Pancreatic B-cells as mediators of metabolic effects of regulatory peptides

1996 ◽  
Vol 24 (2) ◽  
pp. 570-575 ◽  
Author(s):  
P. R. Flatt
Keyword(s):  
B Cells ◽  
Regulatory Peptides ◽  
Metabolic Effects ◽  
Pancreatic B Cells

scholarly journals B cell-specific GPR55 deficiency promotes atherosclerosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Guillamat-Prats ◽  
D Hering ◽  
M Rami ◽  
C Haerdtner ◽  
L Bindila ◽  
...  
Keyword(s):  
Body Weight ◽  
B Cells ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Function ◽  
Metabolic Effects ◽  
Atherosclerotic Plaques ◽  
Funding Source ◽  
Sequencing Analysis ◽  
B Cell Function

Abstract Background Atherosclerosis is accompanied by an imbalance between resolving and pro-inflammatory lipid mediators. Targeting lipid signaling pathways might offer a new anti-inflammatory therapy for improving the clinical outcome in cardiovascular disease patients. We considered lysophosphatidylinositol (LPI) and its receptor G protein-coupled receptor (GPR)55 as a potential modulator of atherosclerosis. Its role in regulating atherosclerosis and B cell function is unknown. Hypothesis We assessed the hypothesis that GPR55 signaling causally affects atherosclerosis and whether it has a specific role in regulating B cell function in this disease. Methods Atherosclerotic plaques were compared between apolipoprotein E deficient (ApoE−/−) and ApoE−/−Gpr55−/− mice after 4 to 16 weeks Western Diet (WD; 0.15% cholesterol; n=12–15 per group). To specifically test the role of B cell GPR55 in atherosclerosis, we generated mixed chimeras by lethally irradiating low density lipoprotein receptor deficient (Ldlr−/−) mice and reconstituting with a mixture of μMT and wildtype (control) or μMT and Gpr55−/− bone marrow cells. Circulating B cells were sorted and bulk RNA sequencing analysis was performed. We performed lipid and immunostainings of murine aortic root plaques, qPCR and ELISA of tissue lysates, as well as multiplex analysis of plasma immunoglobulins. Leukocyte plasma and tissue counts were determined by flow cytometry. Results GPR55 expression in mouse and human atherosclerotic plaques was detected by immunostaining. Furthermore, we confirmed murine Gpr55 mRNA expression on sorted circulating B220+B cells via qPCR, which was higher compared to CD3+ T cells, while CD11+ myeloid cells as well as NK cells had only low Gpr55 mRNA levels. ApoE−/−Gpr55−/− mice had significantly larger plaques after 4&16 weeks WD compared to ApoE−/− controls, with more pronounced body weight increases and higher cholesterol levels at the 16 weeks WD time point. In addition, global Gpr55 deficiency resulted in enhanced aortic pro-inflammatory cytokine mRNA expression (IL-1β, IL-6, TNFα) and a massively upregulated IgG1 plasma levels and increased percentages of splenic germinal center and plasma cells. B-cell RNA-seq analysis showed 460 differential expressed regulated genes in the ApoE−/−Gpr55−/− compared to ApoE−/−. The main pathways affected were calcium ion transport, immunoglobulin production, negative regulation of phosphorylation, and cellular component morphogenesis, suggesting a dsysregulation of B cell function. B cell specific Gpr55 deficiency blunted the metabolic effects on body weight and cholesterol, but still translated in larger atherosclerotic plaques and elevated plasma IgG levels compared to the respective controls. Conclusion Both global and B cell-restricted Gpr55 deficiency promotes atherosclerosis and is associated with a more pro-inflammatory phenotype. Our findings suggest a novel role for GPR55 in regulating B cell development and function. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells

Nature ◽  
1991 ◽  
Vol 349 (6304) ◽  
pp. 77-79 ◽  
Author(s):  
Patrik Rorsman ◽  
Krister Bokvist ◽  
Carina Ämmälä ◽  
Per Arkhammar ◽  
Per-Olof Berggren ◽  
...  
Keyword(s):  
B Cells ◽  
G Protein ◽  
K Channel ◽  
Pancreatic B Cells

P724Antibody treatment against pathological pancreatic islet amyloid polypeptide (IAPP) aggregates restores endothelial dysfunction in human-IAPP transgenic rats

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Taheri ◽  
P Doytcheva ◽  
E Tarasco ◽  
W Gut ◽  
M Engeli ◽  
...  
Keyword(s):  
B Cells ◽  
Endothelial Dysfunction ◽  
Glucose Tolerance ◽  
B Cell ◽  
Aortic Arch ◽  
Islet Amyloid Polypeptide ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Islet Amyloid ◽  
Pancreatic B Cells

Abstract Background Islet amyloid polypeptide (IAPP; or amylin) is produced in pancreatic B-cells and co-secreted with insulin in response to nutrients. In insulin resistance and type 2 diabetes (T2D), higher secretion and impaired processing of IAPP results in its aggregation, contributing to amyloid-induced apoptosis of pancreatic B-cells. Insight into IAPP's role in diabetic endothelial dysfunction is scarce. Purpose Rats transgenic for human IAPP (hIAPP), which in contrast to rodent IAPP produces amyloid deposits and contributes to diabetes due to B-cell failure, were studied to understand the mechanisms of endothelial dysfunction in T2D and test the vasoprotective actions of an anti-hIAPP antibody. Methods Male hemizygous transgenic Sprague-Dawley rats with islet B-cell expression of hIAPP (TG) and wild-type (WT) controls were sacrificed at 2, 3, 6- and 9-months age to assess endothelial function. In a second experiment, TG rats received weekly injections of antibody against aggregated hIAPP (3 mg/kg; TG-Ab) from 3–12 months of age; TG and WT controls received PBS. Oral glucose tolerance was assessed before harvesting. At the respective time points (12 mts in exp. 2), thoracic aortic rings were isolated and subjected to ex vivo isometric tension recording. After contraction with norepinephrine (NE 1x10–7 mol/L), cumulative relaxation responses were performed to glucagon-like peptide-1 (GLP-1; 10–12 to 10–6 mol/L) and insulin (10–11 to 10–6 mol/L). Pancreas and aortic arch samples were used for immunostaining of hIAPP antibody engagement. Results GLP-1 and insulin-mediated vasodilation was impaired in 3 month-old TG rats compared to WT. Glucose intolerance appeared in TG rats at 6 months in comparison to WT (p<0.0001), indicating that endothelial dysfunction in TG rats precedes the onset of glucose intolerance. Anti-hIAPP antibody showed selectivity against aggregated IAPP in pancreatic islets, but there was no target engagement in the aortic arch, questioning a pathogenic role of IAPP deposition in the aortic wall. At 12 months, glucose control in TG-Ab rats was improved in comparison to TG control rats (p<0.013). Vasodilatation in TG-Ab rats was restored in response to GLP-1 (35.5% ± 4.6 vs. 16.0% ± 3.1 in TG controls), similar to that of WT rats (35.5% ± 6.5). Vasodilatation in response to insulin (48.9% ± 4.2) was improved in comparison to both TG (29.4% ± 3.0) and WT controls (32.5% ± 5.7) (p<0.0001; 2-way ANOVA, n=6–11 for all groups. Conclusion Early endothelial dysfunction develops in hIAPP rats compared to WT. Endothelial dysfunction is restored by the anti-hIAPP antibody treatment via improved oral glucose tolerance, but it remains unclear whether this effect is due to a local action in the aorta or a secondary effect, e.g. due to a reduction in pancreatic IAPP deposition.

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