Type 2 diabetes (T2D) is characterized by decreased functional β-cell mass and poor compensation to insulin resistance. Thus, understanding of the mechanism(s) responsible for the physiological adaptation of β-cells to states of high metabolic demand is desirable. We aimed to dissect the transcriptome and m6A mRNA methylation landscape in the β-cell adaptation to insulin resistance. To this end we conducted RNA-sequencing in sorted β-cells and m6A-sequencing in whole islets from three mouse models: a) a dietary model (60% high-fat diet: Control-HF), b) a genetic model (liver-specific insulin receptor KO mouse on chow: LIRKO-C), and c) a superimposed dietary and genetic model of insulin resistance (LIRKO on a high fat diet: LIRKO-HF). These data were compared to littermate controls fed a chow diet (Control-C). Control-HF, LIRKO-C and LIRKO-HF each presented an increase in insulin resistance compared to Control-C. However, LIRKO-C and LIRKO-HF presented a robust insulin secretion capacity and a graded increase in β-cell proliferation and mass compared to Control-C. First, we correlated the transcriptome with surrogates of β-cell adaptation such as insulin secretion, β-cell mass or proliferation. Next, we intersected the genes that positively correlated with β-cell compensation with single-cell RNA seq datasets performed in islets from humans with or without T2D. This bioinformatics analyses identified extracellular matrix (ECM) as the most enriched pathway in the β-cell adaptation to insulin resistance. On the other hand, m6A-sequencing of Control-C, LIRKO-C and LIRKO-HF islets and the intersection of this dataset with the differentially methylated genes in human T2D islets, revealed enrichment in pathways associated with chromatin modifications. Together, these results point to ECM pathways as being important in the transcriptomic remodeling and that m6A acts on chromatin-modifying enzymes in the β-cell compensation to mammalian insulin resistance.

Disclosure

D.F.De jesus: None. Z.Zhang: Research Support; SinoVac. J.Wei: None. N.K.Brown: None. J.Hu: None. S.Kahraman: Employee; Boehringer Ingelheim Pharmaceuticals Inc. E.Dirice: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago.

Funding

American Diabetes Association (7-21-PDF-140 to D.F.DJ.); National Institutes of Health (R01067536)

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