GPR120 protects lipotoxicity-induced pancreatic β-cell dysfunction through regulation of PDX1 expression and inhibition of islet inflammation

2019 ◽  
Vol 133 (1) ◽  
pp. 101-116 ◽  
Author(s):  
Yi Wang ◽  
Ting Xie ◽  
Dan Zhang ◽  
Po Sing Leung
Keyword(s):  
Signaling Pathways ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells ◽  
Cell Dysfunction ◽  
Obesity And Diabetes ◽  
Β Cell Function ◽  
Islet Inflammation ◽  
Pdx1 Expression

Abstract G-protein coupled receptor 120 (GPR120) has been shown to act as an omega-3 unsaturated fatty acid sensor and is involved in insulin secretion. However, the underlying mechanism in pancreatic β cells remains unclear. To explore the potential link between GPR120 and β-cell function, its agonists docosahexaenoic acid (DHA) and GSK137647A were used in palmitic acid (PA)-induced pancreatic β-cell dysfunction, coupled with GPR120 knockdown (KD) in MIN6 cells and GPR120 knockout (KO) mice to identify the underlying signaling pathways. In vitro and ex vivo treatments of MIN6 cells and islets isolated from wild-type (WT) mice with DHA and GSK137647A restored pancreatic duodenal homeobox-1 (PDX1) expression levels and β-cell function via inhibiting PA-induced elevation of proinflammatory chemokines and activation of nuclear factor κB, c-Jun amino (N)-terminal kinases1/2 and p38MAPK signaling pathways. On the contrary, these GPR120 agonism-mediated protective effects were abolished in GPR120 KD cells and islets isolated from GPR120 KO mice. Furthermore, GPR120 KO mice displayed glucose intolerance and insulin resistance relative to WT littermates, and β-cell functional related genes were decreased while inflammation was exacerbated in islets with increased macrophages in pancreas from GPR120 KO mice. DHA and GSK137647A supplementation ameliorated glucose tolerance and insulin sensitivity, as well as improved Pdx1 expression and islet inflammation in diet-induced obese WT mice, but not in GPR120 KO mice. These findings indicate that GPR120 activation is protective against lipotoxicity-induced pancreatic β-cell dysfunction, via the mediation of PDX1 expression and inhibition of islet inflammation, and that GPR120 activation may serve as a preventative and therapeutic target for obesity and diabetes.

scholarly journals Impaired Pancreatic β-Cell Function in Critically Ill Children

2021 ◽  
Vol 9 ◽  
Author(s):  
Shereen A. Mohamed ◽  
Nora E. Badawi ◽  
Hoiyda A. AbdelRasol ◽  
Hossam M. AbdelAziz ◽  
Nirvana A. Khalaf ◽  
...  
Keyword(s):  
Cell Function ◽  
Multivariate Logistic Regression Analysis ◽  
Pediatric Intensive Care ◽  
Glucose Production ◽  
Critically Ill Children ◽  
Model Assessment ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

Critical illness hyperglycemia (CIH) is common in the pediatric intensive care unit (PICU). Increased glucose production, insulin resistance (IR), and pancreatic β-cell dysfunction are responsible mechanisms. We aimed to investigate β-cell function in the PICU and to uncover its relation to clinical and laboratory variables and ICU mortality. We prospectively recruited 91 children. Pancreatic β-cell function was assessed by using a homeostasis model assessment (HOMA)-β. Patients with β-cell function <40.0% had significantly higher Pediatric Risk of Mortality III (PRISM III) scores, higher rates of a positive C-reactive protein (CRP), lower IR, and a longer hospital stay. The patients with 40–80% β-cell function had the highest IR. Intermediate IR was found when the β-cell function was >80%. ICU survivors had better β-cell function than ICU non-survivors. A multivariate logistic regression analysis revealed that higher PRISM III score and HOMA-β <80.0% were significant predictors of mortality. In conclusion, β-cell dysfunction is prevalent among PICU patients and influences patient morbidity and mortality.

Vitexin restores pancreatic β-cell function and insulin signaling through Nrf2 and NF-κB signaling pathways

2020 ◽  
Vol 888 ◽  
pp. 173606
Author(s):  
Kumar Ganesan ◽  
Kunka Mohanram Ramkumar ◽  
Baojun Xu
Keyword(s):  
Signaling Pathways ◽  
Insulin Signaling ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

scholarly journals Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

2019 ◽  
Author(s):  
Xin Tong ◽  
Zunaira Chaudry ◽  
Chih-Chun Lee ◽  
Robert N. Bone ◽  
Sukrati Kanojia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smoking Cessation ◽  
Weight Gain ◽  
Cell Function ◽  
Ex Vivo ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function ◽  
Ceramide Accumulation

ABSTRACTObjectivesEpidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.MethodsBeginning at 8 weeks of age, C57BL/6J mice were concurrently fed high fat-diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD exposure. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured β-cells (INS-1) and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide in lungs cells and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.ResultsCompared to HFD-fed ambient air-exposed mice, HFD-fed and CS- exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and a significantly greater increase in glucose intolerance compared to non-smoking control mice. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p=0.02), and reduced β-cell proliferation (p=0.006), and increased islet ceramide accumulation. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide accumulation, reduce insulin gene expression and glucose-stimulated insulin secretion, and increase β-cell oxidative and ER stress. Treatment with the antioxidant N-acetylcysteine, markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.ConclusionsOur results indicate that CS exposure inhibits insulin production, processing, and secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

scholarly journals The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

2021 ◽  
Vol 22 (4) ◽  
pp. 1509
Author(s):  
Natsuki Eguchi ◽  
Nosratola D. Vaziri ◽  
Donald C. Dafoe ◽  
Hirohito Ichii
Keyword(s):  
Oxidative Stress ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Antioxidative Capacity ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Cell Dysfunction ◽  
Elevated Glucose ◽  
Β Cell Function

Diabetes is a chronic metabolic disorder characterized by inappropriately elevated glucose levels as a result of impaired pancreatic β cell function and insulin resistance. Extensive studies have been conducted to elucidate the mechanism involved in the development of β cell failure and death under diabetic conditions such as hyperglycemia, hyperlipidemia, and inflammation. Of the plethora of proposed mechanisms, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress have been shown to play a central role in promoting β cell dysfunction. It has become more evident in recent years that these 3 factors are closely interrelated and importantly aggravate each other. Oxidative stress in particular is of great interest to β cell health and survival as it has been shown that β cells exhibit lower antioxidative capacity. Therefore, this review will focus on discussing factors that contribute to the development of oxidative stress in pancreatic β cells and explore the downstream effects of oxidative stress on β cell function and health. Furthermore, antioxidative capacity of β cells to counteract these effects will be discussed along with new approaches focused on preserving β cells under oxidative conditions.

scholarly journals Impact of Magnesium Deficiency on Pancreatic β-Cell Function in Type 2 Diabetic Nigerians

2020 ◽  
Author(s):  
Abdullahi Mohammed ◽  
Ibrahim M. Bello
Keyword(s):  
Cell Function ◽  
Magnesium Deficiency ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Mg Deficiency ◽  
Cell Dysfunction ◽  
North Eastern ◽  
Β Cell Function ◽  
Type 2 Diabetic

Objective: Pancreatic β-cell dysfunction is described to be present at the diagnosis of type 2 diabetes mellitus (T2DM) and progressively deteriorated with disease duration. However, its progression is variable and potentially influenced by several factors. The Magnesium (Mg) deficiency mediates insulin resistance but reports regarding its role in pancreatic β-cell dysfunction are scarce and conflicting. The aim of this study was to evaluate Mg deficiency effect on pancreatic β-cell function in T2DM patients at a specialist hospital in north eastern Nigeria. Materials and Methods: Study subjects were categorized in to two groups according to plasma Mg levels; 34 subjects with hypomagnesemia and 45 subjects with normal magnesium levels. Fasting blood samples were analyzed for Mg, glucose and insulin. Pancreatic β-cell function was estimated as HOMA-β. Results: Degree of pancreatic β-cell function, as measured by HOMA-β, was significantly lower among T2DM subjects with hypomagnesemia compared to the subjects with normal magnesium levels (38.1± 5.5 vs. 41.2± 6.2, Pvalue< 0.05). Lower plasma Mg was associated with decreased pancreatic β-cell function among the study subjects independent of age, BMI and duration of diabetes. Conclusion: We concluded that among subjects with T2DM in this study, Mg deficiency might be linked with worsening of pancreatic β-cell function.

scholarly journals Role of leptin in the pancreatic β-cell: effects and signaling pathways

2012 ◽  
Vol 49 (1) ◽  
pp. R9-R17 ◽  
Author(s):  
Laura Marroquí ◽  
Alejandro Gonzalez ◽  
Patricia Ñeco ◽  
Ernesto Caballero-Garrido ◽  
Elaine Vieira ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Glucose Homeostasis ◽  
Endocrine Pancreas ◽  
Cell Function ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Leptin Receptors ◽  
Β Cell Function ◽  
Insulin Gene Expression

Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic β-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the β-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, β-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the β-cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic β-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of β-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic β-cell.

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

2011 ◽  
Vol 300 (2) ◽  
pp. E255-E262 ◽  
Author(s):  
Adria Giacca ◽  
Changting Xiao ◽  
Andrei I. Oprescu ◽  
Andre C. Carpentier ◽  
Gary F. Lewis
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

scholarly journals Retinol-Binding Protein 4 Activates STRA6 Provoking Pancreatic β Cell Dysfunction in Type 2 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Rong Huang ◽  
Xinxiu Bai ◽  
Xueyan Li ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Cell Dysfunction ◽  
Β Cell Function

Pancreatic β cell dysfunction plays a decisive role in progression of type 2 diabetes. Retinol binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes while its effect on β cell function remains elusive and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4-transgenic overexpressing mice (RBP4-Tg) showed a dynamic decrease of GSIS which appeared as early as 8-week-old preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6(STRA6), RBP4’s only known specific membrane receptor, is expressed in β cells and mediates the inhibitory effect of RBP4 on insulin synthesis via JAK2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β cell dysfunction which provided new insight into the diabetogenic effect of RBP4.

scholarly journals Retinol-Binding Protein 4 Activates STRA6 Provoking Pancreatic β Cell Dysfunction in Type 2 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Rong Huang ◽  
Xinxiu Bai ◽  
Xueyan Li ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Cell Dysfunction ◽  
Β Cell Function

Pancreatic β cell dysfunction plays a decisive role in progression of type 2 diabetes. Retinol binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes while its effect on β cell function remains elusive and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4-transgenic overexpressing mice (RBP4-Tg) showed a dynamic decrease of GSIS which appeared as early as 8-week-old preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6(STRA6), RBP4’s only known specific membrane receptor, is expressed in β cells and mediates the inhibitory effect of RBP4 on insulin synthesis via JAK2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β cell dysfunction which provided new insight into the diabetogenic effect of RBP4.

Adipokines as key players in β cell function and failure

2019 ◽  
Vol 133 (22) ◽  
pp. 2317-2327 ◽  
Author(s):  
Nicolás Gómez-Banoy ◽  
James C. Lo
Keyword(s):  
Metabolic Diseases ◽  
Cell Function ◽  
Whole Body ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Axis ◽  
Β Cell Function ◽  
Prevalence Of Obesity ◽  
Specific Factors ◽  
Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

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