Functional genomics of human islet gluco/lipotoxicity and type 2 diabetes

Gluco- and lipotoxicity impair β cell function and survival, potentially contributing to type 2 diabetes onset and progression. Here we profiled transcriptomes of human islets in gluco/lipotoxic and type 2 diabetes conditions. Human islets from 26 nondiabetic donors were exposed to 0.5 mM palmitate (P), 22.2 mM glucose (G), P+G, 1 mM palmitate+oleate, (1:2 ratio, P+O) and P+O+G for 2 days (n=2-5/condition), followed by 4 days of washout. Glucose-stimulated insulin secretion and RNA-seq transcriptomes were assessed. Data were compared to RNA-seq of islets from 34 type 2 diabetic and 62 nondiabetic donors by rank-rank hypergeometric overlap (RRHO), and to the Connectivity Map to identify therapeutic targets. PO did not impair insulin secretion, P or G induced transient dysfunction (resolved after washout), while PG or POG induced persistent β cell dysfunction. Among common upregulated pathways in lipo- and gluco/lipotoxicity were PPAR signaling, protein processing in the endoplasmic reticulum and aminoacyl tRNA biosynthesis (gene set enrichment analysis). The greatest overlap by RRHO between upregulated genes in gluco/lipotoxicity and type 2 diabetes was seen for washout of PG and POG (conditions of persistent β cell dysfunction), with gene set enrichment for inflammatory responses and extracellular matrix organization. Comparison of gluco/lipotoxic and type 2 diabetes gene signatures with the Connectivity Map identified endoplasmic reticulum stress signaling and knockdown of the cholesterol sensor SCAP as strongly positively correlated pathways. A negative correlation was found for JNK and DNA protein kinase inhibitors, pointing to compounds that could revert gluco/lipotoxic and type 2 diabetes gene expression signatures. In conclusion, human islet transcriptome signatures of transient or persistent gluco/lipotoxicity identify similarities to type 2 diabetes islet transcriptomes and point to novel therapeutic targets. Disclosure X. Yi: None. L. Marselli: None. A. Piron: None. M. Suleiman: None. D.L. Eizirik: None. P. Marchetti: Consultant; Self; Menarini Group. Research Support; Self; Janssen Pharmaceuticals, Inc. M. Cnop: None.