Persistent or Transient Human β-cell Dysfunction Induced by Metabolic Stress Associated with Specific Signatures and Shared Gene Expression of Type 2 Diabetes

Pancreatic β-cell failure is key to type 2 diabetes (T2D) onset and progression. We assessed whether human β-cell dysfunction induced by metabolic stress is reversible, evaluated the molecular pathways underlying persistent or transient damage, and explored the relationships with T2D islet traits. Twenty-six human islet preparations were exposed to several lipo- and/or glucotoxicity conditions, some of which impaired insulin release depending on stressor type, concentration and combination. Interestingly, reversal of dysfunction occurred after washout for some, but not for all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA-sequencing and eQTL analysis identified specific pathways underlying β-cell failure and recovery. Notably, comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β-cell lipoglucotoxicity showed shared gene expression signatures. The identification of mechanisms associated with human β-cell dysfunction and recovery, and their overlap with T2D islet traits provide novel insights into T2D pathogenesis and should foster the development of improved β-cell targeted therapeutic strategies. Human islets from 26 non-diabetic 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) (D4), followed by 4 days of washout (D8). Glucose-stimulated insulin secretion and RNA-seq (llumina HiSeq 2500 instrument) transcriptomes of P, G, P+G conditions were assessed. The reads were assigned to reference and quantified by Salmon v.0.13.2. We run the bioconductor R package Deseq2 to generate a paired differential analysis between metabolic stress condition vs matched control. Data were compared to RNA-seq of islets from 29 type 2 diabetic and 59 non-diabetic donors by rank-rank hypergeometric overlap (RRHO)