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Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic β-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Ι interferon (IFN) mediated intracellular signaling. To study the role of TYK2 in human pancreatic β-cell development and response to IFNα, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromised the emergence of endocrine precursors by regulating KRAS expression while mature stem cell-islets (SC-islets) function was not affected. In the maturing SC-islets, the loss or inhibition of TYK2 prevented IFNα-induced antigen processing and presentation, including MHC Class Ι expression in pancreatic endocrine and progenitor cells. Furthermore, in a CD8+ cytotoxic T-cell co-culture model, the survival of β-cells was enhanced by a selective TYK2 inhibitor. These results identify an unsuspected role for TYK2 on β-cell development and support TYK2 inhibition in adult β-cells as a potent therapeutic target to halt T1D progression.

Diabetic kidney disease (DKD) is a severe complication of type 1 diabetes (T1D), which lacks non-invasive early biomarkers. Although less explored, mRNAs in urinary extracellular vesicles (uEV) could reflect changes in the kidney transcriptome during DKD development. We performed genome-wide mRNA sequencing of >100 uEV samples from two T1D cohorts with 24-hour and overnight urine collections. Our uEV pipeline allowed reproducible detection of >10,000 mRNAs bearing overall similarity to kidney transcriptome. uEV from T1D DKD groups showed significant upregulation of 13 genes, prevalently expressed by proximal tubular cells within the kidney. Strikingly, six genes involved in cellular stress responses including protection against oxidative stress (GPX3, NOX4, MSRB, MSRA, HRSP12 and CRYAB) correlated with hyperglycemia and long-term changes in kidney function independent of albuminuria status. The study identified genes associated with glycemic stress in T1D DKD and confirmed the utility of uEV in capturing pathological gene expression signatures from kidney.

BackgroundType 2 diabetes (T2D) is a multi-organ disease defined by hyperglycemia resulting from different disease mechanisms. Using clinical parameters measured at diagnosis (age, BMI, HbA1c, HOMA2-B, HOMA2-IR and GAD autoantibodies) adult patients with diabetes have been reproducibly clustered into five subtypes, that differed clinically with respect to disease progression and outcomes.1 In this study we use genetic information to investigate if these subtypes have distinct underlying genetic drivers.MethodsGenome-wide association (GWAS) and genetic risk score (GRS) analysis was performed in Swedish (N=12230) and Finnish (N=4631) cohorts. Family history was recorded by questionnaires.ResultsSevere insulin-deficient diabetes (SIDD) and mild obesity-related diabetes (MOD) groups had the strongest family history of T2D. A GRS including known T2D loci was strongly associated with SIDD (OR per 1 SD increment [95% CI]=1.959 [1.814-2.118]), MOD (OR 1.726 [1.607-1.855]) and mild age-related diabetes (MARD) (OR 1.771 [1.671-1.879]), whereas it was less strongly associated with severe insulin-resistant diabetes (SIRD, OR 1.244 [1.157-1.337]), which was similar to severe autoimmune diabetes (SAID, OR 1.282 [1.160-1.418]). SAID showed strong association with the GRS for T1D, whereas the non-autoimmune subtype SIDD was most strongly associated with the GRS for insulin secretion rate (P−9). SIRD showed no association with variants in TCF7L2 or any GRS reflecting insulin secretion. Instead, only SIRD was associated with GRS for fasting insulin (P=3.10×10−8). Finally, a T2D locus, rs10824307 near the ZNF503 gene was uniquely associated with MOD (ORmeta=1.266 (1.170-1.369), P=4.3×10−9).ConclusionsNew diabetes subtypes have partially different genetic backgrounds and subtype-specific risk loci can be identified. Especially the SIRD subtype stands out by having lower heritability and less involvement of beta-cell related pathways in its pathogenesis.Research in contextEvidence before this studyIn March 2018 we suggested a novel subclassification of diabetes into five subtypes. This classification was based on clustering using clinical parameters commonly measured at diabetes diagnosis (age at diabetes onset, HbA1c, bodymass index, presence of GAD autoantibodies and HOMA2 indices for insulin resistance and secretion). These subtypes differed with respect to clinical characteristics, disease progression and risk of complications, but it remained unclear to what extent these subtypes have different underlying pathologies. In our original publication we analysed a small set of genetic risk variants for diabetes and found differential associations between subtypes, suggesting potential aetiological differences.Added value of this studyIn this study we have conducted a full genome analysis of the original ANDIS cohort, including genome-wide association studies and polygenic risk score analysis with replication in an independent cohort. We have also compared heritability and prevalence of having a family history of diabetes in the subtypes.Implications of all the available evidenceWe demonstrate that stratification into subtypes facilitates identification of genetic risk loci and that the aetiology of the subtypes is at least partially distinct. These results are especially important for the future study and treatment of individuals belonging to the severe insulin-resistant diabetes (SIRD) subtype, whose pathogenesis appears to differ substantially from that of traditional T2D.