PNLIPRP1 Hypermethylation in Exocrine Pancreas Links Type 2 Diabetes and Cholesterol Metabolism.

We postulated that type 2 diabetes (T2D) predisposes patients to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (using MethylationEPIC arrays) of the exocrine pancreas in 141 donors, assessing the impact of T2D. An epigenome-wide association study of T2D identified hypermethylation in an enhancer of the pancreatic lipase-related protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression.

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.

Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D.

Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.

Aims/hypothesis: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes.

Interferons are key cytokines acting on pancreatic islets in type 1 diabetes.

Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown.

Methods: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes.