Molecular composition of the peri-islet basement membrane in NOD mice: a barrier against destructive insulitis

Irving-Rodgers, Helen F.; Ziolkowski, Andrew; Parish, Christopher R.; Sado, Yoshikazu; Ninomiya, Yoshifumi; Simeonovic, Charmaine J.; Rodgers, Raymond J.

doi:10.1007/s00125-008-1085-x

Cited by 84 publications

(116 citation statements)

References 32 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…It has earlier been shown that LM-411 and LM-511 are the major LM isoforms in vascular basement membranes [29]. In addition, the peri-islet capsule seems to be composed of LM chains α2, β1 and γ1, suggesting the presence of LM-211 [30]. At least in humans, LM-421 and LM-521 also seem to be present in the islet basement membranes [31].…”

Section: Discussionmentioning

confidence: 95%

Endothelial cell signalling supports pancreatic beta cell function in the rat

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis The proximity of endothelial cells and beta cells in islets by necessity means that they are exposed to each other's products. Whereas islet endothelial cells require signals from beta cells to function properly, endothelin-1, thrombospondin-1 and laminins, among others, have been identified as endothelial-derived molecules, although their full effects on beta cells have not been explored. We tested the hypothesis that islet endothelialderived products affect beta cell function. Methods Endothelial cells from rat islets were proliferated and purified. Endothelium-conditioned culture medium (ECCM) was obtained by maintaining the endothelial cells in culture medium. Islet function was evaluated following exposure of cultured islets to standard culture medium or ECCM. Changes in mRNA levels for key beta cell metabolic enzymes were also measured in islets after ECCM exposure.Results Glucose-stimulated insulin release and islet insulin content were markedly enhanced by exposure to ECCM. This was at least partly explained by improved mitochondrial function, as assessed by glucose oxidation and an upregulation of the mitochondrial gene for glycerol-3-phosphate dehydrogenase (mGpdh [also known as Gpd2]), combined with upregulation of the rate-limiting enzyme in the glycolysis, glucokinase, in the islets. The intracellular degradation of insulin was also decreased in the islets. Islet endothelial cells produced laminins, and the positive effects of islet endothelial cells were prevented by addition of a neutralising antibody to the β1-chain of laminin. Addition of exogenous laminin stimulated islet function. Conclusions/interpretation This study provides proof of principle that endothelial cells can affect the function of beta cells in their vicinity and that this is at least partially mediated by laminins.

show abstract

Section: Discussionmentioning

confidence: 95%

Endothelial cell signalling supports pancreatic beta cell function in the rat

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Further, lysolipids and eicosanoids act as "chemoattractants" ( 230,(279)(280)(281), and increased generation of these could promote migration of immune cells toward the islet and subsequent infi ltration, raising the possibility that in vivo inhibition of iPLA 2 ␤ could mitigate immune responses leading to T1D. Autoimmune insulitis is marked by degradation of the islet basement membrane, which presents a physical barrier to infi ltrating leukocytes ( 282 ). Remarkably, the abundance of infi ltrating cells is signifi cantly reduced in NOD mice treated with FKGK18 ( 161 ).…”

Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

167

201

View full text Add to dashboard Cite

The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

show abstract

“…Conversely, the extent to which islets and β cells use intrinsic defense and survival mechanisms for their protection has largely been underexplored. We recently reported that in situ NOD mouse islets are surrounded by a continuous basement membrane (BM) containing the heparan sulfate proteoglycan (HSPG) perlecan (19). HSPGs consist of a core protein to which a number of side-chains of the glycosaminoglycan or complex sugar heparan sulfate (HS) are covalently attached.…”

Section: Introductionmentioning

confidence: 99%

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

145

200

View full text Add to dashboard Cite

The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.

show abstract

Molecular composition of the peri-islet basement membrane in NOD mice: a barrier against destructive insulitis

Cited by 84 publications

References 32 publications

Endothelial cell signalling supports pancreatic beta cell function in the rat

Endothelial cell signalling supports pancreatic beta cell function in the rat

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Contact Info

Product

Resources

About