Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from "physiological" to "apoptotic" UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1␣ is critical for this transition. IRE1␣ activation is regulated by both intra-ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1␣-interacting protein ubiquitin D (UBD) on the regulation of IRE1␣ and its downstream targets. UBD was identified by use of a MAPPIT (mammalian protein-protein interaction trap)-based IRE1␣ interactome screen followed by comparison against functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines. Knockdown of UBD in human and rodent beta cells and detailed signal transduction studies indicated that UBD modulates cytokine-induced UPR/IRE1␣ activation and apoptosis. UBD expression is induced by the pro-inflammatory cytokines interleukin (IL)-1␤ and interferon (IFN)-␥ in rat and human pancreatic beta cells, and it is also up-regulated in beta cells of inflamed islets from non-obese diabetic mice. UBD interacts with IRE1␣ in human and rodent beta cells, modulating IRE1␣-dependent activation of JNK and cytokine-induced apoptosis. Our data suggest that UBD provides a negative feedback on cytokine-induced activation of the IRE1␣/JNK pro-apoptotic pathway in cytokine-exposed beta cells. Endoplasmic reticulum (ER)8 stress and the consequent triggering of the unfolded protein response (UPR) are induced in human pancreatic beta cells by the pro-inflammatory cytokines interleukin-1␤ (IL-1␤) and tumor necrosis factor-␣ (TNF-␣), in combination with interferon-␥ (IFN-␥), and probably contribute to beta cell apoptosis in type 1 diabetes (T1D) (1-3). Markers of the UPR are expressed in inflamed islets of both non-obese diabetic (NOD) mice (4, 5) and patients affected by T1D (6).The UPR is mediated through activation of three ER transmembrane proteins as follows: inositol-requiring protein 1␣ (IRE1␣), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). These proteins sense the accumulation of unfolded proteins in the ER lumen and activate mechanisms to restore its homeostasis (2, 7). Fine-tuning of the activity of these transmembrane proteins is provided by signals from the cytosol (8). In the case of unresolved ER stress, the persistent stimulation of the UPR triggers apoptosis via activation of C/EBP homologous protein (CHOP), c-Jun N-terminal kinase (JNK), death protein 5 (DP5), and other pro-apoptotic signals (9, 10). What determines the transition from "physiological" to "apoptotic" UPR remains to be clarified (8), but accumulating evidence indicates that the changing nature of IRE1␣ signaling is critical for this transition (11). In particular, IRE1␣-induced JNK activation i...

OBJECTIVEThis study assessed the relationship between autoantibodies against zinc transporter 8 (ZnT8A) and disease characteristics at diagnosis of type 1 diabetes and during the first 2 years.RESEARCH DESIGN AND METHODSChildren, younger than 15 years of age (n = 723) who were newly diagnosed with diabetes, were analyzed for ZnT8A, other diabetes-associated autoantibodies, HLA DR-DQ alleles, and metabolic status, which was monitored by pH, plasma glucose, and occurrence of ketoacidosis at diagnosis and through follow-up of C-peptide concentrations, exogenous insulin dose, and glycosylated hemoglobin for 2 years after the diagnosis.RESULTSZnT8A positivity was detected in 530 children (73%). Positivity for ZnT8A was associated with older age (median 8.9 vs. 8.2 years, P = 0.002) and more frequent ketoacidosis (24% vs. 15%, P = 0.013). Children carrying the HLA DR3 allele were less often ZnT8A positive (66% vs. 77%, P = 0.002) than others. ZnT8A-positive children had lower serum C-peptide concentrations (P = 0.008) and higher insulin doses (P = 0.012) over time than their ZnT8A-negative peers.CONCLUSIONSPositivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis.

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