Endocrine Abstracts

The pig is an interesting model species for translational endocrine and metabolic research. Many organ systems relevant for endocrine research, including pancreas and gastrointestinal tract, are more similar to the corresponding human organs than those of other species. The human-like size and weight of pigs allows direct transfer of medical products, surgical techniques and in vivo imaging techniques to applications in human patients. Moreover, metabolic tests, such as glucose tolerance tests, can be performed with frequent blood sampling of volumes sufficient for a broad spectrum of clinical-chemical, metabolomic and other analyses. Due to the establishment of efficient and precise techniques for genetic modification of pigs, it is possible to generate tailored pig models, which resemble human disease mechanisms on a molecular and functional level. To mimic the markedly reduced insulinotropic action of glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetic patients, we generated transgenic pigs expressing a dominant-negative GIP receptor (GIPR^dn) in the pancreatic islets. GIPR^dn transgenic pigs exhibit an impaired incretin effect due to a blunted insulinotropic action of GIP, a progressive deterioration of glucose control due to delayed and – at later stages – quantitatively reduced insulin secretion, and an impairment of physiological age-related expansion of beta-cell volume. GIPR^dn transgenic pigs provide a unique opportunity to screen for biomarker candidates during the pre-diabetic period and to test therapeutic strategies targeting the glucagon-like peptide 1 (GLP1) receptor. In addition, we generated transgenic pigs expressing INS^C94Y as a model for mutant INS gene-induced diabetes of youth (MIDY). MIDY pigs show early-onset clinical diabetes mellitus, markedly reduced body weight gain and beta-cell volume associated with a marked reduction of insulin secretory granules and severe dilation of the endoplasmic reticulum in the beta cells. MIDY pigs can be used for insulin treatment studies or for testing the efficacy of gene or cell therapies as well as islet transplantation. Secondary lesions of diabetes mellitus are another interesting area of research. We thus established the Munich MIDY pig biobank as a unique resource for studying systemic consequences of chronic insulin deficiency and hyperglycaemia. A multi-omics analysis (transcriptome, proteome, metabolome, lipidome) of liver samples revealed increased activity in gluconeogenesis, ketogenesis, amino acid metabolism and oxidation of fatty acids in the MIDY samples, whereas pathways related to extracellular matrix and inflammation/pathogen defence response were less active than in wild-type samples. The multi-omics data set provides a valuable resource for comparisons with other experimental or clinical data sets.