Dataset Information

Siglec-7 restores ?-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes.

ABSTRACT: Chronic inflammation plays a key role in both type 1 and type 2 diabetes. Cytokine and chemokine production within the islets in a diabetic milieu results in ?-cell failure and diabetes progression. Identification of targets, which both prevent macrophage activation and infiltration into islets and restore ?-cell functionality is essential for effective diabetes therapy. We report that certain Sialic-acid-binding immunoglobulin-like-lectins (siglecs) are expressed in human pancreatic islets in a cell-type specific manner. Siglec-7 was expressed on ?-cells and down-regulated in type 1 and type 2 diabetes and in infiltrating activated immune cells. Over-expression of Siglec-7 in diabetic islets reduced cytokines, prevented ?-cell dysfunction and apoptosis and reduced recruiting of migrating monocytes. Our data suggest that restoration of human Siglec-7 expression may be a novel therapeutic strategy targeted to both inhibition of immune activation and preservation of ?-cell function and survival.

SUBMITTER: Dharmadhikari G

PROVIDER: S-EPMC5381285 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes.

Dharmadhikari Gitanjali G Stolz Katharina K Hauke Michael M Morgan Noel G NG Varki Ajit A de Koning Eelco E Kelm Sørge S Maedler Kathrin K

Scientific reports 20170405

Chronic inflammation plays a key role in both type 1 and type 2 diabetes. Cytokine and chemokine production within the islets in a diabetic milieu results in β-cell failure and diabetes progression. Identification of targets, which both prevent macrophage activation and infiltration into islets and restore β-cell functionality is essential for effective diabetes therapy. We report that certain Sialic-acid-binding immunoglobulin-like-lectins (siglecs) are expressed in human pancreatic islets in a ...[more]

PMID: 28378743

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Project description:BackgroundPancreatic islets are heavily vascularized in vivo yet lose this vasculature after only a few days in culture. Determining how to maintain islet vascularity in culture could lead to better outcomes in transplanting this tissue for the treatment of type 1 diabetes as well as provide insight into the complex communication between beta-cells and endothelial cells (ECs). We previously showed that islet ECs die in part due to limited diffusion of serum albumin into the tissue. We now aim to determine the impact of hypoxia on islet vascularization.MethodsWe induced hypoxia in cultured mouse islets using the hypoxia mimetic cobalt chloride (100 ?M CoCl2). We measured the impact on islet metabolism (two-photon NAD(P)H and Rh123 imaging) and function (insulin secretion and survival). We also measured the impact on hypoxia related transcripts (HIF-1?, VEGF-A, PDK-1, LDHA, COX4) and confirmed increased VEGF-A expression and secretion. Finally, we measured the vascularization of islets in static and flowing culture using PECAM-1 immunofluorescence.ResultsCoCl2 did not induce significant changes in beta cell metabolism (NAD(P)H and Rh123), insulin secretion, and survival. Consistent with hypoxia induction, CoCl2 stimulated HIF-1?, PDK-1, and LDHA transcripts and also stimulated VEGF expression and secretion. We observed a modest switch to the less oxidative isoform of COX4 (isoform 1 to 2) and this switch was noted in the glucose-stimulated cytoplasmic NAD(P)H responses. EC morphology and survival were greater in CoCl2 treated islets compared to exogenous VEGF-A in both static (dish) and microfluidic flow culture.ConclusionsHypoxia induction using CoCl2 had a positive effect on islet EC morphology and survival with limited impact on beta-cell metabolism, function, and survival. The EC response appears to be due to endogenous production and secretion of angiogenic factors (e.g. VEGF-A), and mechanistically independent from survival induced by serum albumin.

Dataset Information

Siglec-7 restores ?-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes.

Publications

Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes.

Similar Datasets

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