. Bissinger A, Grycewicz T, Grabowicz W, Lubinski A (2011) The effect of diabetic autonomic neuropathy on P-wave duration, dispersion and atrial fibrillation. Arch Med Sci 7:806–812PubMedPubMedCentralCrossRefGoogle Scholar
  27. Bloodworth JMB, Gutgesell HP, Engerman RL (1965) Retinal vasculature of the pig: light and electron microscope studies. Exp Eye Res 4:174–178PubMedCrossRefPubMedCentralGoogle Scholar
  28. Blutke A, Wanke R (2018) Sampling strategies and processing of biobank tissue samples from porcine biomedical models. J Vis Exp  6;(133).  https://doi.org/10.3791/57276
  29. Blutke A, Schneider MR, Wolf E, Wanke R (2016) Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth. Physiol Rep 4:e12709PubMedPubMedCentralCrossRefGoogle Scholar
  30. Blutke A, Renner S, Flenkenthaler F, Backman M, Haesner S, Kemter E, Landstrom E, Braun-Reichhart C, Albl B, Streckel E, Rathkolb B, Prehn C, Palladini A, Grzybek M, Krebs S, Bauersachs S, Bahr A, Bruhschwein A, Deeg CA, De Monte E, Dmochewitz M, Eberle C, Emrich D, Fux R, Groth F, Gumbert S, Heitmann A, Hinrichs A, Kessler B, Kurome M, Leipig-Rudolph M, Matiasek K, Ozturk H, Otzdorff C, Reichenbach M, Reichenbach HD, Rieger A, Rieseberg B, Rosati M, Saucedo MN, Schleicher A, Schneider MR, Simmet K, Steinmetz J, Ubel N, Zehetmaier P, Jung A, Adamski J, Coskun U, Hrabe de Angelis M, Simmet C, Ritzmann M, Meyer-Lindenberg A, Blum H, Arnold GJ, Frohlich T, Wanke R, Wolf E (2017) The Munich MIDY Pig Biobank - A unique resource for studying organ crosstalk in diabetes. Mol Metab 6:931–940PubMedPubMedCentralCrossRefGoogle Scholar
  31. Boodhwani M, Sodha NR, Mieno S, Ramlawi B, Xu SH, Feng J, Clements RT, Ruel M, Sellke FW (2007a) Insulin treatment enhances the myocardial angiogenic response in diabetes. J Thorac Cardiovasc Surg 134:1453–1460 discussion 1460PubMedPubMedCentralCrossRefGoogle Scholar
  32. Boodhwani M, Sodha NR, Mieno S, Xu SH, Feng J, Ramlawi B, Clements RT, Sellke FW (2007b) Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes. Circulation 116:I31–I37PubMedPubMedCentralCrossRefGoogle Scholar
  33. Brem G, Brenig B, Goodman HM, Selden RC, Graf F, Kruff B, Springmann K, Hondele J, Meyer J, Winnacker EL, Kräusslich H (1985) Production of transgenic mice, rabbits and pigs by microinjection into pronuclei. Zuchthygiene 20:251–252CrossRefGoogle Scholar
  34. Brenner BM (1983) Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23:647–655PubMedCrossRefPubMedCentralGoogle Scholar
  35. Broe R (2015) Early risk stratification in pediatric type 1 diabetes. Acta Ophthalmol 93(Thesis 1):1–19PubMedCrossRefPubMedCentralGoogle Scholar
  36. Broe R, Rasmussen ML, Frydkjaer-Olsen U, Olsen BS, Mortensen HB, Hodgson L, Wong TY, Peto T, Grauslund J (2014) Retinal vessel calibers predict long-term microvascular complications in type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). Diabetes 63:3906–3914PubMedCrossRefPubMedCentralGoogle Scholar
  37. Burnett JR, Hooper AJ (2008) Common and rare gene variants affecting plasma LDL cholesterol. Clin Biochem Rev 29:11–26PubMedPubMedCentralGoogle Scholar
  38. Caie PD, Harrison DJ (2016) Next-generation pathology. Methods Mol Biol 1386:61–72PubMedCrossRefPubMedCentralGoogle Scholar
  39. Cardoso CR, Salles GF, Deccache W (2003) Prognostic value of QT interval parameters in type 2 diabetes mellitus: results of a long-term follow-up prospective study. J Diabetes Complications 17:169–178PubMedCrossRefPubMedCentralGoogle Scholar
  40. Carlson DF, Tan W, Lillico SG, Stverakova D, Proudfoot C, Christian M, Voytas DF, Long CR, Whitelaw CB, Fahrenkrug SC (2012) Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci U S A 109:17382–17387PubMedPubMedCentralCrossRefGoogle Scholar
  41. Chen H, Liu YQ, Li CH, Guo XM, Huang LJ (2009) The susceptibility of three strains of Chinese minipigs to diet-induced type 2 diabetes mellitus. Lab Anim (NY) 38:355–363CrossRefGoogle Scholar
  42. Chen T, Sun M, Wang JQ, Cui JJ, Liu ZH, Yu B (2017a) A novel swine model for evaluation of dyslipidemia and atherosclerosis induced by human CETP overexpression. Lipids Health Dis 16:169PubMedPubMedCentralCrossRefGoogle Scholar
  43. Chen Y, Sun X-B, Lu H-e, Wang F, Fan X-H (2017b) Effect of luteoin in delaying cataract in STZ-induced diabetic rats. Arch Pharm Res 40:88–95PubMedCrossRefPubMedCentralGoogle Scholar
  44. Chen Y-L, Xu W, Rosa RH, Kuo L, Hein TW (2019) Hyperglycemia enhances constriction of retinal venules via activation of the reverse-mode sodium-calcium exchanger. Diabetes 68:1624–1634PubMedCrossRefPubMedCentralGoogle Scholar
  45. Chinda K, Palee S, Surinkaew S, Phornphutkul M, Chattipakorn S, Chattipakorn N (2013) Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury. Int J Cardiol 167:451–457PubMedCrossRefPubMedCentralGoogle Scholar
  46. Cho B, Kim SJ, Lee EJ, Ahn SM, Lee JS, Ji DY, Lee K, Kang JT (2018) Generation of insulin-deficient piglets by disrupting INS gene using CRISPR/Cas9 system. Transgenic Res 27:289–300PubMedCrossRefPubMedCentralGoogle Scholar
  47. Chous AP, Richer SP, Gerson JD, Kowluru RA (2016) The Diabetes Visual Function Supplement Study (DiVFuSS). Br J Ophthalmol 100:227–234PubMedCrossRefPubMedCentralGoogle Scholar
  48. Clark AJ, Adeniyi-Jones RO, Knight G, Leiper JM, Wiles PG, Jones RH, Keen H, MacCuish AC, Ward JD, Watkins PJ, Cauldwell JM, Glynne A, Scotton JB (1982) Biosynthetic human insulin in the treatment of diabetes A double-blind crossover trial in established diabetic patients. Lancet 2:354–357PubMedCrossRefPubMedCentralGoogle Scholar
  49. Clauss S, Sinner MF, Kaab S, Wakili R (2015) The role of microRNAs in antiarrhythmic therapy for atrial fibrillation. Arrhythm Electrophysiol Rev 4:146–155PubMedPubMedCentralCrossRefGoogle Scholar
  50. Clauss S, Bleyer C, Schuttler D, Tomsits P, Renner S, Klymiuk N, Wakili R, Massberg S, Wolf E, Kaab S (2019) Animal models of arrhythmia: classic electrophysiology to genetically modified large animals. Nat Rev Cardiol 16:457–475PubMedCrossRefPubMedCentralGoogle Scholar
  51. Clements RT, Sodha NR, Feng J, Boodhwani M, Liu Y, Mieno S, Khabbaz KR, Bianchi C, Sellke FW (2009) Impaired coronary microvascular dilation correlates with enhanced vascular smooth muscle MLC phosphorylation in diabetes. Microcirculation 16:193–206PubMedPubMedCentralCrossRefGoogle Scholar
  52. Cohn JS, Tremblay M, Batal R, Jacques H, Rodriguez C, Steiner G, Mamer O, Davignon J (2004) Increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia. Atherosclerosis 177:137–145PubMedCrossRefPubMedCentralGoogle Scholar
  53. Cooper DKC, Ezzelarab M, Iwase H, Hara H (2018) Perspectives on the optimal genetically engineered pig in 2018 for initial clinical trials of kidney or heart xenotransplantation. Transplantation 102:1974–1982PubMedPubMedCentralCrossRefGoogle Scholar
  54. Cui J, Chen Y, Wang HY, Wang RF (2014) Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum Vaccin Immunother 10:3270–3285PubMedCrossRefPubMedCentralGoogle Scholar
  55. Davis BT, Wang XJ, Rohret JA, Struzynski JT, Merricks EP, Bellinger DA, Rohret FA, Nichols TC, Rogers CS (2014) Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs. PLoS One 9:e93457PubMedPubMedCentralCrossRefGoogle Scholar
  56. Denton KM (2000) Blood flow in the glomerular capillary network. Adv Organ Biol 9:93–107Google Scholar
  57. Diemar SS, Sejling AS, Iversen KK, Engstrom T, Honge JL, Tonder N, Vejlstrup N, Idorn M, Ekstrom K, Pedersen-Bjergaard U, Thorsteinsson B, Dalsgaard M (2015) Influence of acute glycaemic level on measures of myocardial infarction in non-diabetic pigs. Scand\ Cardiovasc J 49:376–382PubMedPubMedCentralGoogle Scholar
  58. Doetschman T, Georgieva T (2017) Gene editing with CRISPR/Cas9 RNA-directed nuclease. Circ Res 120:876–894PubMedCrossRefPubMedCentralGoogle Scholar
  59. Drinkwater JJ, Davis WA, Davis TME (2019) A systematic review of risk factors for cataract in type 2 diabetes. Diabetes Metab Res Rev 35:e3073PubMedCrossRefPubMedCentralGoogle Scholar
  60. Dufrane D, Goebbels RM, Fdilat I, Guiot Y, Gianello P (2005) Impact of porcine islet size on cellular structure and engraftment after transplantation: adult versus young pigs. Pancreas 30:138–147PubMedCrossRefPubMedCentralGoogle Scholar
  61. Dufrane D, van Steenberghe M, Guiot Y, Goebbels RM, Saliez A, Gianello P (2006) Streptozotocin-induced diabetes in large animals (pigs/primates): role of GLUT2 transporter and beta-cell plasticity. Transplantation 81:36–45PubMedCrossRefPubMedCentralGoogle Scholar
  62. Dyson MC, Alloosh M, Vuchetich JP, Mokelke EA, Sturek M (2006) Components of metabolic syndrome and coronary artery disease in female Ossabaw swine fed excess atherogenic diet. Comp Med 56:35–45PubMedPubMedCentralGoogle Scholar
  63. El Ouaamari A, Kawamori D, Dirice E, Liew CW, Shadrach JL, Hu J, Katsuta H, Hollister-Lock J, Qian WJ, Wagers AJ, Kulkarni RN (2013) Liver-derived systemic factors drive beta cell hyperplasia in insulin-resistant states. Cell reports 3:401–410PubMedPubMedCentralCrossRefGoogle Scholar
  64. Emilsson V, Thorleifsson G, Zhang B, Leonardson AS, Zink F, Zhu J, Carlson S, Helgason A, Walters GB, Gunnarsdottir S, Mouy M, Steinthorsdottir V, Eiriksdottir GH, Bjornsdottir G, Reynisdottir I, Gudbjartsson D, Helgadottir A, Jonasdottir A, Jonasdottir A, Styrkarsdottir U, Gretarsdottir S, Magnusson KP, Stefansson H, Fossdal R, Kristjansson K, Gislason HG, Stefansson T, Leifsson BG, Thorsteinsdottir U, Lamb JR, Gulcher JR, Reitman ML, Kong A, Schadt EE, Stefansson K (2008) Genetics of gene expression and its effect on disease. Nature 452:423–428PubMedCrossRefPubMedCentralGoogle Scholar
  65. Evans RG, Eppel GA, Anderson WP, Denton KM (2004) Mechanisms underlying the differential control of blood flow in the renal medulla and cortex. J Hypertens 22:1439–1451PubMedCrossRefPubMedCentralGoogle Scholar
  66. Ewing DJ, Neilson JM (1990) QT interval length and diabetic autonomic neuropathy. Diabet Med 7:23–26PubMedCrossRefPubMedCentralGoogle Scholar
  67. Fang B, Ren X, Wang Y, Li Z, Zhao L, Zhang M, Li C, Zhang Z, Chen L, Li X, Liu J, Xiong Q, Zhang L, Jin Y, Liu X, Li L, Wei H, Yang H, Li R, Dai Y (2018) Apolipoprotein E deficiency accelerates atherosclerosis development in miniature pigs. Dis Model Mech 11:dmm036632CrossRefGoogle Scholar
  68. Fatemi O, Yuriditsky E, Tsioufis C, Tsachris D, Morgan T, Basile J, Bigger T, Cushman W, Goff D, Soliman EZ, Thomas A, Papademetriou V (2014) Impact of intensive glycemic control on the incidence of atrial fibrillation and associated cardiovascular outcomes in patients with type 2 diabetes mellitus (from the Action to Control Cardiovascular Risk in Diabetes Study). Am J Cardiol 114:1217–1222PubMedPubMedCentralCrossRefGoogle Scholar
  69. Feingold KR, Grunfeld C (2018) Introduction to lipids and lipoproteins. Endotext [Internet]. MDText. com, Inc.Google Scholar
  70. Feng Y, Yang S, Ma Y, Bai XY, Chen X (2015) Role of Toll-like receptors in diabetic renal lesions in a miniature pig model. Sci Adv 1:e1400183PubMedPubMedCentralCrossRefGoogle Scholar
  71. Filardi T, Ghinassi B, Di Baldassarre A, Tanzilli G, Morano S, Lenzi A, Basili S, Crescioli C (2019) Cardiomyopathy associated with diabetes: the central role of the cardiomyocyte. Int J Mol Sci 20: E3299PubMedCentralCrossRefGoogle Scholar
  72. Fogo A, Ichikawa I (1989) Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin Nephrol 9:329–342PubMedPubMedCentralGoogle Scholar
  73. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R (2004) Retinopathy in diabetes. Diabetes Care 27(Suppl 1):S84–S87CrossRefGoogle Scholar
  74. Fontes JD, Lyass A, Massaro JM, Rienstra M, Dallmeier D, Schnabel RB, Wang TJ, Vasan RS, Lubitz SA, Magnani JW, Levy D, Ellinor PT, Fox CS, Benjamin EJ (2012) Insulin resistance and atrial fibrillation (from the Framingham Heart Study). Am J Cardiol 109:87–90PubMedCrossRefPubMedCentralGoogle Scholar
  75. Forbes JM, Cooper ME (2013) Mechanisms of diabetic complications. Physiol Rev 93:137–188PubMedCrossRefPubMedCentralGoogle Scholar
  76. Garrels W, Mates L, Holler S, Dalda A, Taylor U, Petersen B, Niemann H, Izsvak Z, Ivics Z, Kues WA (2011) Germline transgenic pigs by Sleeping Beauty transposition in porcine zygotes and targeted integration in the pig genome. PLoS One 6:e23573PubMedPubMedCentralCrossRefGoogle Scholar
  77. Garside K, Henderson R, Makarenko I, Masoller C (2019) Topological data analysis of high resolution diabetic retinopathy images. PLoS One 14:e0217413PubMedPubMedCentralCrossRefGoogle Scholar
  78. Gerrity RG, Natarajan R, Nadler JL, Kimsey T (2001) Diabetes-induced accelerated atherosclerosis in swine. Diabetes 50:1654–1665PubMedCrossRefPubMedCentralGoogle Scholar
  79. Gerst F, Wagner R, Kaiser G, Panse M, Heni M, Machann J, Bongers MN, Sartorius T, Sipos B, Fend F, Thiel C, Nadalin S, Konigsrainer A, Stefan N, Fritsche A, Haring HU, Ullrich S, Siegel-Axel D (2017) Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia. 60:2240–2251PubMedCrossRefPubMedCentralGoogle Scholar
  80. Gerstein HC, Waltman L (2006) Why don’t pigs get diabetes? Explanations for variations in diabetes susceptibility in human populations living in a diabetogenic environment. CMAJ 174:25–26PubMedPubMedCentralCrossRefGoogle Scholar
  81. Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T (2016) Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol 5:49–56PubMedPubMedCentralGoogle Scholar
  82. Giraud S, Favreau F, Chatauret N, Thuillier R, Maiga S, Hauet T (2011) Contribution of large pig for renal ischemia-reperfusion and transplantation studies: the preclinical model. J Biomed Biotechnol 2011:532127PubMedPubMedCentralCrossRefGoogle Scholar
  83. Grant SFA (2019) The TCF7L2 Locus: a genetic window into the pathogenesis of type 1 and type 2 diabetes. Diabetes Care 42:1624–1629PubMedCrossRefPubMedCentralGoogle Scholar
  84. Grisanti LA (2018) Diabetes and arrhythmias: pathophysiology, mechanisms and therapeutic outcomes. Front Physiol 9:1669PubMedPubMedCentralCrossRefGoogle Scholar
  85. Groenen MAM (2016) A decade of pig genome sequencing: a window on pig domestication and evolution. Genet Sel Evol 48:23–23PubMedPubMedCentralCrossRefGoogle Scholar
  86. Groenen MAM, Archibald AL, Uenishi H, Tuggle CK, Takeuchi Y, Rothschild MF, Rogel-Gaillard C, Park C, Milan D, Megens H-J, Li S, Larkin DM, Kim H, Frantz LAF, Caccamo M, Ahn H, Aken BL, Anselmo A, Anthon C, Auvil L, Badaoui B, Beattie CW, Bendixen C, Berman D, Blecha F, Blomberg J, Bolund L, Bosse M, Botti S, Bujie Z, Bystrom M, Capitanu B, Carvalho-Silva D, Chardon P, Chen C, Cheng R, Choi S-H, Chow W, Clark RC, Clee C, Crooijmans RPMA, Dawson HD, Dehais P, De Sapio F, Dibbits B, Drou N, Du Z-Q, Eversole K, Fadista J, Fairley S, Faraut T, Faulkner GJ, Fowler KE, Fredholm M, Fritz E, Gilbert JGR, Giuffra E, Gorodkin J, Griffin DK, Harrow JL, Hayward A, Howe K, Hu Z-L, Humphray SJ, Hunt T, Hornshøj H, Jeon J-T, Jern P, Jones M, Jurka J, Kanamori H, Kapetanovic R, Kim J, Kim J-H, Kim K-W, Kim T-H, Larson G, Lee K, Lee K-T, Leggett R, Lewin HA, Li Y, Liu W, Loveland JE, Lu Y, Lunney JK, Ma J, Madsen O, Mann K, Matthews L, McLaren S, Morozumi T, Murtaugh MP, Narayan J, Truong Nguyen D, Ni P, Oh S-J, Onteru S, Panitz F, Park E-W, Park H-S, Pascal G, Paudel Y, Perez-Enciso M, Ramirez-Gonzalez R, Reecy JM, Rodriguez-Zas S, Rohrer GA, Rund L, Sang Y, Schachtschneider K, Schraiber JG, Schwartz J, Scobie L, Scott C, Searle S, Servin B, Southey BR, Sperber G, Stadler P, Sweedler JV, Tafer H, Thomsen B, Wali R, Wang J, Wang J, White S, Xu X, Yerle M, Zhang G, Zhang J, Zhang J, Zhao S, Rogers J, Churcher C, Schook LB (2012) Analyses of pig genomes provide insight into porcine demography and evolution. Nature 491:393–398PubMedPubMedCentralCrossRefGoogle Scholar
  87. Gross ML, Amann K, Ritz E (2005) Nephron number and renal risk in hypertension and diabetes. J Am Soc Nephrol 16(Suppl 1):S27–S29PubMedPubMedCentralGoogle Scholar
  88. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3:70ra13PubMedPubMedCentralCrossRefGoogle Scholar
  89. Guo M, Wu MH, Korompai F, Yuan SY (2003) Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes. Physiol Genomics 12:139–146PubMedCrossRefPubMedCentralGoogle Scholar
  90. Gurley SB, Mach CL, Stegbauer J, Yang J, Snow KP, Hu A, Meyer TW, Coffman TM (2010) Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am J Physiol Renal Physiol 298:F788–F795PubMedCrossRefPubMedCentralGoogle Scholar
  91. Haesner S (2018) Charakterisierung von Proben diabetischer INSC94Y transgener Schweine aus dem Munich MIDY-Pig Biobank Projekt. Doctoral thesis, LMU MunichGoogle Scholar
  92. Hai T, Teng F, Guo R, Li W, Zhou Q (2014) One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell research 24:372–375PubMedPubMedCentralCrossRefGoogle Scholar
  93. Hainsworth DP, Katz ML, Sanders DA, Sanders DN, Wright EJ, Sturek M (2002) Retinal capillary basement membrane thickening in a porcine model of diabetes mellitus. Comp Med 52:523–529PubMedPubMedCentralGoogle Scholar
  94. Hall JL, Stanley WC, Lopaschuk GD, Wisneski JA, Pizzurro RD, Hamilton CD, McCormack JG (1996) Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work. Am J Physiol 271:H2320–H2329PubMedCrossRefPubMedCentralGoogle Scholar
  95. Hamamdzic D, Wilensky RL (2013) Porcine models of accelerated coronary atherosclerosis: role of diabetes mellitus and hypercholesterolemia. J Diabetes Res 2013:761415PubMedPubMedCentralCrossRefGoogle Scholar
  96. Hamamdzic D, Fenning RS, Patel D, Mohler ER 3rd, Orlova KA, Wright AC, Llano R, Keane MG, Shannon RP, Birnbaum MJ, Wilensky RL (2010) Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease. Am J Physiol Heart Circ Physiol 299:H699–H706PubMedPubMedCentralCrossRefGoogle Scholar
  97. Hammer RE, Pursel VG, Rexroad CE Jr, Wall RJ, Bolt DJ, Ebert KM, Palmiter RD, Brinster RL (1985) Production of transgenic rabbits, sheep and pigs by microinjection. Nature 315:680–683PubMedCrossRefPubMedCentralGoogle Scholar
  98. Han W, Fang W, Gan Q, Guan S, Li Y, Wang M, Gong K, Qu X (2017) Low-dose sustained-release deoxycorticosterone acetate-induced hypertension in Bama miniature pigs for renal sympathetic nerve denervation. J Am Soc Hypertens 11:314–320PubMedCrossRefPubMedCentralGoogle Scholar
  99. Hara S, Umeyama K, Yokoo T, Nagashima H, Nagata M (2014) Diffuse glomerular nodular lesions in diabetic pigs carrying a dominant-negative mutant hepatocyte nuclear factor 1-alpha, an inheritant diabetic gene in humans. PLoS One 9:e92219PubMedPubMedCentralCrossRefGoogle Scholar
  100. Haring HU (2016) Novel phenotypes of prediabetes? Diabetologia 59:1806–1818PubMedPubMedCentralCrossRefGoogle Scholar
  101. Hasdai D, Rizza RA, Holmes DR Jr, Richardson DM, Cohen P, Lerman A (1998) Insulin and insulin-like growth factor-I cause coronary vasorelaxation in vitro. Hypertension 32:228–234PubMedCrossRefPubMedCentralGoogle Scholar
  102. Hasdai D, Nielsen MF, Rizza RA, Holmes DR Jr, Richardson DM, Cohen P, Lerman A (1999) Attenuated in vitro coronary arteriolar vasorelaxation to insulin-like growth factor I in experimental hypercholesterolemia. Hypertension 34:89–95PubMedCrossRefPubMedCentralGoogle Scholar
  103. Hasin Y, Seldin M, Lusis A (2017) Multi-omics approaches to disease. Genome Biol 18:83PubMedPubMedCentralCrossRefGoogle Scholar
  104. Hasler-Rapacz J, Ellegren H, Fridolfsson AK, Kirkpatrick B, Kirk S, Andersson L, Rapacz J (1998) Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolemia in swine. Am J Med Genet 76:379–386PubMedCrossRefPubMedCentralGoogle Scholar
  105. Hauschild J, Petersen B, Santiago Y, Queisser AL, Carnwath JW, Lucas-Hahn A, Zhang L, Meng X, Gregory PD, Schwinzer R, Cost GJ, Niemann H (2011) Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases. Proc Natl Acad Sci U S A 108:12013–12017PubMedPubMedCentralCrossRefGoogle Scholar
  106. Hein TW, Potts LB, Xu W, Yuen JZ, Kuo L (2012) Temporal development of retinal arteriolar endothelial dysfunction in porcine type 1 diabetesvasomotor function of diabetic retinal arterioles. Invest Ophthalmol Vis Sci 53:7943–7949PubMedPubMedCentralCrossRefGoogle Scholar
  107. Heinke S, Ludwig B, Schubert U, Schmid J, Kiss T, Steffen A, Bornstein S, Ludwig S (2016) Diabetes induction by total pancreatectomy in minipigs with simultaneous splenectomy: a feasible approach for advanced diabetes research. Xenotransplantation 23:405–413PubMedCrossRefPubMedCentralGoogle Scholar
  108. Herbach N, Rathkolb B, Kemter E, Pichl L, Klaften M, de Angelis MH, Halban PA, Wolf E, Aigner B, Wanke R (2007) Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe beta-cell loss in Munich Ins2C95S mutant mice. Diabetes 56:1268–1276PubMedCrossRefPubMedCentralGoogle Scholar
  109. Herbach N, Schairer I, Blutke A, Kautz S, Siebert A, Goke B, Wolf E, Wanke R (2009) Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis. Am J Physiol Renal Physiol 296:F819–F829PubMedCrossRefPubMedCentralGoogle Scholar
  110. Hinkel R, Howe A, Renner S, Ng J, Lee S, Klett K, Kaczmarek V, Moretti A, Laugwitz KL, Skroblin P, Mayr M, Milting H, Dendorfer A, Reichart B, Wolf E, Kupatt C (2017) Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol 69:131–143PubMedCrossRefPubMedCentralGoogle Scholar
  111. Hinrichs A, Kessler B, Kurome M, Blutke A, Kemter E, Bernau M, Scholz AM, Rathkolb B, Renner S, Bultmann S, Leonhardt H, de Angelis MH, Nagashima H, Hoeflich A, Blum WF, Bidlingmaier M, Wanke R, Dahlhoff M, Wolf E (2018) Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver. Mol Metab 11:113–128PubMedPubMedCentralCrossRefGoogle Scholar
  112. Hoang DT, Matsunari H, Nagaya M, Nagashima H, Millis JM, Witkowski P, Periwal V, Hara M, Jo J (2014) A conserved rule for pancreatic islet organization. PloS One 9:e110384PubMedPubMedCentralCrossRefGoogle Scholar
  113. Hofmann A, Kessler B, Ewerling S, Weppert M, Vogg B, Ludwig H, Stojkovic M, Boelhauve M, Brem G, Wolf E, Pfeifer A (2003) Efficient transgenesis in farm animals by lentiviral vectors. EMBO Rep 4:1054–1060PubMedPubMedCentralCrossRefGoogle Scholar
  114. Hou L, Shi J, Cao L, Xu G, Hu C, Wang C (2017) Pig has no uncoupling protein 1. Biochem Biophys Res Commun 487:795–800PubMedCrossRefPubMedCentralGoogle Scholar
  115. Hoy WE, Hughson MD, Bertram JF, Douglas-Denton R, Amann K (2005) Nephron number, hypertension, renal disease, and renal failure. J Am Soc Nephrol 16:2557–2564PubMedCrossRefPubMedCentralGoogle Scholar
  116. Huang L, Hua Z, Xiao H, Cheng Y, Xu K, Gao Q, Xia Y, Liu Y, Zhang X, Zheng X, Mu Y, Li K (2017) CRISPR/Cas9-mediated ApoE−/− and LDLR−/− double gene knockout in pigs elevates serum LDL-C and TC levels. Oncotarget 8:37751–37760PubMedPubMedCentralGoogle Scholar
  117. Hudkins KL, Pichaiwong W, Wietecha T, Kowalewska J, Banas MC, Spencer MW, Muhlfeld A, Koelling M, Pippin JW, Shankland SJ, Askari B, Rabaglia ME, Keller MP, Attie AD, Alpers CE (2010) BTBR Ob/Ob mutant mice model progressive diabetic nephropathy. J Am Soc Nephrol 21:1533–1542PubMedPubMedCentralCrossRefGoogle Scholar
  118. Huxley RR, Filion KB, Konety S, Alonso A (2011) Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation. Am J Cardiol 108:56–62PubMedPubMedCentralCrossRefGoogle Scholar
  119. Inagi R, Yamamoto Y, Nangaku M, Usuda N, Okamato H, Kurokawa K, van Ypersele de Strihou C, Yamamoto H, Miyata T (2006) A severe diabetic nephropathy model with early development of nodule-like lesions induced by megsin overexpression in RAGE/iNOS transgenic mice. Diabetes 55:356–366PubMedCrossRefPubMedCentralGoogle Scholar
  120. International Diabetes Federation (2017) IDF Diabetes Atlas. International Diabetes Federation (IDF), BrüsselGoogle Scholar
  121. Itsumi M, Inoue S, Elia AJ, Murakami K, Sasaki M, Lind EF, Brenner D, Harris IS, Chio II, Afzal S, Cairns RA, Cescon DW, Elford AR, Ye J, Lang PA, Li WY, Wakeham A, Duncan GS, Haight J, You-Ten A, Snow B, Yamamoto K, Ohashi PS, Mak TW (2015) Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Cell Death Differ 22:1837–1845PubMedPubMedCentralCrossRefGoogle Scholar
  122. Jain SS, Paglialunga S, Vigna C, Ludzki A, Herbst EA, Lally JS, Schrauwen P, Hoeks J, Tupling AR, Bonen A, Holloway GP (2014) High-fat diet-induced mitochondrial biogenesis is regulated by mitochondrial-derived reactive oxygen species activation of CaMKII. Diabetes 63:1907–1913PubMedCrossRefPubMedCentralGoogle Scholar
  123. Jakobsen JE, Li J, Kragh PM, Moldt B, Lin L, Liu Y, Schmidt M, Winther KD, Schyth BD, Holm IE, Vajta G, Bolund L, Callesen H, Jorgensen AL, Nielsen AL, Mikkelsen JG (2011) Pig transgenesis by Sleeping Beauty DNA transposition. Transgenic Res 20:533–545PubMedCrossRefPubMedCentralGoogle Scholar
  124. Jastroch M, Andersson L (2015) When pigs fly, UCP1 makes heat. Mol Metab 4:359–362PubMedPubMedCentralCrossRefGoogle Scholar
  125. Jennings RE, Berry AA, Kirkwood-Wilson R, Roberts NA, Hearn T, Salisbury RJ, Blaylock J, Piper Hanley K, Hanley NA (2013) Development of the human pancreas from foregut to endocrine commitment. Diabetes 62:3514–3522PubMedPubMedCentralCrossRefGoogle Scholar
  126. Jensen-Waern M, Andersson M, Kruse R, Nilsson B, Larsson R, Korsgren O, Essen-Gustavsson B (2009) Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism. Lab Anim 43:249–254PubMedCrossRefPubMedCentralGoogle Scholar
  127. Jia G, Hill MA, Sowers JR (2018) Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res 122:624–638PubMedPubMedCentralCrossRefGoogle Scholar
  128. Johnstone DB, Holzman LB (2006) Clinical impact of research on the podocyte slit diaphragm. Nat Clin Pract Nephrol 2:271–282PubMedCrossRefPubMedCentralGoogle Scholar
  129. Jonsson J, Carlsson L, Edlund T, Edlund H (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606–609PubMedCrossRefPubMedCentralGoogle Scholar
  130. Kaabia Z, Poirier J, Moughaizel M, Aguesse A, Billon-Crossouard S, Fall F, Durand M, Dagher E, Krempf M, Croyal M (2018) Plasma lipidomic analysis reveals strong similarities between lipid fingerprints in human, hamster and mouse compared to other animal species. Sci Rep 8:15893PubMedPubMedCentralCrossRefGoogle Scholar
  131. Kang JD, Kim H, Jin L, Guo Q, Cui CD, Li WX, Kim S, Kim JS, Yin XJ (2017) Apancreatic pigs cloned using Pdx1-disrupted fibroblasts created via TALEN-mediated mutagenesis. Oncotarget 8:115480–115489PubMedPubMedCentralGoogle Scholar
  132. Kannel WB, Wolf PA, Benjamin EJ, Levy D (1998) Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 82:2N–9NPubMedCrossRefPubMedCentralGoogle Scholar
  133. Kato T, Yasue T, Shoji Y, Shimabukuro S, Ito Y, Goto S, Motooka S, Uno T, Ojima A (1987) Angiographic difference in coronary artery of man, dog, pig, and monkey. Acta Pathol Jpn 37:361–373PubMedPubMedCentralGoogle Scholar
  134. Kawanishi K, Dhar C, Do R, Varki N, Gordts P, Varki A (2019) Human species-specific loss of CMP-N-acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms. Proc Natl Acad Sci U S A 116:16036–16045CrossRefGoogle Scholar
  135. Kemter E, Wolf E (2018) Recent progress in porcine islet isolation, culture and engraftment strategies for xenotransplantation. Curr Opin Organ Transplant 23:633–641PubMedCrossRefPubMedCentralGoogle Scholar
  136. Kemter E, Cohrs CM, Schafer M, Schuster M, Steinmeyer K, Wolf-van Buerck L, Wolf A, Wuensch A, Kurome M, Kessler B, Zakhartchenko V, Loehn M, Ivashchenko Y, Seissler J, Schulte AM, Speier S, Wolf E (2017) INS-eGFP transgenic pigs: a novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters. Diabetologia 60:1152–1156PubMedCrossRefPubMedCentralGoogle Scholar
  137. Kemter E, Denner J, Wolf E (2018) Will genetic engineering carry xenotransplantation of pig islets to the clinic? Curr Diab Rep 18:103PubMedCrossRefPubMedCentralGoogle Scholar
  138. Kenny HC, Abel ED (2019) Heart failure in type 2 diabetes mellitus. Circ Res 124:121–141PubMedPubMedCentralCrossRefGoogle Scholar
  139. Khairoun M, van den Heuvel M, van den Berg BM, Sorop O, de Boer R, van Ditzhuijzen NS, Bajema IM, Baelde HJ, Zandbergen M, Duncker DJ, Rabelink TJ, Reinders ME, van der Giessen WJ, Rotmans JI (2015) Early systemic microvascular damage in pigs with atherogenic diabetes mellitus coincides with renal angiopoietin dysbalance. PLoS One 10:e0121555PubMedPubMedCentralCrossRefGoogle Scholar
  140. Kim JB (2016) Dynamic cross talk between metabolic organs in obesity and metabolic diseases. Exp Mol Med 48:e214PubMedPubMedCentralCrossRefGoogle Scholar
  141. Kim S, Whitener RL, Peiris H, Gu X, Chang CA, Lam JY, Camunas-Soler J, Park I, Bevacqua R, Tellez K, Quake SR, Lakey JRT, Bottino R, Ross PJ, Kim SK (2019) Molecular and genetic regulation of pig pancreatic islet cell development. bioRxiv 717090Google Scholar
  142. Kimmelstiel P, Wilson C (1936) Intercapillary lesions in the glomeruli of the kidney. Am J Pathol 12(83–98):87Google Scholar
  143. Kitada M, Ogura Y, Koya D (2016) Rodent models of diabetic nephropathy: their utility and limitations. Int J Nephrol Renovasc Dis 9:279–290PubMedPubMedCentralCrossRefGoogle Scholar
  144. Kiziltoprak H, Tekin K, Inanc M, Goker YS (2019) Cataract in diabetes mellitus. World J Diabetes 10:140–153PubMedPubMedCentralCrossRefGoogle Scholar
  145. Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, Huypens P, Beckers J, de Angelis MH, Schurmann A, Bakhti M, Klingenspor M, Heiman M, Cherrington AD, Ristow M, Lickert H, Wolf E, Havel PJ, Muller TD, Tschop MH (2018) Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 14:140–162PubMedCrossRefPubMedCentralGoogle Scholar
  146. Kleinwort KJH, Amann B, Hauck SM, Hirmer S, Blutke A, Renner S, Uhl PB, Lutterberg K, Sekundo W, Wolf E, Deeg CA (2017) Retinopathy with central oedema in an INS (C94Y) transgenic pig model of long-term diabetes. Diabetologia 60:1541–1549PubMedCrossRefPubMedCentralGoogle Scholar
  147. Klymiuk N, Seeliger F, Bohlooly YM, Blutke A, Rudmann DG, Wolf E (2016) Tailored pig models for preclinical efficacy and safety testing of targeted therapies. Toxicol Pathol 44:346–357PubMedCrossRefPubMedCentralGoogle Scholar
  148. Ko SH, Park YM, Yun JS, Cha SA, Choi EK, Han K, Han E, Lee YH, Ahn YB (2018) Severe hypoglycemia is a risk factor for atrial fibrillation in type 2 diabetes mellitus: Nationwide population-based cohort study. J Diabetes Complications 32:157–163PubMedCrossRefPubMedCentralGoogle Scholar
  149. Kodama K, Horikoshi M, Toda K, Yamada S, Hara K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H, Maeda S, Kadowaki T, Butte AJ (2012) Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. Proc Natl Acad Sci U S A 109:7049–7054PubMedPubMedCentralCrossRefGoogle Scholar
  150. Kong LL, Wu H, Cui WP, Zhou WH, Luo P, Sun J, Yuan H, Miao LN (2013) Advances in murine models of diabetic nephropathy. J Diabetes Res 2013:797548PubMedPubMedCentralCrossRefGoogle Scholar
  151. Kong S, Ruan J, Xin L, Fan J, Xia J, Liu Z, Mu Y, Yang S, Li K (2016) Multitransgenic minipig models exhibiting potential for hepatic insulin resistance and pancreatic apoptosis. Mol Med Rep 13:669–680PubMedCrossRefPubMedCentralGoogle Scholar
  152. Koopmans SJ, Mroz Z, Dekker R, Corbijn H, Ackermans M, Sauerwein H (2006) Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type 2-like diabetic pig model. Metabolism 55:960–971PubMedCrossRefPubMedCentralGoogle Scholar
  153. Koopmans SJ, VanderMeulen J, Wijdenes J, Corbijn H, Dekker R (2011) The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs. BMC Biochem 12:25PubMedPubMedCentralCrossRefGoogle Scholar
  154. Kopel J, Pena-Hernandez C, Nugent K (2019) Evolving spectrum of diabetic nephropathy. World J Diabetes 10:269–279PubMedPubMedCentralCrossRefGoogle Scholar
  155. Kronenberg F, Utermann G (2013) Lipoprotein(a): resurrected by genetics. J Intern Med 273:6–30PubMedCrossRefPubMedCentralGoogle Scholar
  156. Kurome M, Geistlinger L, Kessler B, Zakhartchenko V, Klymiuk N, Wuensch A, Richter A, Baehr A, Kraehe K, Burkhardt K, Flisikowski K, Flisikowska T, Merkl C, Landmann M, Durkovic M, Tschukes A, Kraner S, Schindelhauer D, Petri T, Kind A, Nagashima H, Schnieke A, Zimmer R, Wolf E (2013) Factors influencing the efficiency of generating genetically engineered pigs by nuclear transfer: multi-factorial analysis of a large data set. BMC Biotechnol 13:43PubMedPubMedCentralCrossRefGoogle Scholar
  157. Kurome M, Kessler B, Wuensch A, Nagashima H, Wolf E (2015) Nuclear transfer and transgenesis in the pig. Methods Mol Biol 1222:37–59PubMedCrossRefPubMedCentralGoogle Scholar
  158. Langin M, Mayr T, Reichart B, Michel S, Buchholz S, Guethoff S, Dashkevich A, Baehr A, Egerer S, Bauer A, Mihalj M, Panelli A, Issl L, Ying J, Fresch AK, Buttgereit I, Mokelke M, Radan J, Werner F, Lutzmann I, Steen S, Sjoberg T, Paskevicius A, Qiuming L, Sfriso R, Rieben R, Dahlhoff M, Kessler B, Kemter E, Kurome M, Zakhartchenko V, Klett K, Hinkel R, Kupatt C, Falkenau A, Reu S, Ellgass R, Herzog R, Binder U, Wich G, Skerra A, Ayares D, Kind A, Schonmann U, Kaup FJ, Hagl C, Wolf E, Klymiuk N, Brenner P, Abicht JM (2018) Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564:430–433PubMedCrossRefPubMedCentralGoogle Scholar
  159. Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N (2006) Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity). Clin Endocrinol 65:114–117CrossRefGoogle Scholar
  160. Larsen MO, Wilken M, Gotfredsen CF, Carr RD, Svendsen O, Rolin B (2002) Mild streptozotocin diabetes in the Gottingen minipig. A novel model of moderate insulin deficiency and diabetes. Am J Physiol Endocrinol Metab 282:E1342–E1351PubMedCrossRefPubMedCentralGoogle Scholar
  161. Lascar N, Brown J, Pattison H, Barnett AH, Bailey CJ, Bellary S (2018) Type 2 diabetes in adolescents and young adults. Lancet Diabetes Endocrinol 6:69–80PubMedCrossRefPubMedCentralGoogle Scholar
  162. Lee K (1986) Swine as animal models in cardiovascular research. Swine Biomed Res:1481–1498Google Scholar
  163. Lee MS, Song KD, Yang HJ, Solis CD, Kim SH, Lee WK (2012) Development of a type II diabetic mellitus animal model using Micropig(R). Lab Anim Res 28:205–208PubMedPubMedCentralCrossRefGoogle Scholar
  164. Lee JH, Kim D, Oh YS, Jun HS (2019) Lysophosphatidic acid signaling in diabetic nephropathy. Int J Mol Sci 20:2850PubMedCentralCrossRefGoogle Scholar
  165. Lehrke M, Marx N (2017) Diabetes mellitus and heart failure. Am J Med 130:S40–S50PubMedCrossRefPubMedCentralGoogle Scholar
  166. Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226PubMedCrossRefPubMedCentralGoogle Scholar
  167. Lerman LO, Kurtz TW, Touyz RM, Ellison DH, Chade AR, Crowley SD, Mattson DL, Mullins JJ, Osborn J, Eirin A, Reckelhoff JF, Iadecola C, Coffman TM (2019) Animal models of hypertension: a scientific statement from the American Heart Association. Hypertension 73:e87–e120PubMedPubMedCentralCrossRefGoogle Scholar
  168. Li Z, Woollard JR, Wang S, Korsmo MJ, Ebrahimi B, Grande JP, Textor SC, Lerman A, Lerman LO (2011) Increased glomerular filtration rate in early metabolic syndrome is associated with renal adiposity and microvascular proliferation. Am J Physiol Renal Physiol 301:F1078–F1087PubMedPubMedCentralCrossRefGoogle Scholar
  169. Li D, Wang Q, Zhang Y, Li D, Yang D, Wei S, Su L, Ye T, Zheng X, Peng K, Zhang L, Zhang Y, Yang Y, Ma S (2016a) A novel swine model of spontaneous hypertension with sympathetic hyperactivity responds well to renal denervation. Am J Hypertens 29:63–72PubMedCrossRefPubMedCentralGoogle Scholar
  170. Li Y, Fuchimoto D, Sudo M, Haruta H, Lin QF, Takayama T, Morita S, Nochi T, Suzuki S, Sembon S, Nakai M, Kojima M, Iwamoto M, Hashimoto M, Yoda S, Kunimoto S, Hiro T, Matsumoto T, Mitsumata M, Sugitani M, Saito S, Hirayama A, Onishi A (2016b) Development of human-like advanced coronary plaques in low-density lipoprotein receptor knockout pigs and justification for statin treatment before formation of atherosclerotic plaques. J Am Heart Assoc 5:e002779PubMedPubMedCentralGoogle Scholar
  171. Lim RR, Grant DG, Olver TD, Padilla J, Czajkowski AM, Schnurbusch TR, Mohan RR, Hainsworth DP, Walters EM, Chaurasia SS (2018) Young Ossabaw pigs fed a western diet exhibit early signs of diabetic retinopathy. Invest Ophthalmol Vis Sci 59:2325–2338PubMedPubMedCentralCrossRefGoogle Scholar
  172. Lin J, Cao C, Tao C, Ye R, Dong M, Zheng Q, Wang C, Jiang X, Qin G, Yan C, Li K, Speakman JR, Wang Y, Jin W, Zhao J (2017) Cold adaptation in pigs depends on UCP3 in beige adipocytes. J Mol Cell Biol 9:364–375PubMedCrossRefPubMedCentralGoogle Scholar
  173. List EO, Sackmann-Sala L, Berryman DE, Funk K, Kelder B, Gosney ES, Okada S, Ding J, Cruz-Topete D, Kopchick JJ (2011) Endocrine parameters and phenotypes of the growth hormone receptor gene disrupted (GHR−/−) mouse. Endocrine Rev 32:356–386CrossRefGoogle Scholar
  174. Liu JS, Hebrok M (2017) All mixed up: defining roles for beta-cell subtypes in mature islets. Genes Dev 31:228–240PubMedPubMedCentralCrossRefGoogle Scholar
  175. Liu Y, Wang Z, Yin W, Li Q, Cai M, Zhang C, Xiao J, Hou H, Li H, Zu X (2007) Severe insulin resistance and moderate glomerulosclerosis in a minipig model induced by high-fat/ high-sucrose/ high-cholesterol diet. Exp Anim 56:11–20PubMedCrossRefPubMedCentralGoogle Scholar
  176. Liu M, Sun J, Cui J, Chen W, Guo H, Barbetti F, Arvan P (2015) INS-gene mutations: from genetics and beta cell biology to clinical disease. Mol Asp Med 42:3–18CrossRefGoogle Scholar
  177. Liu Y, Yuan J, Xiang L, Zhao Y, Niu M, Dai X, Chen H (2017) A high sucrose and high fat diet induced the development of insulin resistance in the skeletal muscle of Bama miniature pigs through the Akt/GLUT4 pathway. Exp Anim 66:387–395PubMedPubMedCentralCrossRefGoogle Scholar
  178. Longo N, Frigeni M, Pasquali M (2016) Carnitine transport and fatty acid oxidation. Biochim Biophys Acta 1863:2422–2435PubMedPubMedCentralCrossRefGoogle Scholar
  179. Lu L, Zhang Q, Pu LJ, Peng WH, Yan XX, Wang LJ, Chen QJ, Zhu ZB, Michel JB, Shen WF (2008) Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin-induced diabetic minipigs. Int J Exp Pathol 89:125–137PubMedPubMedCentralCrossRefGoogle Scholar
  180. Lu L, Zhou H, Ni M, Wang X, Busuttil R, Kupiec-Weglinski J, Zhai Y (2016) Innate immune regulations and liver ischemia-reperfusion injury. Transplantation 100:2601–2610PubMedPubMedCentralCrossRefGoogle Scholar
  181. Lu L, Ye S, Scalzo RL, Reusch JEB, Greyson CR, Schwartz GG (2017) Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs. Diabetologia 60:1550–1558PubMedPubMedCentralCrossRefGoogle Scholar
  182. Ludvigsen TP, Kirk RK, Christoffersen BO, Pedersen HD, Martinussen T, Kildegaard J, Heegaard PM, Lykkesfeldt J, Olsen LH (2015a) Gottingen minipig model of diet-induced atherosclerosis: influence of mild streptozotocin-induced diabetes on lesion severity and markers of inflammation evaluated in obese, obese and diabetic, and lean control animals. J Transl Med 13:312PubMedPubMedCentralCrossRefGoogle Scholar
  183. Ludvigsen TP, Kirk RK, Christoffersen BØ, Pedersen HD, Martinussen T, Kildegaard J, Heegaard PMH, Lykkesfeldt J, Olsen LH (2015b) Göttingen minipig model of diet-induced atherosclerosis: influence of mild streptozotocin-induced diabetes on lesion severity and markers of inflammation evaluated in obese, obese and diabetic, and lean control animals. J Transl Med 13:312PubMedPubMedCentralCrossRefGoogle Scholar
  184. Maile LA, Busby WH, Gollahon KA, Flowers W, Garbacik N, Garbacik S, Stewart K, Nichols T, Bellinger D, Patel A, Dunbar P, Medlin M, Clemmons D (2014) Blocking ligand occupancy of the alphaVbeta3 integrin inhibits the development of nephropathy in diabetic pigs. Endocrinology 155:4665–4675PubMedPubMedCentralCrossRefGoogle Scholar
  185. Marques IP, Alves D, Santos T, Mendes L, Santos AR, Lobo C, Durbin M, Cunha-Vaz J (2019) Multimodal imaging of the initial stages of diabetic retinopathy: different disease pathways in different patients. Diabetes 68:648–653PubMedCrossRefPubMedCentralGoogle Scholar
  186. Marso SP, House JA, Klauss V, Lerman A, Margolis P, Leon MB, Global V-I (2010) Diabetes mellitus is associated with plaque classified as thin cap fibroatheroma: an intravascular ultrasound study. Diab Vasc Dis Res 7:14–19PubMedCrossRefPubMedCentralGoogle Scholar
  187. Martinez DA, Guhl DJ, Stanley WC, Vailas AC (2003) Extracellular matrix maturation in the left ventricle of normal and diabetic swine. Diabetes Res Clin Pract 59:1–9PubMedCrossRefPubMedCentralGoogle Scholar
  188. Matoba K, Takeda Y, Nagai Y, Kawanami D, Utsunomiya K, Nishimura R (2019) Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease. Int J Mol Sci 20PubMedCentralCrossRefGoogle Scholar
  189. Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, Kobayashi T, Yamaguchi T, Sumazaki R, Herzenberg LA, Nakauchi H (2013) Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc Natl Acad Sci U S A 110:4557–4562PubMedPubMedCentralCrossRefGoogle Scholar
  190. Matsunari H, Kobayashi T, Watanabe M, Umeyama K, Nakano K, Kanai T, Matsuda T, Nagaya M, Hara M, Nakauchi H, Nagashima H (2014) Transgenic pigs with pancreas-specific expression of green fluorescent protein. J Reprod Dev 60:230–237PubMedPubMedCentralCrossRefGoogle Scholar
  191. McGaugh S, Schwartz TS (2017) Here and there, but not everywhere: repeated loss of uncoupling protein 1 in amniotes. Biol Lett 13:Google Scholar
  192. Meier M, Haller H (2004) Diabetic nephropathy - current concepts in early diagnosis and treatment of diabetic microvascular complications. Herz 29:496–503PubMedCrossRefPubMedCentralGoogle Scholar
  193. Meng Q, Makinen VP, Luk H, Yang X (2013) Systems biology approaches and applications in obesity, diabetes, and cardiovascular diseases. Curr Cardiovasc Risk Rep 7:73–83PubMedCrossRefPubMedCentralGoogle Scholar
  194. Mesangeau D, Laude D, Elghozi JL (2000) Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability. Cardiovasc Res 45:889–899PubMedCrossRefPubMedCentralGoogle Scholar
  195. Middleton S (2010) Porcine ophthalmology. Vet Clin North Am Food Anim Pract 26:557–572PubMedCrossRefPubMedCentralGoogle Scholar
  196. Mitasikova M, Lin H, Soukup T, Imanaga I, Tribulova N (2009) Diabetes and thyroid hormones affect connexin-43 and PKC-epsilon expression in rat heart atria. Physiological research 58:211–217PubMedPubMedCentralGoogle Scholar
  197. Mizutani M, Gerhardinger C, Lorenzi M (1998) Muller cell changes in human diabetic retinopathy. Diabetes 47:445–449PubMedCrossRefPubMedCentralGoogle Scholar
  198. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB (2016) Mechanisms of diabetes-induced liver damage: the role of oxidative stress and inflammation. Sultan Qaboos Univ Med J 16:e132–e141PubMedPubMedCentralCrossRefGoogle Scholar
  199. Mohiuddin MM, Singh AK, Corcoran PC, Thomas Iii ML, Clark T, Lewis BG, Hoyt RF, Eckhaus M, Pierson Iii RN, Belli AJ, Wolf E, Klymiuk N, Phelps C, Reimann KA, Ayares D, Horvath KA (2016) Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat Commun 7:11138PubMedPubMedCentralCrossRefGoogle Scholar
  200. Mokelke EA, Hu Q, Song M, Toro L, Reddy HK, Sturek M (2003) Altered functional coupling of coronary K+ channels in diabetic dyslipidemic pigs is prevented by exercise. J Appl Physiol (1985) 95:1179–1193CrossRefGoogle Scholar
  201. Mokelke EA, Dietz NJ, Eckman DM, Nelson MT, Sturek M (2005) Diabetic dyslipidemia and exercise affect coronary tone and differential regulation of conduit and microvessel K+ current. Am J Physiol Heart Circ Physiol 288:H1233–H1241PubMedCrossRefPubMedCentralGoogle Scholar
  202. Mooradian AD (2009) Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab 5:150–159PubMedPubMedCentralGoogle Scholar
  203. Nauck MA, Meier JJ (2016) The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol 4:525–536PubMedCrossRefPubMedCentralGoogle Scholar
  204. Neeb ZP, Edwards JM, Alloosh M, Long X, Mokelke EA, Sturek M (2010) Metabolic syndrome and coronary artery disease in Ossabaw compared with Yucatan swine. Comp Med 60:300–315PubMedPubMedCentralGoogle Scholar
  205. Newman JC, Verdin E (2014) Ketone bodies as signaling metabolites. Trends Endocrinol Metab 25:42–52PubMedCrossRefPubMedCentralGoogle Scholar
  206. Nyengaard JR (1999) Stereologic methods and their application in kidney research. J Am Soc Nephrol 10:1100–1123PubMedPubMedCentralGoogle Scholar
  207. Obrochta KM, Krois CR, Campos B, Napoli JL (2015) Insulin regulates retinol dehydrogenase expression and all-trans-retinoic acid biosynthesis through FoxO1. J Biol Chem 290:7259–7268PubMedPubMedCentralCrossRefGoogle Scholar
  208. Odeh M, Oliven A, Bassan H (1990) Transient atrial fibrillation precipitated by hypoglycemia. Ann Emerg Med 19:565–567PubMedCrossRefPubMedCentralGoogle Scholar
  209. Olivares AM, Althoff K, Chen GF, Wu S, Morrisson MA, DeAngelis MM, Haider N (2017) Animal models of diabetic retinopathy. Curr Diab Rep 17:93–93PubMedPubMedCentralCrossRefGoogle Scholar
  210. Ozawa M, Himaki T, Ookutsu S, Mizobe Y, Ogawa J, Miyoshi K, Yabuki A, Fan J, Yoshida M (2015) Production of cloned miniature pigs expressing high levels of human apolipoprotein(a) in plasma. PLoS One 10:e0132155PubMedPubMedCentralCrossRefGoogle Scholar
  211. Palee S, Weerateerangkul P, Surinkeaw S, Chattipakorn S, Chattipakorn N (2011) Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart. Exp Physiol 96:778–789PubMedCrossRefPubMedCentralGoogle Scholar
  212. Panasevich MR, Meers GM, Linden MA, Booth FW, Perfield JW 2nd, Fritsche KL, Wankhade UD, Chintapalli SV, Shankar K, Ibdah JA, Rector RS (2018) High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Am J Physiol Endocrinol Metab 314:E78–e92PubMedCrossRefPubMedCentralGoogle Scholar
  213. Park J, Shrestha R, Qiu C, Kondo A, Huang S, Werth M, Li M, Barasch J, Susztak K (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758–763PubMedPubMedCentralCrossRefGoogle Scholar
  214. Park JJ, Kim SH, Kim MA, Chae IH, Choi DJ, Yoon CH (2019) Effect of Hyperglycemia on myocardial perfusion in diabetic porcine models and humans. J Korean Med Sci 34:e202PubMedPubMedCentralCrossRefGoogle Scholar
  215. Pickar-Oliver A, Gersbach CA (2019) The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol 20:490–507PubMedCrossRefPubMedCentralGoogle Scholar
  216. Pollreisz A, Schmidt-Erfurth U (2010) Diabetic cataract-pathogenesis, epidemiology and treatment. J Ophthalmol 2010:608751PubMedPubMedCentralGoogle Scholar
  217. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Group ESCSD (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200PubMedCrossRefPubMedCentralGoogle Scholar
  218. Pontoglio M (2000) Hepatocyte nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis. J Am Soc Nephrol 11(Suppl 16):S140–S143PubMedPubMedCentralGoogle Scholar
  219. Popper B (2014) Impact of the genetic background on the development of diabetes-associated renal lesions in GIPRdn transgenic diabetic mice. Doctoral thesis, LMU MunichGoogle Scholar
  220. Ramirez AH, Schildcrout JS, Blakemore DL, Masys DR, Pulley JM, Basford MA, Roden DM, Denny JC (2011) Modulators of normal electrocardiographic intervals identified in a large electronic medical record. Heart Rhythm 8:271–277PubMedCrossRefPubMedCentralGoogle Scholar
  221. Rapacz J, Hasler-Rapacz J, Taylor KM, Checovich WJ, Attie AD (1986) Lipoprotein mutations in pigs are associated with elevated plasma cholesterol and atherosclerosis. Science 234:1573–1577PubMedCrossRefPubMedCentralGoogle Scholar
  222. Rask-Madsen C, King GL (2013) Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 17:20–33PubMedPubMedCentralCrossRefGoogle Scholar
  223. Remuzzi G, Bertani T (1990) Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int 38:384–394PubMedCrossRefPubMedCentralGoogle Scholar
  224. Ren Z, Wang Y, Ren Y, Zhang Z, Gu W, Wu Z, Chen L, Mou L, Li R, Yang H, Dai Y (2017) Enhancement of porcine intramuscular fat content by overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase in skeletal muscle. Sci Rep 7:43746PubMedPubMedCentralCrossRefGoogle Scholar
  225. Renner S, Fehlings C, Herbach N, Hofmann A, von Waldthausen DC, Kessler B, Ulrichs K, Chodnevskaja I, Moskalenko V, Amselgruber W, Goke B, Pfeifer A, Wanke R, Wolf E (2010) Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59:1228–1238PubMedPubMedCentralCrossRefGoogle Scholar
  226. Renner S, Romisch-Margl W, Prehn C, Krebs S, Adamski J, Goke B, Blum H, Suhre K, Roscher AA, Wolf E (2012) Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced beta-cell mass. Diabetes 61:2166–2175PubMedPubMedCentralCrossRefGoogle Scholar
  227. Renner S, Braun-Reichhart C, Blutke A, Herbach N, Emrich D, Streckel E, Wunsch A, Kessler B, Kurome M, Bahr A, Klymiuk N, Krebs S, Puk O, Nagashima H, Graw J, Blum H, Wanke R, Wolf E (2013) Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes 62:1505–1511PubMedPubMedCentralCrossRefGoogle Scholar
  228. Renner S, Blutke A, Streckel E, Wanke R, Wolf E (2016a) Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models. J Pathol 238:345–358PubMedCrossRefPubMedCentralGoogle Scholar
  229. Renner S, Dobenecker B, Blutke A, Zols S, Wanke R, Ritzmann M, Wolf E (2016b) Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research. Theriogenology 86:406–421PubMedCrossRefPubMedCentralGoogle Scholar
  230. Renner S, Blutke A, Dobenecker B, Dhom G, Muller TD, Finan B, Clemmensen C, Bernau M, Novak I, Rathkolb B, Senf S, Zols S, Roth M, Gotz A, Hofmann SM, Hrabe de Angelis M, Wanke R, Kienzle E, Scholz AM, DiMarchi R, Ritzmann M, Tschop MH, Wolf E (2018) Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Gottingen minipigs. Mol Metab 16:180–190PubMedPubMedCentralCrossRefGoogle Scholar
  231. Renner S, Martins AS, Streckel E, Braun-Reichhart C, Backman M, Prehn C, Klymiuk N, Bahr A, Blutke A, Landbrecht-Schessl C, Wunsch A, Kessler B, Kurome M, Hinrichs A, Koopmans SJ, Krebs S, Kemter E, Rathkolb B, Nagashima H, Blum H, Ritzmann M, Wanke R, Aigner B, Adamski J, Hrabe de Angelis M, Wolf E (2019) Mild maternal hyperglycemia in INS (C93S) transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring. Dis Model MechGoogle Scholar
  232. Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ (2013) Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes 62:3570–3581PubMedPubMedCentralCrossRefGoogle Scholar
  233. Rieger A, Kemter E, Kumar S, Popper B, Aigner B, Wolf E, Wanke R, Blutke A (2016) Missense mutation of POU domain class 3 transcription factor 3 in Pou3f3L423P mice causes reduced nephron number and impaired development of the thick ascending limb of the loop of henle. PloS One 11:e0158977PubMedPubMedCentralCrossRefGoogle Scholar
  234. Roberts AC, Porter KE (2013) Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res 10:472–482PubMedCrossRefPubMedCentralGoogle Scholar
  235. Robinson R, Barathi VA, Chaurasia SS, Wong TY, Kern TS (2012) Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Dis Model Mech 5:444–456CrossRefGoogle Scholar
  236. Roden M (2015) Future of muscle research in diabetes: a look into the crystal ball. Diabetologia 58:1693–1698PubMedCrossRefPubMedCentralGoogle Scholar
  237. Romacho T, Elsen M, Rohrborn D, Eckel J (2014) Adipose tissue and its role in organ crosstalk. Acta Physiologica (Oxf) 210:733–753CrossRefGoogle Scholar
  238. Ruan J, Zhang Y, Yuan J, Xin L, Xia J, Liu N, Mu Y, Chen Y, Yang S, Li K (2016) A long-term high-fat, high-sucrose diet in Bama minipigs promotes lipid deposition and amyotrophy by up-regulating the myostatin pathway. Mol Cell Endocrinol 425:123–132PubMedCrossRefPubMedCentralGoogle Scholar
  239. Rukstalis JM, Habener JF (2009) Neurogenin3: a master regulator of pancreatic islet differentiation and regeneration. Islets 1:177–184PubMedCrossRefPubMedCentralGoogle Scholar
  240. Saito S, Teshima Y, Fukui A, Kondo H, Nishio S, Nakagawa M, Saikawa T, Takahashi N (2014) Glucose fluctuations increase the incidence of atrial fibrillation in diabetic rats. Cardiovasc Res 104:5–14PubMedCrossRefPubMedCentralGoogle Scholar
  241. Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A, Imran A, Abbas S, Majeed F, Akhtar S, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Mallick NH, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Frossard P, Tsimikas S, Witztum JL, Marcovina S, Sandhu M, Rader DJ, Danesh J (2017) Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol 5:524–533PubMedPubMedCentralCrossRefGoogle Scholar
  242. Samdani P, Singhal M, Sinha N, Tripathi P, Sharma S, Tikoo K, Rao KV, Kumar D (2015) A comprehensive inter-tissue crosstalk analysis underlying progression and control of obesity and diabetes. Scientific Rep 5:12340CrossRefGoogle Scholar
  243. Sas KM, Karnovsky A, Michailidis G, Pennathur S (2015) Metabolomics and diabetes: analytical and computational approaches. Diabetes 64:718–732PubMedPubMedCentralCrossRefGoogle Scholar
  244. Schneider MR, Wolf E (2016) Genetically engineered pigs as investigative and translational models in dermatology. Br J Dermatol 174:237–239PubMedCrossRefPubMedCentralGoogle Scholar
  245. Shankland SJ (2006) The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 69:2131–2147PubMedCrossRefPubMedCentralGoogle Scholar
  246. Shapiro MD, Tavori H, Fazio S (2018) PCSK9: From basic science discoveries to clinical trials. Circ Res 122:1420–1438PubMedPubMedCentralCrossRefGoogle Scholar
  247. Sheets TP, Park KE, Park CH, Swift SM, Powell A, Donovan DM, Telugu BP (2018) Targeted mutation of NGN3 gene disrupts pancreatic endocrine cell development in pigs. Sci Rep 8:3582PubMedPubMedCentralCrossRefGoogle Scholar
  248. Shimatsu Y, Horii W, Nunoya T, Iwata A, Fan J, Ozawa M (2016) Production of human apolipoprotein(a) transgenic NIBS miniature pigs by somatic cell nuclear transfer. Exp Anim 65:37–43PubMedCrossRefPubMedCentralGoogle Scholar
  249. Shirakawa J, De Jesus DF, Kulkarni RN (2017) Exploring inter-organ crosstalk to uncover mechanisms that regulate beta-cell function and mass. Eur J Clin Nutr 71:896–903PubMedCrossRefPubMedCentralGoogle Scholar
  250. Shu X, Nelbach L, Ryan RO, Forte TM (2010) Apolipoprotein A-V associates with intrahepatic lipid droplets and influences triglyceride accumulation. Biochim Biophys Acta 1801:605–608PubMedPubMedCentralCrossRefGoogle Scholar
  251. Singh JP, Larson MG, O’Donnell CJ, Wilson PF, Tsuji H, Lloyd-Jones DM, Levy D (2000) Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study). Am J Cardiol 86:309–312PubMedCrossRefPubMedCentralGoogle Scholar
  252. Sivieri R, Veglio M, Chinaglia A, Scaglione P, Cavallo-Perin P (1993) Prevalence of QT prolongation in a type 1 diabetic population and its association with autonomic neuropathy. The Neuropathy Study Group of the Italian Society for the Study of Diabetes. Diabet Med 10:920–924PubMedCrossRefPubMedCentralGoogle Scholar
  253. Skold BH, Getty R, Ramsey FK (1966) Spontaneous atherosclerosis in the arterial system of aging swine. Am J Vet Res 27:257–273PubMedPubMedCentralGoogle Scholar
  254. Sodha NR, Clements RT, Boodhwani M, Xu SH, Laham RJ, Bianchi C, Sellke FW (2009) Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation. Am J Physiol Heart Circ Physiol 296:H428–H434PubMedCrossRefPubMedCentralGoogle Scholar
  255. Sorop O, van den Heuvel M, van Ditzhuijzen NS, de Beer VJ, Heinonen I, van Duin RW, Zhou Z, Koopmans SJ, Merkus D, van der Giessen WJ, Danser AH, Duncker DJ (2016) Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia. Am J Physiol Heart Circ Physiol 311:H1339–H1351PubMedCrossRefPubMedCentralGoogle Scholar
  256. Sorop O, Heinonen I, van Kranenburg M, van de Wouw J, de Beer VJ, Nguyen ITN, Octavia Y, van Duin RWB, Stam K, van Geuns RJ, Wielopolski PA, Krestin GP, van den Meiracker AH, Verjans R, van Bilsen M, Danser AHJ, Paulus WJ, Cheng C, Linke WA, Joles JA, Verhaar MC, van der Velden J, Merkus D, Duncker DJ (2018) Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. Cardiovasc Res 114:954–964PubMedPubMedCentralCrossRefGoogle Scholar
  257. Sowton AP, Griffin JL, Murray AJ (2019) Metabolic profiling of the diabetic heart: toward a richer picture. Front Physiol 10:639PubMedPubMedCentralCrossRefGoogle Scholar
  258. Stanley WC, Hall JL, Hacker TA, Hernandez LA, Whitesell LF (1997) Decreased myocardial glucose uptake during ischemia in diabetic swine. Metabolism 46:168–172PubMedCrossRefPubMedCentralGoogle Scholar
  259. Stern JH, Rutkowski JM, Scherer PE (2016) Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 23:770–784PubMedPubMedCentralCrossRefGoogle Scholar
  260. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106–110PubMedCrossRefPubMedCentralGoogle Scholar
  261. Stoy J, Steiner DF, Park SY, Ye H, Philipson LH, Bell GI (2010) Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord 11:205–215PubMedPubMedCentralCrossRefGoogle Scholar
  262. Streckel E, Braun-Reichhart C, Herbach N, Dahlhoff M, Kessler B, Blutke A, Bahr A, Ubel N, Eddicks M, Ritzmann M, Krebs S, Goke B, Blum H, Wanke R, Wolf E, Renner S (2015) Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition. J Transl Med 13:73PubMedPubMedCentralCrossRefGoogle Scholar
  263. Suchy F, Nakauchi H (2018) Interspecies chimeras. Curr Opin Genet Dev 52:36–41PubMedCrossRefPubMedCentralGoogle Scholar
  264. Sumazaki R, Shiojiri N, Isoyama S, Masu M, Keino-Masu K, Osawa M, Nakauchi H, Kageyama R, Matsui A (2004) Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 36:83–87PubMedCrossRefPubMedCentralGoogle Scholar
  265. Sun YV, Hu YJ (2016) Integrative analysis of multi-omics data for discovery and functional studies of complex human diseases. Adv Genet 93:147–190PubMedPubMedCentralCrossRefGoogle Scholar
  266. Susan-Resiga D, Girard E, Kiss RS, Essalmani R, Hamelin J, Asselin MC, Awan Z, Butkinaree C, Fleury A, Soldera A, Dory YL, Baass A, Seidah NG (2017) The proprotein convertase subtilisin/kexin type 9-resistant R410S low density lipoprotein receptor mutation: a novel mechanism causing familial hypercholesterolemia. J Biol Chem 292:1573–1590PubMedCrossRefPubMedCentralGoogle Scholar
  267. Szabo G (2015) Gut-liver axis in alcoholic liver disease. Gastroenterology 148:30–36PubMedCrossRefPubMedCentralGoogle Scholar
  268. Tang X, Wang G, Liu X, Han X, Li Z, Ran G, Li Z, Song Q, Ji Y, Wang H, Wang Y, Ouyang H, Pang D (2015) Overexpression of porcine lipoprotein-associated phospholipase A2 in swine. Biochem Biophys Res Commun 465:507–511PubMedCrossRefPubMedCentralGoogle Scholar
  269. Targher G, Lonardo A, Byrne CD (2018) Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol 14:99–114PubMedCrossRefPubMedCentralGoogle Scholar
  270. Topf F, Schvartz D, Gaudet P, Priego-Capote F, Zufferey A, Turck N, Binz P-A, Fontana P, Wiederkehr A, Finamore F, Xenarios I, Goodlett D, Kussmann M, Bergsten P, Sanchez J-C (2013) The Human Diabetes Proteome Project (HDPP): from network biology to targets for therapies and prevention. Transl Proteomics 1:3–11CrossRefGoogle Scholar
  271. Tritschler S, Theis FJ, Lickert H, Bottcher A (2017) Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. Mol Metab 6:974–990PubMedPubMedCentralCrossRefGoogle Scholar
  272. Tu CF, Hsu CY, Lee MH, Jiang BH, Guo SF, Lin CC, Yang TS (2018) Growing pigs developed different types of diabetes induced by streptozotocin depending on their transcription factor 7-like 2 gene polymorphisms. Lab Anim Res 34:185–194PubMedPubMedCentralCrossRefGoogle Scholar
  273. Umeyama K, Watanabe M, Saito H, Kurome M, Tohi S, Matsunari H, Miki K, Nagashima H (2009) Dominant-negative mutant hepatocyte nuclear factor 1alpha induces diabetes in transgenic-cloned pigs. Transgenic Res 18:697–706PubMedCrossRefPubMedCentralGoogle Scholar
  274. Umeyama K, Nakajima M, Yokoo T, Nagaya M, Nagashima H (2017) Diabetic phenotype of transgenic pigs introduced by dominant-negative mutant hepatocyte nuclear factor 1alpha. J Diabetes Complications 31:796–803PubMedCrossRefPubMedCentralGoogle Scholar
  275. van den Heuvel M, Sorop O, Koopmans SJ, Dekker R, de Vries R, van Beusekom HM, Eringa EC, Duncker DJ, Danser AH, van der Giessen WJ (2012) Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes. Am J Physiol Heart Circ Physiol 302:H85–H94PubMedCrossRefPubMedCentralGoogle Scholar
  276. van Ditzhuijzen NS, van den Heuvel M, Sorop O, Rossi A, Veldhof T, Bruining N, Roest S, Ligthart JMR, Witberg KT, Dijkshoorn ML, Nieman K, Mulder MT, Zijlstra F, Duncker DJ, van Beusekom HMM, Regar E (2016) Serial coronary imaging of early atherosclerosis development in fast-food-fed diabetic and nondiabetic swine. JACC Basic Transl Sci 1:449–460PubMedPubMedCentralCrossRefGoogle Scholar
  277. Vijayakumar A, Novosyadlyy R, Wu Y, Yakar S, LeRoith D (2010) Biological effects of growth hormone on carbohydrate and lipid metabolism. Growth Horm IGF Res 20:1–7PubMedCrossRefPubMedCentralGoogle Scholar
  278. Wang H, Eckel RH (2009) Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab 297:E271–E288PubMedCrossRefPubMedCentralGoogle Scholar
  279. Wang X, Garrett MR (2017) Nephron number, hypertension, and CKD: physiological and genetic insight from humans and animal models. Physiol Genomics 49:180–192PubMedPubMedCentralCrossRefGoogle Scholar
  280. Wang SQ, Li D, Yuan Y (2019) Long-term moderate intensity exercise alleviates myocardial fibrosis in type 2 diabetic rats via inhibitions of oxidative stress and TGF-beta1/Smad pathway. J Physiol Sci 69:861–873PubMedCrossRefPubMedCentralGoogle Scholar
  281. Wanke R, Wolf E, Brem G, Hermanns W (2001) Role of podocyte damage in the pathogenesis of glomerulosclerosis and tubulointerstitial lesions: findings in the growth hormone transgenic mouse model of progressive nephropathy. Verh Dtsch Ges Pathol 85:250–256PubMedPubMedCentralGoogle Scholar
  282. Warr A, Affara N, Aken B, Beiki H, Bickhart DM, Billis K, Chow W, Eory L, Finlayson HA, Flicek P, Girón CG, Griffin DK, Hall R, Hannum G, Hourlier T, Howe K, Hume DA, Izuogu O, Kim K, Koren S, Liu H, Manchanda N, Martin FJ, Nonneman DJ, O’Connor RE, Phillippy AM, Rohrer GA, Rosen BD, Rund LA, Sargent CA, Schook LB, Schroeder SG, Schwartz AS, Skinner BM, Talbot R, Tseng E, Tuggle CK, Watson M, Smith TPL, Archibald AL (2019) An improved pig reference genome sequence to enable pig genetics and genomics research. bioRxiv 668921Google Scholar
  283. Wei J, Ouyang H, Wang Y, Pang D, Cong NX, Wang T, Leng B, Li D, Li X, Wu R, Ding Y, Gao F, Deng Y, Liu B, Li Z, Lai L, Feng H, Liu G, Deng X (2012) Characterization of a hypertriglyceridemic transgenic miniature pig model expressing human apolipoprotein CIII. FEBS J 279:91–99PubMedCrossRefPubMedCentralGoogle Scholar
  284. Whitfield J (2003) Fat pigs ape obese humans. Nature Publishing GroupGoogle Scholar
  285. Whitham M, Febbraio MA (2016) The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov 15:719–729PubMedCrossRefPubMedCentralGoogle Scholar
  286. Whyte JJ, Zhao J, Wells KD, Samuel MS, Whitworth KM, Walters EM, Laughlin MH, Prather RS (2011) Gene targeting with zinc finger nucleases to produce cloned eGFP knockout pigs. Mol Reprod Dev 78:2PubMedPubMedCentralCrossRefGoogle Scholar
  287. Wiggins RC (2007) The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 71:1205–1214PubMedCrossRefPubMedCentralGoogle Scholar
  288. Wolf G (2004) New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest 34:785–796PubMedCrossRefPubMedCentralGoogle Scholar
  289. Wolf E, Braun-Reichhart C, Streckel E, Renner S (2014) Genetically engineered pig models for diabetes research. Transgenic Res 23:27–38PubMedCrossRefPubMedCentralGoogle Scholar
  290. Wolf E, Kemter E, Klymiuk N, Reichart B (2019) Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation. Animal Front 9:13–20CrossRefGoogle Scholar
  291. Wolfrum C, Besser D, Luca E, Stoffel M (2003) Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc Natl Acad Sci U S A 100:11624–11629PubMedPubMedCentralCrossRefGoogle Scholar
  292. Xu Z, Patel KP, Rozanski GJ (1996) Metabolic basis of decreased transient outward K+ current in ventricular myocytes from diabetic rats. Am J Physiol 271:H2190–H2196PubMedPubMedCentralGoogle Scholar
  293. Xu Y, Lu L, Greyson C, Lee J, Gen M, Kinugawa K, Long CS, Schwartz GG (2003) Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs. Diabetes 52:1187–1194PubMedPubMedCentralCrossRefGoogle Scholar
  294. Yacoub R, Campbell KN (2015) Inhibition of RAS in diabetic nephropathy. Int J Nephrol Renovasc Dis 8:29–40PubMedPubMedCentralGoogle Scholar
  295. Yamagata K (2003) Regulation of pancreatic beta-cell function by the HNF transcription network: lessons from maturity-onset diabetes of the young (MODY). Endocr J 50:491–499PubMedCrossRefPubMedCentralGoogle Scholar
  296. Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI et al (1996) Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384:455–458PubMedCrossRefPubMedCentralGoogle Scholar
  297. Yamagishi S, Matsui T (2016) Pathologic role of dietary advanced glycation end products in cardiometabolic disorders, and therapeutic intervention. Nutrition 32:157–165PubMedCrossRefPubMedCentralGoogle Scholar
  298. Yamagishi S, Nakamura N, Suematsu M, Kaseda K, Matsui T (2015) Advanced glycation end products: a molecular target for vascular complications in diabetes. Mol Med 21(Suppl 1):S32–S40PubMedPubMedCentralCrossRefGoogle Scholar
  299. Yan J, Risacher SL, Shen L, Saykin AJ (2017) Network approaches to systems biology analysis of complex disease: integrative methods for multi-omics data. Brief Bioinform  19:1370-1381Google Scholar
  300. Yang Y, Wang K, Wu H, Jin Q, Ruan D, Ouyang Z, Zhao B, Liu Z, Zhao Y, Zhang Q, Fan N, Liu Q, Guo S, Bu L, Fan Y, Sun X, Li X, Lai L (2016) Genetically humanized pigs exclusively expressing human insulin are generated through custom endonuclease-mediated seamless engineering. J Mol Cell Biol 8:174–177PubMedCrossRefPubMedCentralGoogle Scholar
  301. Young MD, Mitchell TJ, Vieira Braga FA, Tran MGB, Stewart BJ, Ferdinand JR, Collord G, Botting RA, Popescu DM, Loudon KW, Vento-Tormo R, Stephenson E, Cagan A, Farndon SJ, Del Castillo V-HM, Guzzo C, Richoz N, Mamanova L, Aho T, Armitage JN, Riddick ACP, Mushtaq I, Farrell S, Rampling D, Nicholson J, Filby A, Burge J, Lisgo S, Maxwell PH, Lindsay S, Warren AY, Stewart GD, Sebire N, Coleman N, Haniffa M, Teichmann SA, Clatworthy M, Behjati S (2018) Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science:361, 594–599PubMedPubMedCentralCrossRefGoogle Scholar
  302. Yuan F, Guo L, Park KH, Woollard JR, Taek-Geun K, Jiang K, Melkamu T, Zang B, Smith SL, Fahrenkrug SC, Kolodgie FD, Lerman A, Virmani R, Lerman LO, Carlson DF (2018) Ossabaw pigs with a PCSK9 gain-of-function mutation develop accelerated coronary atherosclerotic lesions: a novel model for preclinical studies. J Am Heart Assoc 7:e006207Google Scholar
  303. Zalewski A, Macphee C (2005) Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol 25:923–931PubMedCrossRefPubMedCentralGoogle Scholar
  304. Zhang L, Huang Y, Wang M, Guo Y, Liang J, Yang X, Qi W, Wu Y, Si J, Zhu S, Li Z, Li R, Shi C, Wang S, Zhang Q, Tang Z, Wang L, Li K, Fei JF, Lan G (2019) Development and genome sequencing of a laboratory-inbred miniature pig facilitates study of human diabetic disease. iScience 19:162–176PubMedPubMedCentralCrossRefGoogle Scholar
  305. Zhao HJ, Wang S, Cheng H, Zhang MZ, Takahashi T, Fogo AB, Breyer MD, Harris RC (2006) Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 17:2664–2669PubMedPubMedCentralCrossRefGoogle Scholar
  306. Zheng Q, Lin J, Huang J, Zhang H, Zhang R, Zhang X, Cao C, Hambly C, Qin G, Yao J, Song R, Jia Q, Wang X, Li Y, Zhang N, Piao Z, Ye R, Speakman JR, Wang H, Zhou Q, Wang Y, Jin W, Zhao J (2017) Reconstitution of UCP1 using CRISPR/Cas9 in the white adipose tissue of pigs decreases fat deposition and improves thermogenic capacity. Proc Natl Acad Sci U S A 114:E9474–E9482PubMedPubMedCentralCrossRefGoogle Scholar
  307. Zhong P, Quan D, Huang Y, Huang H (2017) CaMKII activation promotes cardiac electrical remodeling and increases the susceptibility to arrhythmia induction in high-fat diet-fed mice with hyperlipidemia conditions. J Cardiovasc Pharmacol 70:245–254PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Chair for Molecular Animal Breeding and Biotechnology, Gene CenterLMU MunichMunichGermany
  2. 2.Laboratory for Functional Genome Analysis (LAFUGA), Gene CenterLMU MunichMunichGermany
  3. 3.Center for Innovative Medical Models (CiMM), Department of Veterinary SciencesLMU MunichOberschleißheimGermany
  4. 4.German Center for Diabetes Research (DZD)NeuherbergGermany
  5. 5.Research Unit Analytical PathologyHelmholtz Zentrum München – German Research Center for Environmental HealthNeuherbergGermany
  6. 6.Department of Medicine IUniversity Hospital Munich, Campus Grosshadern, LMU MunichMunichGermany
  7. 7.German Center for Cardiovascular Research (DZHK)Partner Site Munich, Munich Heart Alliance (MHA)MunichGermany
  8. 8.Walter Brendel Center of Experimental Medicine (WBex)LMU MunichMunichGermany
  9. 9.Chair for Animal Physiology, Department of Veterinary SciencesLMU MunichMartinsriedGermany
  10. 10.Department of CardiologyErasmus University Medical Center RotterdamRotterdamThe Netherlands
  11. 11.Institute of Veterinary Pathology, Center for Clinical Veterinary MedicineLMU MunichMunichGermany

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