Abstract
In periods of sustained hyper-nutrition, pancreatic β-cells undergo functional compensation through transcriptional upregulation of gene programs driving insulin secretion. This adaptation is essential for maintaining systemic glucose homeostasis and metabolic health. Using single nuclei multiomics, we have mapped the early transcriptional compensation mechanisms in murine islets of Langerhans exposed to high-fat diet (HFD) for one and three weeks. We show that β-cells exhibit the largest transcriptional response to HFD, characterized by early activation of proinflammatory eRegulons and downregulation of β-cell identity genes, particularly in a distinct subset of β-cells. Our observations translate to humans, as we observe an increase in the inflammatory gene signatures in human β-cells in pre-diabetes and diabetes. Collectively, these observations point to cellular cross-talk through proinflammatory signaling as a central and early driver of β-cell dysfunction that limits the compensatory capacity of β-cells, which is closely linked to the development of diabetes.