Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress.

Regenerative medicine approaches to enhancing beta cell growth and survival represent potential treatments for diabetes. It is known that growth factors such as insulin, IGF-1 and HGF support beta cell growth and survival, but in people with type 2 diabetes the destructive effects of metabolic stress predominate and beta cell death or dysfunction occurs. In this study we explore the novel hypothesis that regulation of growth factor receptor trafficking can be used to promote islet beta cell survival.

Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the matricellular protein SPARC has been robustly associated with poor patient prognosis. However, the precise role of SPARC has been highly controversial, with multiple studies demonstrating tumour-suppressor properties of this protein in vitro.

A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.

SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study.

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation.

Matricellular proteins influence wide-ranging fundamental cellular processes including cell adhesion, migration, growth and differentiation. They achieve this both through interactions with cell surface receptors and regulation of the matrix environment. Many matricellular proteins are also associated with diverse clinical disorders including cancer and diabetes.

Novel role for matricellular proteins in the regulation of islet β cell survival: the effect of SPARC on survival, proliferation, and signaling.

Understanding the mechanisms regulating islet growth and survival is critical for developing novel approaches to increasing or sustaining β cell mass in both type 1 and type 2 diabetes patients. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that is important for the regulation of cell growth and adhesion. Increased SPARC can be detected in the serum of type 2 diabetes patients.

Recent acquisitions on the genetic basis of autoimmune disease.

In this review we will discuss recent progress from studies on the genetic basis of autoimmune disease and how this has advanced our understanding of the processes behind disease susceptibility and pathogenesis. We review the genetic associations with autoimmune and inflammatory disease discovered in the latest genome-wide association (GWA) scans, and discuss the importance of animal models both for generating candidates and for mechanistic studies. Investigating the natural variants of key immune regulatory molecules can give us an additional level of insight into their function and physiological regulation over gene knockouts.

The target tissue in autoimmunity--an influential niche.

Central and peripheral tolerance mechanisms were for a long time the only regulatory circuits known in autoimmunity. It is now becoming clear that the target tissue itself may have the capacity to control its own destiny. Here we review mechanisms by which the target tissue regulates local inflammation, and the way this could influence progression to overt autoimmunity.

Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes.

Unlabelled: Type 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet beta cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at the Idd9 diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction.

Distinct regulation of autoreactive CD4 T cell expansion by interleukin-4 under conditions of lymphopenia.

IL-4 is protective against Type 1 diabetes in the NOD mouse. IL-4 promotes T cell survival in vitro, but little is known about the effect of IL-4 on clonal expansion in vivo. Here, we show that IL-4 only enhances the expansion of autoreactive CD4 T cells during lymphopenia and that neither the presence of islet IL-4 nor IL-4 deficiency affects T cell expansion significantly under conditions of immunosufficiency.

Th1 and Th2 pancreatic inflammation differentially affects homing of islet-reactive CD4 cells in nonobese diabetic mice.

The control of lymphocyte recruitment to the site of inflammation is an important component determining the pathogenicity of an autoimmune response. Progression from insulitis to diabetes in the nonobese diabetic mouse is typically associated with Th1 pancreatic inflammation, whereas Th2 inflammation can seemingly be controlled indefinitely. We show that a Th1 (IFN-gamma) pancreatic environment greatly accelerates the recruitment of adoptively transferred islet-specific CD4 T cells to the islets and also accelerates the onset of diabetes.