Imeglimin Protects INS-1 Cells and Human Islets against High Glucose– and High Fructose–Induced Cell Death by Inhibiting the Mitochondrial PTP Opening

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 81-OR ◽  
Author(s):  
SANDRINE LABLANCHE ◽  
EMILY TUBBS ◽  
CÉCILE COTTET-ROUSSELLE ◽  
FREDERIC LAMARCHE ◽  
ANAÏCK MOISAN ◽  
...  
2007 ◽  
Vol 30 (4) ◽  
pp. 92 ◽  
Author(s):  
K Potter ◽  
K Park

Background: Pancreatic islet transplantation offers improved glycemic control in type 1 diabetic patients above standard insulin therapy, ideally minimizing macro- and microvascular complications of diabetes mellitus. However success is limited thus far, with fewer than 10% of patients retaining insulin independence at two years post-transplantation. In addition to immune rejection, many non-immune factors may promote long-term graft secretory dysfunction and loss of viable graft mass. One such important non-immune factor may be the formation of islet amyloid, a pathologic lesion of the islet in type 2 diabetes that contributes to the progressive loss of b cells in that disease and that has been shown to form rapidly in human islets transplanted into NOD.scid mice. Amyloid deposits are composed primarily of the b cell secretory product islet amyloid polypeptide (IAPP), are cytotoxic, and develop in environments in which b cells are stressed. Heparin sulfate is used as an anti-coagulant in clinical islet transplantation and to prevent the instant blood-mediated inflammatory reaction (IBMIR), which occurs upon contact between islets and blood and may destroy a substantial proportion of the grafted islet mass. However, heparin is also known to stimulate amyloid fibril formation. Methods: To determine whether heparin may enhance amyloid formation in human islets and contribute to graft failure, we cultured isolated human islets in the presence or absence of heparin sulfate (42 and 420 units/ml) for 2 weeks in 11.1 mM glucose. Results: Histological assessment of sections of cultured islets for the presence of amyloid (by thioflavin S staining) revealed a marked, concentration-dependent increase in amyloid deposition following culture in the presence of heparin. Quantitative analysis of these sections showed that the proportion of islet area comprised of amyloid was increased approximately 2-fold (0.15%±0.12% vs 0.46%±0.15% of islet area) following culture in 42 units/ml heparin, and the proportion of islets in which amyloid was detectable (amyloid prevalence) was also increased (35%±24% vs 68%±10% of islets). At 420 units/ml heparin, the amyloid area was even greater (0.23%±0.15% vs 0.97%±0.42% of islet area) as was the amyloid prevalence (53%±29% vs 81%±14% of islets). To affirm that heparin can stimulate IAPP fibrillogenesis and enhance IAPP toxicity, we incubated synthetic human IAPP in the presence of heparin and measured amyloid formation in real time by thioflavin T fluorescence, and cell toxicity by Alamar blue viability assay in transformed rat (INS-1) ß-cell cultures. Heparin stimulated IAPP fibril formation and increased death of INS-1 cells exposed to IAPP (78.2%±10.9% vs 51.8%±12.2% of control viability), suggesting that heparin stimulates IAPP aggregation and toxicity. Remarkably, preliminary assessment of human islets cultured in heparin did not show increased islet cell death by TUNEL staining or loss of insulin immunostaining. Conclusion: In summary, heparin increases amyloid formation in cultured human islets. Although our preliminary data does not suggest that heparin-induced amyloid formation contributes to islet cell death, we speculate that heparin-induced amyloid formation may contribute to graft dysfunction and that caution should be used in the clinical application of this drug in islet transplantation.


2016 ◽  
Vol 7 (5) ◽  
pp. e2233-e2233 ◽  
Author(s):  
B R Tennant ◽  
B Vanderkruk ◽  
J Dhillon ◽  
D Dai ◽  
C B Verchere ◽  
...  
Keyword(s):  

Islets ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 57-64 ◽  
Author(s):  
You Jeong Kim ◽  
Su Min Park ◽  
Hye Sook Jung ◽  
Eun Ju Lee ◽  
Tae Kyoon Kim ◽  
...  

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1865
Author(s):  
Andris Elksnis ◽  
Jing Cen ◽  
Per Wikström ◽  
Per-Ola Carlsson ◽  
Nils Welsh

Previous studies have reported beneficial effects of NADPH oxidase 4 (NOX4) inhibition on beta-cell survival in vitro and in vivo. The mechanisms by which NOX4 inhibition protects insulin producing cells are, however, not known. The aim of the present study was to investigate the effects of a pharmacological NOX4 inhibitor (GLX7013114) on human islet and EndoC-βH1 cell mitochondrial function, and to correlate such effects with survival in islets of different size, activity, and glucose-stimulated insulin release responsiveness. We found that maximal oxygen consumption rates, but not the rates of acidification and proton leak, were increased in islets after acute NOX4 inhibition. In EndoC-βH1 cells, NOX4 inhibition increased the mitochondrial membrane potential, as estimated by JC-1 fluorescence; mitochondrial reactive oxygen species (ROS) production, as estimated by MitoSOX fluorescence; and the ATP/ADP ratio, as assessed by a bioluminescent assay. Moreover, the insulin release from EndoC-βH1 cells at a high glucose concentration increased with NOX4 inhibition. These findings were paralleled by NOX4 inhibition-induced protection against human islet cell death when challenged with high glucose and sodium palmitate. The NOX4 inhibitor protected equally well islets of different size, activity, and glucose responsiveness. We conclude that pharmacological alleviation of NOX4-induced inhibition of beta-cell mitochondria leads to increased, and not decreased, mitochondrial ROS, and this was associated with protection against cell death occurring in different types of heterogeneous islets. Thus, NOX4 inhibition or modulation may be a therapeutic strategy in type 2 diabetes that targets all types of islets.


2020 ◽  
Vol 12 (1) ◽  
pp. 1-7
Author(s):  
Inggita Kusumastuty ◽  
Frinny Sembiring ◽  
Sri Andarini ◽  
Dian Handayani

BACKGROUND: Consumption of foods and drinks high in energy, fat, and/or sugar beyond the recommended quantities can cause obesity, which triggers the incidence of brain nerve cell death related to oxidative stress, high levels of tumor necrosis factor (TNF)-α and triglycerides, and low high-density lipoprotein (HDL) levels. Progressive nerve cell death causes decreasing cognitive performance. This study aims to prove that an American Institute of Nutrition committee in 1993 (AIN-93M) diet modified with high-fat-high-fructose (HFHF) can decrease the number of hippocampal neurons. A decrease in the number of hippocampal neurons indicates progressive nerve cell death.METHODS: An experimental study using a post-test control group design was carried out using male Sprague Dawley rats. Samples were selected using simple random sampling to divide them into two groups, Group I was AIN-93M-modified HFHF diet (n=14) and Group II was AIN-93M standard (n=16). The number of visible neurons was measured in the hippocampus area of Sprague Dawley rats’ brains, stained with haemotoxylin and eosin (H&E) and scanned under 400x magnification. Neurons were counted in 10 visual fields using the "Cell_Count" application.RESULTS: The data were analysed by Pearson’s correlation test using SPSS. The results show that rats in Group I had a greater weight gain and fewer neurons than those in the Group II (p=0.023, r=-0.413).CONCLUSION: The consumption of foods high in fat and fructose can cause an increase in nerve cell death, as shown by the decrease in the number of hippocampal neurons.KEYWORDS: brain nerve cells, high fat, high fructose, increased body weight


2012 ◽  
Vol 12 (1) ◽  
pp. 463-469 ◽  
Author(s):  
YUAN-YUAN SHANG ◽  
NING-NING FANG ◽  
FENG WANG ◽  
HUI WANG ◽  
ZHI-HAO WANG ◽  
...  

2012 ◽  
Vol 21 (5) ◽  
pp. 889-900 ◽  
Author(s):  
Sarita Negi ◽  
Soon Hyang Park ◽  
Arif Jetha ◽  
Reid Aikin ◽  
Michel Tremblay ◽  
...  

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wanzhen Jiao ◽  
Jia-Fu Ji ◽  
Wenwen Xu ◽  
Wenjuan Bu ◽  
Yuanjie Zheng ◽  
...  

Abstract Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) plays a crucial role in breakdown of the blood-retinal barrier due to hyperpermeability in diabetic retinopathy (DR). However, the distinct signaling driven by VEGF and PlGF in the pathogenesis of DR remains unclear. In this study, we investigated VEGF- and PlGF- related signaling pathways and their roles in cultured human microvascular retinal endothelial cells (hRECs) under high glucose conditions (HG; 25 mM). Apoptotic cell death was evaluated, and FITC conjugated bovine serum albumin across monolayer hRECs served as an index of permeability. Western blots were used to assess the protein levels of VEGF and PlGF, as well as the phosphorylation of p38MAPK, STAT1 and Erk1/2. Knockdown of VEGF and PlGF was performed by using siRNA. Following HG treatment, increases of VEGF and PlGF as well as PKC activity were detected in hRECs. Increased phosphorylations of p38MAPKThr180/Thr182, STAT1Ser727, and Erk1/2Tyr202/Tyr185 as well as VEGFR1Tyr1213 and VEGFR2Tyr1175 were also detected in HG-treated hRECs. Inhibition of PKC activity by Go 6976 prevented HG-induced increases of phosphor-Erk1/2 and nitric oxide synthase (NOS1) expressions as well as hyperpermeability, whereas inhibition of p38MAPK pathway by SB203580 selectively suppressed activation of STAT1 and decreased apoptotic cell death under HG conditions. Moreover, VEGF knockdown predominantly inhibited activation of VEGFR2, and phosphorylation of p38MAPK and STAT1, as well as apoptotic cell death in HG-treated hRECs. Nevertheless, PlGF knockdown mainly suppressed phosphorylation of VEGFR1, PKC, and Erk1/2, as well as NOS1 expressions and hyperpermeability. Taken together, we provide evidence demonstrating that HG-induced elevation of PlGF is responsible for hyperpermeability mainly through increasing activation of PKC-Erk1/2-NOS axis via VEGFR1, while HG-induced elevation of VEGF is associated with induction of apoptotic cell death mainly through increasing activation of p38MAPK/STAT1 signaling via VEGFR2.


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