Normoglycemia and physiological cortisone level maintain glucose homeostasis in a pancreas-liver microphysiological system.

Rigal S, Casas B, Kanebratt KP, Wennberg Huldt C, Magnusson LU, Müllers E, Karlsson F, Clausen M, Hansson SF, Leonard L, Cairns J, Jansson Löfmark R, Ämmälä C, Marx U, Gennemark P, Cedersund G, Andersson TB, Vilén LK

Commun Biol 7 (1) 877 [2024-07-18; online 2024-07-18]

Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with standard in vitro assays. Here, we have connected cell models of key metabolic organs, the pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modeling, we demonstrate that hyperglycemia and high cortisone concentration induce glucose dysregulation in the pancreas-liver microphysiological system (MPS), mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, the pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. Conversely, a physiological culture condition maintains glucose tolerance and beta-cell function. This method was reproducible in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins, as demonstrated with a combined transcriptome and proteome analysis.

Glycoproteomics and MS Proteomics [Service]

PubMed 39025915

DOI 10.1038/s42003-024-06514-w

Crossref 10.1038/s42003-024-06514-w

pmc: PMC11258270
pii: 10.1038/s42003-024-06514-w