12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets

Context: Inflammation in the pancreas can cause β-cell stress, leading to diabetes development. Access to human pancreas tissues via the Network for Pancreatic Organ Donors with Diabetes (nPOD) has allowed characterization of pathways leading to this inflammation. Objective: 12-Lipoxygenase (12-LO) induces inflammation and has been implicated in diabetes development. Our goal was to determine expression of 12-LO in human islets from control, autoantibody-positive, type 1 diabetic, and type 2 diabetic nPOD pancreas donors. Design: Pancreas tissues from nPOD donors were examined by immunohistochemistry and immunofluorescence for islet expression of 12-LO in different subsets of islet cells. Participants: Donor pancreas samples were obtained from nPOD based on disease status (control, n = 7; autoantibody-positive, n = 8; type 1 diabetic, n = 17; or type 2 diabetic donors, n = 15). Main Outcome Measure: Determination of 12-LO expression within human islets served as the main outcome measure, including distinguishing which types of islet cells expressed 12-LO. Results: Islets from control participants (nondiabetic) lacked islet expression of 12-LO. Of donors in the other groups, 25% to 37% expressed islet 12-LO with a clear inverse relation between the numbers of β-cells and 12-LO+ cells within islets of 12-LO+ cases. 12-LO expression was not seen within macrophages, endothelial cells, α-cells, or β-cells, but only within cells expressing low levels of pancreatic polypeptide (PP) and increased levels of vimentin. Conclusions: 12-LO expression colocalizes within a specific type of islet PP+ cell under prediabetic and diabetic conditions. The costaining of PP and vimentin suggests that 12-LO participates in the process leading to β-cell dedifferentiation in the islet.

Download Full-text

Angiotensin II type 1 receptor expression is increased via 12-lipoxygenase in high glucose-stimulated glomerular cells and type 2 diabetic glomeruli

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfn703 ◽

2008 ◽

Vol 24 (6) ◽

pp. 1744-1752 ◽

Cited By ~ 24

Author(s):

Z.-G. Xu ◽

L.-N. Miao ◽

Y.-C. Cui ◽

Y. Jia ◽

H. Yuan ◽

...

Keyword(s):

Angiotensin Ii ◽

High Glucose ◽

Receptor Expression ◽

12 Lipoxygenase ◽

Type 2 Diabetic

Download Full-text

Role of 12-lipoxygenase in decreasing P-cadherin and increasing angiotensin II type 1 receptor expression according to glomerular size in type 2 diabetic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00624.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. E708-E716 ◽

Cited By ~ 10

Author(s):

Qiao-Yan Guo ◽

Li-Ning Miao ◽

Bing Li ◽

Fu-Zhe Ma ◽

Nian Liu ◽

...

Keyword(s):

Angiotensin Ii ◽

Diabetic Rats ◽

Ang Ii ◽

Direct Infusion ◽

Protein Expressions ◽

12 Lipoxygenase ◽

Type 2 Diabetic

12-lipoxygenase (12-LO) was implicated in the development of diabetic nephropathy (DN), in which the proteinuria was thought to be associated with a decreased expression of glomerular P-cadherin. Therefore, we investigated the role of 12-LO in the glomerular P-cadherin expression in type 2 diabetic rats according to the glomerular sizes. Rats fed with high-fat diet for 6 wk were treated with low-dose streptozotocin. Once diabetes onset, diabetic rats were treated with 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) for 8 wk. Then glomeruli were isolated from diabetic and control rats with a sieving method. RT-PCR, Western blotting, and immunofluorescent staining were used for mRNA and protein expressions of P-cadherin and angiotensin II (Ang II) type 1 receptor (AT1). We found that CDC did not affect the glucose levels but completely attenuated diabetic increases in glomerular volume and proteinuria. Diabetes significantly decreased the P-cadherin mRNA and protein expressions and increased the AT1 mRNA and protein expressions in the glomeruli. These changes were significantly prevented by CDC and recaptured by direct infusion of 12-LO product [12(S)-HETE] to normal rats for 7 days. The decreased P-cadherin expression was similar between large and small glomeruli, but the increased AT1 expression was significantly higher in the large than in the small glomeruli from diabetic and 12(S)-HETE-treated rats. Direct infusion of normal rats with Ang II for 14 days also significantly decreased the glomerular P-cadherin expression. These results suggest that diabetic proteinuria is mediated by the activation of 12-LO pathway that is partially attributed to the decreased glomerular P-cadherin expression.

Download Full-text

Asymmetrical distribution of δ and PP cells in human pancreatic islets

Journal of Endocrinology ◽

10.1530/joe-15-0542 ◽

2016 ◽

Vol 229 (2) ◽

pp. 123-132 ◽

Cited By ~ 4

Author(s):

Charlotte Barbieux ◽

Géraldine Parnaud ◽

Vanessa Lavallard ◽

Estelle Brioudes ◽

Jérémy Meyer ◽

...

Keyword(s):

Endothelial Cells ◽

Pancreatic Islets ◽

Islet Cells ◽

Human Islets ◽

Human Pancreatic Islets ◽

Asymmetrical Distribution ◽

Computerized Morphometry ◽

Vascular Channels ◽

Type 2 Diabetic

The aim of this study was to evaluate the location of PP and δ cells in relation to the vascularization within human pancreatic islets. To this end, pancreas sections were analysed by immunofluorescence using antibodies against endocrine islet and endothelial cells. Staining in different islet areas corresponding to islet cells adjacent or not to peripheral or central vascular channels was quantified by computerized morphometry. As results, α, PP and δ cells were preferentially found adjacent to vessels. In contrast to α cells, which were evenly distributed between islet periphery and intraislet vascular channels, PP and δ cells had asymmetric and opposite distributions: PP staining was higher and somatostatin staining was lower in the islet periphery than in the area around intraislet vascular channels. Additionally, frequencies of PP and δ cells were negatively correlated in the islets. No difference was observed between islets from the head and the tail of the pancreas, and from type 2 diabetic and non-diabetic donors. In conclusion, the distribution of δ cells differs from that of PP cells in human islets, suggesting that vessels at the periphery and at the centre of islets drain different hormonal cocktails.

Download Full-text

Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors

Biology ◽

10.3390/biology9080215 ◽

2020 ◽

Vol 9 (8) ◽

pp. 215 ◽

Cited By ~ 5

Author(s):

Jalal Taneera ◽

Waseem El-Huneidi ◽

Mawieh Hamad ◽

Abdul Khader Mohammed ◽

Esraa Elaraby ◽

...

Keyword(s):

Pancreatic Islets ◽

Endocrine Cells ◽

Human Islets ◽

Diabetic Patients ◽

Rna Seq ◽

Human Pancreatic Islets ◽

Diabetes Status ◽

Subcutaneous Adipose ◽

Type 2 Diabetic

Cellular entry of SARS-CoV-2 is thought to occur through the binding of viral spike S1 protein to ACE2. The entry process involves priming of the S protein by TMPRSS2 and ADAM17, which collectively mediate the binding and promote ACE2 shedding. In this study, microarray and RNA-sequencing (RNA-seq) expression data were utilized to profile the expression pattern of ACE2, ADAM17, and TMPRSS2 in type 2 diabetic (T2D) and non-diabetic human pancreatic islets. Our data show that pancreatic islets express all three receptors irrespective of diabetes status. The expression of ACE2 was significantly increased in diabetic/hyperglycemic islets compared to non-diabetic/normoglycemic. Islets from female donors showed higher ACE2 expression compared to males; the expression of ADAM17 and TMPRSS2 was not affected by gender. The expression of the three receptors was statistically similar in young (≤40 years old) versus old (≥60 years old) donors. Obese (BMI > 30) donors have significantly higher expression levels of ADAM17 and TMPRSS2 relative to those from non-obese donors (BMI < 25). TMPRSS2 expression correlated positively with HbA1c and negatively with age, while ADAM17 and TMPRSS2 correlated positively with BMI. The expression of the three receptors was statistically similar in muscle and subcutaneous adipose tissues obtained from diabetic and nondiabetic donors. Lastly, ACE2 expression was higher in sorted pancreatic β-cell relative to other endocrine cells. In conclusion, ACE2 expression is increased in diabetic human islets. More studies are required to investigate whether variations of ACE2 expression could explain the severity of COVID-19 infection-related symptoms between diabetics and non-diabetic patients.

Download Full-text