Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus.

Growing evidence shows that the lung is an organ prone to injury by diabetes mellitus. However, the molecular mechanisms of these pulmonary complications have not yet been characterized comprehensively. To systematically study the effects of insulin deficiency and hyperglycaemia on the lung, we combined proteomics and lipidomics with quantitative histomorphological analyses to compare lung tissue samples from a clinically relevant pig model for mutant INS gene induced diabetes of youth (MIDY) with samples from wild-type (WT) littermate controls. Among others, the level of pulmonary surfactant-associated protein A (SFTPA1), a biomarker of lung injury, was moderately elevated. Furthermore, key proteins related to humoral immune response and extracellular matrix (ECM) organization were significantly altered in abundance. Importantly, a lipoxygenase pathway was dysregulated as indicated by a 2.5-fold reduction of polyunsaturated fatty acid lipoxygenase ALOX15 levels, associated with corresponding changes in the levels of lipids influenced by this enzyme. Our multi-omics study points to an involvement of reduced ALOX15 levels and an associated lack of eicosanoid switching as mechanisms contributing to a proinflammatory milieu in the lungs of subjects suffering from diabetes mellitus.

Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe beta-cell loss in Munich Ins2C95S mutant mice.

The novel diabetic mouse model Munich Ins2(C95S) was discovered within the Munich N-ethyl-N-nitrosourea mouse mutagenesis screen. These mice exhibit a T-->A transversion in the insulin 2 (Ins2) gene at nucleotide position 1903 in exon 3, which leads to the amino acid exchange C95S and loss of the A6-A11 intrachain disulfide bond. From 1 month of age onwards, blood glucose levels of heterozygous Munich Ins2(C95S) mutant mice were significantly increased compared with controls. The fasted and postprandial serum insulin levels of the heterozygous mutants were indistinguishable from those of wild-type littermates. However, serum insulin levels after glucose challenge, pancreatic insulin content, and homeostasis model assessment (HOMA) beta-cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. The initial blood glucose decrease during an insulin tolerance test was lower and HOMA insulin resistance indices were significantly higher in mutant mice, indicating the development of insulin resistance in mutant mice. The total islet volume, the volume density of beta-cells in the islets, and the total beta-cell volume of heterozygous male mutants was significantly reduced compared with wild-type mice. Electron microscopy of the beta-cells of male mutants showed virtually no secretory insulin granules, the endoplasmic reticulum was severely enlarged, and mitochondria appeared swollen. Thus, Munich Ins2(C95S) mutant mice are considered a valuable model to study the mechanisms of beta-cell dysfunction and death during the development of diabetes.