Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis.

Autoimmune diseases are typically studied with a focus on the immune system, and less attention is paid to responses of target tissues exposed to the immune assault. We presently evaluated, based on available RNA sequencing data, whether inflammation induces similar molecular signatures at the target tissues in type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. We identified confluent signatures, many related to interferon signaling, indicating pathways that may be targeted for therapy, and observed a high (>80%) expression of candidate genes for the different diseases at the target tissue level. These observations suggest that future research on autoimmune diseases should focus on both the immune system and the target tissues, and on their dialog. Discovering similar disease-specific signatures may allow the identification of key pathways that could be targeted for therapy, including the repurposing of drugs already in clinical use for other diseases.

Nitric oxide stress and activation of AMP-activated protein kinase impair ß-cell sarcoendoplasmic reticulum calcium ATPase 2b activity and protein stability.

The sarcoendoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) concentration gradient between the cytosol and ER lumen in the pancreatic ß-cell, and the integrity of this gradient has a central role in regulated insulin production and secretion, maintenance of ER function and ß-cell survival. We have previously demonstrated loss of ß-cell SERCA2b expression under diabetic conditions. To define the mechanisms underlying this, INS-1 cells and rat islets were treated with the proinflammatory cytokine interleukin-1ß (IL-1ß) combined with or without cycloheximide or actinomycin D. IL-1ß treatment led to increased inducible nitric oxide synthase (iNOS) gene and protein expression, which occurred concurrently with the activation of AMP-activated protein kinase (AMPK). IL-1ß led to decreased SERCA2b mRNA and protein expression, whereas time-course experiments revealed a reduction in protein half-life with no change in mRNA stability. Moreover, SERCA2b protein but not mRNA levels were rescued by treatment with the NOS inhibitor l-NMMA (NG-monomethyl L-arginine), whereas the NO donor SNAP (S-nitroso-N-acetyl-D,L-penicillamine) and the AMPK activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) recapitulated the effects of IL-1ß on SERCA2b protein stability. Similarly, IL-1ß-induced reductions in SERCA2b expression were rescued by pharmacological inhibition of AMPK with compound C or by transduction of a dominant-negative form of AMPK, whereas ß-cell death was prevented in parallel. Finally, to determine a functional relationship between NO and AMPK signaling and SERCA2b activity, fura-2/AM (fura-2-acetoxymethylester) Ca(2+) imaging experiments were performed in INS-1 cells. Consistent with observed changes in SERCA2b expression, IL-1ß, SNAP and AICAR increased cytosolic Ca(2+) and decreased ER Ca(2+) levels, suggesting congruent modulation of SERCA activity under these conditions. In aggregate, these results show that SERCA2b protein stability is decreased under inflammatory conditions through NO- and AMPK-dependent pathways and provide novel insight into pathways leading to altered ß-cell calcium homeostasis and reduced ß-cell survival in diabetes.

Lost in translation: endoplasmic reticulum stress and the decline of ß-cell health in diabetes mellitus.

Emerging data illustrate a pivotal role for activation of ß-cell endoplasmic reticulum (ER) stress pathways in diabetes pathophysiology. The purpose of this review is to appraise the evidence for ß-cell ER stress in human type 1 and 2 diabetes, review the molecular signalling pathways involved in the unfolded protein response and ER stress signalling, and to provide data from polyribosome profiling to illustrate the impact of ER stress on the mRNA translation response. Finally, we will discuss existing and novel therapeutic strategies that target ß-cell ER stress and discuss their use in rodent and human type 1 and 2 diabetes.

The role of peroxisome proliferator-activated receptor γ in pancreatic ß cell function and survival: therapeutic implications for the treatment of type 2 diabetes mellitus.

The pathogenesis of type 2 diabetes mellitus involves both peripheral insulin resistance and dysfunctional insulin secretion from the pancreatic ß cell. Currently, there is intense research focus on delineating the etiologies of pancreatic ß cell dysfunction in type 2 diabetes. However, there remains an unmet clinical need to establish therapeutic guidelines and strategies that emphasize the preservation of pancreatic ß cell function in at-risk and affected individuals. Thiazolidinediones are orally active agents approved for use in type 2 diabetes and act as agonists of the nuclear hormone receptor PPAR-γ. These drugs improve insulin sensitivity, but there is also a growing appreciation of PPAR-γ actions within the ß cell. PPAR-γ has been shown to regulate directly key ß cell genes involved in glucose sensing, insulin secretion and insulin gene transcription. Further, pharmacologic PPAR-γ activation has been shown to protect against glucose-, lipid-, cytokine- and islet amyloid polypeptide (IAPP)-induced activation of numerous stress pathways. This article will review the mechanisms by which PPAR-γ activation acts to maintain ß cell function and survival in type 2 diabetes mellitus and highlight some of the current controversies in this field.