Andreas Blutke 1 , Simone Renner 2 , 3 , Florian Flenkenthaler 4 , Mattias Backman 4 , Serena Haesner 1 , Elisabeth Kemter 2 , Erik Ländström 4 , Christina Braun-Reichhart 2 , Barbara Albl 1 , Elisabeth Streckel 2 , Birgit Rathkolb 2 , 3 , 5 , Cornelia Prehn 6 , Alessandra Palladini 3 , 7 , Michal Grzybek 3 , 7 , Stefan Krebs 4 , Stefan Bauersachs 8 , Andrea Bähr 2 , Andreas Brühschwein 9 , Cornelia A. Deeg 10 , 15 , Erica De Monte 2 , Michaela Dmochewitz 2 , Caroline Eberle 1 , Daniela Emrich 1 , Robert Fux 11 , Frauke Groth 1 , Sophie Gumbert 12 , Antonia Heitmann 1 , Arne Hinrichs 2 , Barbara Keßler 2 , Mayuko Kurome 2 , Miriam Leipig-Rudolph 1 , Kaspar Matiasek 1 , 13 , Hazal Öztürk 1 , Christiane Otzdorff 9 , Myriam Reichenbach 2 , Horst Dieter Reichenbach 14 , Alexandra Rieger 1 , Birte Rieseberg 1 , Marco Rosati 1 , Manuel Nicolas Saucedo 2 , Anna Schleicher 2 , Marlon R. Schneider 2 , Kilian Simmet 2 , Judith Steinmetz 1 , Nicole Übel 12 , Patrizia Zehetmaier 15 , Andreas Jung 16 , Jerzy Adamski 6 , 17 , Ünal Coskun 3 , 7 , Martin Hrabě de Angelis 3 , 5 , 17 , Christian Simmet 18 , Mathias Ritzmann 12 , Andrea Meyer-Lindenberg 9 , Helmut Blum 4 , Georg J. Arnold 4 , Thomas Fröhlich 4 , Rüdiger Wanke 1 , 19 , Eckhard Wolf 2 , 3 , 4 , ∗ , 19
13 June 2017
MIDY, Hyperglycemia, Insulin insufficiency, Pig model, Biobank, Random systematic sampling, Transcriptomics, Proteomics, Metabolomics, Stereology, CE, cholesterol ester, CPT1, carnitine O-palmitoyltransferase 1, ER, endoplasmic reticulum, FFA, free fatty acids, MIDY, mutant INS gene-induced diabetes of youth, PC, phosphatidylcholine, PCA, principal component analysis, SM, sphingomyelin, TAG, triacylglycerol, WT, wild-type
The prevalence of diabetes mellitus and associated complications is steadily increasing. As a resource for studying systemic consequences of chronic insulin insufficiency and hyperglycemia, we established a comprehensive biobank of long-term diabetic INS C94Y transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates.
Female MIDY pigs (n = 4) were maintained with suboptimal insulin treatment for 2 years, together with female WT littermates (n = 5). Plasma insulin, C-peptide and glucagon levels were regularly determined using specific immunoassays. In addition, clinical chemical, targeted metabolomics, and lipidomics analyses were performed. At age 2 years, all pigs were euthanized, necropsied, and a broad spectrum of tissues was taken by systematic uniform random sampling procedures. Total beta cell volume was determined by stereological methods. A pilot proteome analysis of pancreas, liver, and kidney cortex was performed by label free proteomics.
MIDY pigs had elevated fasting plasma glucose and fructosamine concentrations, C-peptide levels that decreased with age and were undetectable at 2 years, and an 82% reduced total beta cell volume compared to WT. Plasma glucagon and beta hydroxybutyrate levels of MIDY pigs were chronically elevated, reflecting hallmarks of poorly controlled diabetes in humans. In total, ∼1900 samples of different body fluids (blood, serum, plasma, urine, cerebrospinal fluid, and synovial fluid) as well as ∼17,000 samples from ∼50 different tissues and organs were preserved to facilitate a plethora of morphological and molecular analyses. Principal component analyses of plasma targeted metabolomics and lipidomics data and of proteome profiles from pancreas, liver, and kidney cortex clearly separated MIDY and WT samples.