Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, LMU Munich, Veterinärstr. 13, D-80539 Munich, Germany.
Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, and Center for Innovative Medical Models (CiMM), LMU Munich, Feodor-Lynen-Str. 25, D-81377 Munich, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Mol Metab. 2017 Jun 13;6(8):931-940. doi: 10.1016/j.molmet.2017.06.004. eCollection 2017 Aug.
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 transgenic pigs, a model of mutant 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.
The 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.
糖尿病及其相关并发症的患病率正在稳步上升。我们建立了一个长期糖尿病转基因猪的综合生物库，作为研究慢性胰岛素不足和高血糖系统后果的资源，该模型为突变基因诱导的青年糖尿病（MIDY）和野生型（WT）同窝仔的模型。
4 头雌性 MIDY 猪（n=4）接受了 2 年的次优胰岛素治疗，同时还有 5 头雌性 WT 同窝仔。使用特定的免疫测定法定期测定血浆胰岛素、C 肽和胰高血糖素水平。此外，还进行了临床化学、靶向代谢组学和脂质组学分析。2 岁时，所有猪均被安乐死，进行尸检，并通过系统均匀随机采样程序采集广泛的组织。使用体视学法测定总胰岛β细胞体积。通过无标记蛋白质组学对胰腺、肝脏和肾脏皮质进行了初步的蛋白质组分析。
MIDY 猪的空腹血糖和果糖胺浓度升高，C 肽水平随年龄下降，2 岁时无法检测到，总胰岛β细胞体积比 WT 减少 82%。MIDY 猪的血浆胰高血糖素和β-羟丁酸水平持续升高，反映了人类糖尿病控制不佳的特征。总共保存了来自不同体液（血液、血清、血浆、尿液、脑脊液和滑液）的约 1900 个样本，以及来自约 50 个不同组织和器官的约 17000 个样本，以促进形态和分子分析。对来自胰腺、肝脏和肾脏皮质的血浆靶向代谢组学和脂质组学数据以及蛋白质组图谱进行主成分分析，可清楚地区分 MIDY 和 WT 样本。
慕尼黑 MIDY 猪生物库中广泛的、定义明确的生物样本，将为科学界提供一个独特的资源，用于在多器官、多组学维度上系统研究糖尿病中的器官串扰。
