Abstract
ObjectiveThe 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 INSC94Y transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates. MethodsFemale 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. ResultsMIDY 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. ConclusionsThe broad spectrum of well-defined biosamples in the Munich MIDY Pig Biobank that will be available to the scientific community provides a unique resource for systematic studies of organ crosstalk in diabetes in a multi-organ, multi-omics dimension.
Highlights
Diabetes mellitus is a complex metabolic disease with markedly increasing prevalence worldwide
We established a complex biobank from a pig model of mutant INS gene-induced diabetes of youth (MIDY) caused by expression of an INSC94Y transgene in the beta cells [9]
Since no sex-related differences in the phenotypic consequences of beta cell specific INSC94Y expression were noted during the initial characterization of the MIDY pig model [9] and no sex-specific effects were described in human patients with INS mutations, we used only female pigs for our long-term study
Summary
Diabetes mellitus is a complex metabolic disease with markedly increasing prevalence worldwide (http://www.diabetes.org/diabetesbasics/statistics/). Targeted and non-targeted metabolomics approaches are available for diabetes research and have been used for analyzing human samples and samples from model organisms Cross-tissue networks with a limited spectrum of tissues have been constructed in several studies, integration of multi-omics data with expanded tissue coverage would markedly benefit disease-related network analyses on an organism-wide scale [2]. This is true for metabolic diseases such as diabetes and obesity, for which multiple tissues/organs may be causally involved in and/or affected by disease-relevant tissue crosstalk A comprehensive standardized protocol, taking the principles of systematic uniform random sampling into account, was established [12] to ensure uniform high quality of representative samples for a broad spectrum of analyses, including molecular profiling as well as qualitative and quantitative morphological investigations
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