scholarly journals Lipotoxicity-induced circGlis3 impairs beta cell function and is transmitted by exosomes to promote islet endothelial cell dysfunction

Diabetologia ◽  
2021 ◽  
Author(s):  
Li Xiong ◽  
Li Chen ◽  
Liting Wu ◽  
Weiman He ◽  
Dubo Chen ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Cell Dysfunction

scholarly journals Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

2017 ◽  
Vol 232 (1) ◽  
pp. R27-R44 ◽  
Author(s):  
D S Boeldt ◽  
I M Bird
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Hypertensive Disorders Of Pregnancy ◽  
Endothelial Cell Function ◽  
Vascular Adaptation ◽  
Cell Dysfunction ◽  
Maternal Adaptation ◽  
Flow Through

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell–cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

scholarly journals Methylglyoxal triggers human aortic endothelial cell dysfunction via modulation of the KATP/MAPK pathway

2019 ◽  
Vol 317 (1) ◽  
pp. C68-C81 ◽  
Author(s):  
Yihan Wang ◽  
Leo M. Hall ◽  
Marisa Kujawa ◽  
Hainan Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Network Formation ◽  
Cell Function ◽  
Mapk Pathway ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Type 2 Diabetic

Endothelial dysfunction is a key risk factor in diabetes-related multiorgan damage. Methylglyoxal (MGO), a highly reactive dicarbonyl generated primarily as a by-product of glycolysis, is increased in both type 1 and type 2 diabetic patients. MGO can rapidly bind with proteins, nucleic acids, and lipids, resulting in structural and functional changes. MGO can also form advanced glycation end products (AGEs). How MGO causes endothelial cell dysfunction, however, is not clear. Human aortic endothelial cells (HAECs) from healthy (H-HAECs) and type 2 diabetic (D-HAECs) donors were cultured in endothelial growth medium (EGM-2). D-HAECs demonstrated impaired network formation (on Matrigel) and proliferation (MTT assay), as well as increased apoptosis (caspase-3/7 activity and TUNEL staining), compared with H-HAECs. High glucose (25 mM) or AGEs (200 ng/ml) did not induce such immediate, detrimental effects as MGO (10 µM). H-HAECs were treated with MGO (10 µM) for 24 h with or without the ATP-sensitive potassium (KATP) channel antagonist glibenclamide (1 µM). MGO significantly impaired H-HAEC network formation and proliferation and induced cell apoptosis, which was reversed by glibenclamide. Furthermore, siRNA against the KATP channel protein Kir6.1 significantly inhibited endothelial cell function at basal status but rescued impaired endothelial cell function upon MGO exposure. Meanwhile, activation of MAPK pathways p38 kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) (determined by Western blot analyses of their phosphorylated forms, p-JNK, p-p38, and p-ERK) in D-HAECs were significantly enhanced compared with those in H-HAECs. MGO exposure enhanced the activation of all three MAPK pathways in H-HAECs, whereas glibenclamide reversed the activation of p-stress-activated protein kinase/JNK induced by MGO. Glyoxalase-1 (GLO1) is the endogenous MGO-detoxifying enzyme. In healthy mice that received an inhibitor of GLO1, MGO deposition in aortic wall was enhanced and endothelial cell sprouting from isolated aortic segment was significantly inhibited. Our data suggest that MGO triggers endothelial cell dysfunction by activating the JNK/p38 MAPK pathway. This effect arises partly through activation of KATP channels. By understanding how MGO induces endothelial dysfunction, our study may provide useful information for developing MGO-targeted interventions to treat vascular disorders in diabetes.

Dissociation of endothelial cell dysfunction and blood pressure in SHR

1995 ◽  
Vol 269 (1) ◽  
pp. H189-H194 ◽  
Author(s):  
B. Tesfamariam ◽  
M. L. Ogletree
Keyword(s):  
Blood Pressure ◽  
Endothelial Cell ◽  
Cell Function ◽  
Receptor Activation ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Tp Receptor ◽  
Wistar Kyoto ◽  
Endothelium Dependent Relaxation

This study was designed to examine the impairment of endothelium-dependent relaxation in spontaneously hypertensive rats (SHR), to determine whether endothelial cell function is normalized by in vivo treatment with a thromboxane A2-prostaglandin endoperoxide (TP)-receptor blocker, and to establish whether endothelial dysfunction contributes to the elevated blood pressure. In isolated aortic rings from SHR, endothelium-dependent relaxations caused by acetylcholine, adenosine diphosphate, and alpha-thrombin were markedly impaired compared with those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid-induced contractions were significantly enhanced in aorta from SHR. In contrast, relaxations caused by direct smooth muscle vasodilators, nitroprusside and cromakalim, and contractions caused by U-46619 were not different between SHR and WKY rats. Treatment of SHR with the oral TP-receptor antagonist, ifetroban, at 20 and 50 mg.kg-1.day-1 fully restored endothelium-dependent relaxation toward normal. However, ifetroban produced no effect on blood pressure in SHR. In vitro incubation of aortic rings from SHR with ifetroban also normalized relaxations to acetylcholine but had no effect in aorta from WKY. In contrast, the thromboxane A synthase inhibitor, dazoxiben, only partially improved abnormal acetylcholine-induced relaxations in aorta from SHR. The results demonstrate that endothelial cell dysfunction in hypertension can be restored to normal by selective TP-receptor blockade. Furthermore, endothelial cell dysfunction and TP-receptor activation may not significantly contribute to elevated systemic blood pressure in SHR.

scholarly journals JOE DOUPE LECTURE: Emerging Strategies for the Preservation of Pancreatic Beta-cell Function in early Type 2 Diabetes

2014 ◽  
Vol 37 (6) ◽  
pp. 414 ◽  
Author(s):  
Ravi Retnakaran
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Fundamental Problem ◽  
Pancreatic Beta Cell ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction ◽  
Pancreatic Beta Cell Function

A fundamental problem in the clinical management of type 2 diabetes is the inability to prevent the ongoing deterioration of pancreatic beta-cell function over time that underlies the chronic progressive nature of this condition. Importantly, beta-cell dysfunction has both reversible and irreversible components. Furthermore, the amelioration of reversible beta-cell dysfunction through the early institution of short-term insulin-based therapy has emerged as a strategy that can yield temporary remission of type 2 diabetes. In this context, we have forwarded a novel therapeutic paradigm consisting of initial induction therapy to improve beta-cell function early in the course of diabetes followed by maintenance therapy aimed at preserving this beneficial beta-cell effect. Ultimately, this approach may yield an optimized therapeutic strategy for the durable preservation of beta-cell function and consequent modification of the natural history of type 2 diabetes.

scholarly journals The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

2020 ◽  
Vol 27 (SP2) ◽  
pp. e22-e38
Author(s):  
Maximilian Andreas Storz
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood. The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function. Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction. Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels. All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

scholarly journals Hypoxia induction in cultured pancreatic islets enhances endothelial cell morphology and survival while maintaining beta-cell function

PLoS ONE ◽  
2019 ◽  
Vol 14 (10) ◽  
pp. e0222424 ◽  
Author(s):  
Krishana S. Sankar ◽  
Svetlana M. Altamentova ◽  
Jonathan V. Rocheleau
Keyword(s):  
Endothelial Cell ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Cell Morphology ◽  
Beta Cell Function ◽  
Cell Function

scholarly journals Beta cell function, insulin resistance and vitamin D status among type 2 diabetes patients in Western Kenya

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamil Said ◽  
David Lagat ◽  
Allan Kimaina ◽  
Chrispine Oduor
Keyword(s):  
Insulin Resistance ◽  
Vitamin D ◽  
Beta Cell ◽  
Vitamin D Deficiency ◽  
Beta Cell Function ◽  
Cell Function ◽  
Serum Vitamin ◽  
Beta Cell Dysfunction ◽  
Serum Vitamin D ◽  
Cell Dysfunction

AbstractSerum vitamin D status exerts effects on glucose-insulin-homeostatic states underlying Diabetes-Mellitus, Type 2 (T2DM). This has been described in white and Asian population where low Vitamin D levels predicted future impairments in beta cell function and worsening of insulin resistance. This study aimed to examine the relationship between serum vitamin D, insulin resistance and beta cell function in a sub population of black Kenyan T2DM patients. The primary objective was to determine the levels of serum 25 hydroxy (25-OH) vitamin D, and estimate the insulin resistance, and beta cell function among T2DM patients at Moi Teaching and Referral Hospital (MTRH). This was a cross sectional study. 124 T2DM patients attending the MTRH Diabetes clinic between February and May 2016 were enrolled. Patients on insulin therapy and/or thiazolidinediones were excluded. Anthropometric, clinical and demographic data was obtained. Samples were drawn for estimation of serum 25-OH vitamin D, fasting insulin levels and fasting blood glucose levels. HOMA (Homeostatic model of assessment) model was used to estimate Beta cell secretion (HOMA-B) and insulin resistance (HOMA-IR); while the Disposition index {(DI) hyperbola product of insulin sensitivity (1/HOMA-IR) and beta cell secretion} was used to estimate the beta cell function. The relationships between serum vitamin D, insulin resistance and beta cell function were explored using a linear regression model. The study participants had a mean age of 56.2 (± 9.2) years, and a mean BMI of 26.9 kg/m2 (4.3). Forty nine percent (n = 61) were males. Vitamin D deficiency was present in 71.1% (n = 88) of the respondents. Relatively low levels of insulin resistance and higher levels of beta cell dysfunction were observed {median HOMA-IR of 2.3 (0.7, 6.5) and Disposition Index (DI) of 25.5 (14.3, 47.2)}. Vitamin D levels exhibited a low positive correlation with DI [r = 0.22 (95% CI: 0.03, 0.37)], but was not significantly correlated with HOMA-IR [r = 0.07(95% CI: − 0.11, 0.25)]. These results indicate that beta cell dysfunction rather than insulin resistance as the predominant defect among black T2DM patients seeking care at the MTRH diabetes clinic. Vitamin D deficiency is also prevalent among them and exhibits a low positive correlation with beta cell dysfunction. There was no correlation observed between Vitamin D deficiency and insulin resistance.

Endothelial cell dysfunction occurs very early following trauma-hemorrhage and persists despite fluid resuscitation

1993 ◽  
Vol 265 (3) ◽  
pp. H973-H979 ◽  
Author(s):  
P. Wang ◽  
Z. F. Ba ◽  
I. H. Chaudry
Keyword(s):  
Endothelial Cell ◽  
Fluid Resuscitation ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Cellular Functions ◽  
Midline Laparotomy ◽  
Endothelial Cell Function ◽  
Shed Blood ◽  
Cell Dysfunction ◽  
Significant Difference

Although hemorrhage produces alterations in hemodynamics and cellular functions, it remains unknown if endothelial cell function is depressed in a nonheparinized model of trauma-hemorrhage and resuscitation. To study this, rats underwent a 5-cm midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleed-out volume was returned in the form of Ringer lactate (RL). They were then resuscitated with four times the volume of the shed blood with RL over 60 min. At the time of maximal bleed out (approximately 50 min from the onset of hemorrhage), 1.5, and 4 h after the completion of resuscitation, aortic rings (approximately 2.5 mm in length) were isolated and mounted in organ chambers. Dose responses for an endothelium-dependent vasodilator (acetylcholine) and endothelium-independent vasodilator (nitroglycerin) were determined. The results indicate that endothelium-dependent relaxation was depressed at the time of maximal bleed out and persisted even after resuscitation. However, there was no significant difference in nitroglycerin-induced relaxation at any point during the study period. In addition, hypoxia-induced contraction, a process mediated by endothelium-derived contracting factor, decreased significantly following hemorrhage and resuscitation. Thus endothelial cell dysfunction (i.e., reduced release of endothelium-derived relaxing and contracting factors) occurs very early after trauma-hemorrhage and persists despite fluid resuscitation.

scholarly journals The Dynamic Roles of Visfatin and Obestatin Serum Concentration in Pancreatic Beta Cells Dysfunction (HOMA-beta) and Insulin Resistance (HOMA-IR) in Centrally Obese Men

2012 ◽  
Vol 4 (1) ◽  
pp. 43
Author(s):  
Bayu Winata Putera ◽  
Cynthia Retna Sartika ◽  
Andi Wijaya
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Cell Dysfunction ◽  
Pancreas Cell

BACKGROUND: Obesity is a major health problem in the world today. Obesity is closely associated with insulin resistance and type 2 diabetes. Epidemiological studies have shown that obese persons are in a state of insulin resistance, however, most of them do not progress to type 2 diabetes. This occurs because the beta cell function is still good enough for maintaining normal glucose level. Obestatin and visfatin are cytokines that are known to have a role in beta cell function. The aim of this study was to assess the relationship between visfatin and obestatin and Homeostasis Model Assessment of beta cell function (HOMA-β) and Homeostasis Model Assessment of insulin resistance (HOMA-IR).METHODS: This was a cross-sectional study involving 80 central obesity men with waist circumference >90 cm, age 30-65 years old. Visfatin and obestatin were measured by ELISA method. Beta pancreas cell dysfunction and insulin resistance were calculated by HOMA model.RESULTS: Our study showed a correlation between visfatin and HOMA-β (r=0.244 and p = 0.029) and visfatin with HOMA-IR (r=0.287 and p=0.001) and no correlation was found between obestatin with HOMA-β (r=0.010 and p=0.990) and obestatin with HOMA-IR (r=0.080 and p=0.480). We also found visfatin and obestatin concentrations were fluctuative depending on the measurements of the waist circumferences.CONCLUSIONS: High visfatin and low obestatin concentration were independently associated with increased beta pancreas cell dysfunction and insulin resistance.KEYWORDS: obesity. visfatin, obestatin, beta cell dysfunction (HOMA-β), insulin resistance (HOMA-IR)

scholarly journals Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

2021 ◽  
Vol 22 (19) ◽  
pp. 10427
Author(s):  
Michala Prause ◽  
Signe Schultz Pedersen ◽  
Violeta Tsonkova ◽  
Min Qiao ◽  
Nils Billestrup
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Beta Cell Dysfunction ◽  
Beta Cell Proliferation ◽  
Cell Dysfunction ◽  
Mouse Islets

Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.

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