scholarly journals Effects of Obesogenic Feeding and Free Fatty Acids on Circadian Secretion of Metabolic Hormones: Implications for the Development of Type 2 Diabetes

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2297
Author(s):  
Alexandre Martchenko ◽  
Patricia Lee Brubaker
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Metabolic Diseases ◽  
Cell Function ◽  
Biological Clock ◽  
Rhythmic Activity ◽  
Hierarchical Organization ◽  
Causative Role ◽  
Β Cells

Circadian rhythms are 24-h internal biological rhythms within organisms that govern virtually all aspects of physiology. Interestingly, metabolic tissues have been found to express cell-autonomous clocks that govern their rhythmic activity throughout the day. Disruption of normal circadian rhythmicity, as induced by environmental factors such as shift work, significantly increases the risk for the development of metabolic diseases, including type 2 diabetes and obesity. More recently, obesogenic feeding and its fatty acid components have also been shown to be potent disruptors of normal circadian biology. Two key hormones that are released in response to nutrient intake are the anti-diabetic incretin hormone glucagon-like peptide-1, from intestinal L cells, and insulin secreted by pancreatic β cells, both of which are required for the maintenance of metabolic homeostasis. This review will focus on the circadian function of the L and β cells and how both obesogenic feeding and the saturated fatty acid, palmitate, affect their circadian clock and function. Following introduction of the core biological clock and the hierarchical organization of the mammalian circadian system, the circadian regulation of normal L and β cell function and the importance of GLP-1 and insulin in establishing metabolic control are discussed. The central focus of the review then considers the circadian-disrupting effects of obesogenic feeding and palmitate exposure in L and β cells, while providing insight into the potential causative role in the development of metabolic disease.

Effects of palmitate on ER and cytosolic Ca2+ homeostasis in β-cells

2009 ◽  
Vol 296 (4) ◽  
pp. E690-E701 ◽  
Author(s):  
Kamila S. Gwiazda ◽  
Ting-Lin B. Yang ◽  
Yalin Lin ◽  
James D. Johnson
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acids ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

There are strong links between obesity, elevated free fatty acids, and type 2 diabetes. Specifically, the saturated fatty acid palmitate has pleiotropic effects on β-cell function and survival. In the present study, we sought to determine the mechanism by which palmitate affects intracellular Ca2+, and in particular the role of the endoplasmic reticulum (ER). In human β-cells and MIN6 cells, palmitate rapidly increased cytosolic Ca2+ through a combination of Ca2+ store release and extracellular Ca2+ influx. Palmitate caused a reversible lowering of ER Ca2+, measured directly with the fluorescent protein-based ER Ca2+ sensor D1ER. Using another genetically encoded indicator, we observed long-lasting oscillations of cytosolic Ca2+ in palmitate-treated cells. In keeping with this observed ER Ca2+ depletion, palmitate induced rapid phosphorylation of the ER Ca2+ sensor protein kinase R-like ER kinase (PERK) and subsequently ER stress and β-cell death. We detected little palmitate-induced insulin secretion, suggesting that these Ca2+ signals are poorly coupled to exocytosis. In summary, we have characterized Ca2+-dependent mechanisms involved in altered β-cell function and survival induced by the free fatty acid palmitate. We present the first direct evidence that free fatty acids reduce ER Ca2+ and shed light on pathways involved in lipotoxicity and the pathogenesis of type 2 diabetes.

scholarly journals Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3328
Author(s):  
Eloisa Aparecida Vilas-Boas ◽  
Davidson Correa Almeida ◽  
Leticia Prates Roma ◽  
Fernanda Ortis ◽  
Angelo Rafael Carpinelli
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Nadph Oxidase ◽  
Er Stress ◽  
Cell Function ◽  
Caloric Intake ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

scholarly journals Selenoprotein P as a significant regulator of pancreatic β cell function

2019 ◽  
Author(s):  
Yoshiro Saito
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Insulin Signalling ◽  
Selenoprotein P ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Abstract Selenoprotein P (SeP; encoded by SELENOP) is selenium (Se)-rich plasma protein that is mainly produced in the liver. SeP functions as a Se-transport protein to deliver Se from the liver to other tissues, such as the brain and testis. The protein plays a pivotal role in Se metabolism and antioxidative defense, and it has been identified as a ‘hepatokine’ that causes insulin resistance in type 2 diabetes. SeP levels are increased in type 2 diabetes patients, and excess SeP impairs insulin signalling, promoting insulin resistance. Furthermore, increased levels of SeP disturb the functioning of pancreatic β cells and inhibit insulin secretion. This review focuses on the biological function of SeP and the molecular mechanisms associated with the adverse effects of excess SeP on pancreatic β cells’ function, particularly with respect to redox reactions. Interactions between the liver and pancreas are also discussed.

scholarly journals A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
Author(s):  
Xiao-Ting Huang ◽  
Shao-Jie Yue ◽  
Chen Li ◽  
Yan-Hong Huang ◽  
Qing-Mei Cheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Stimulation Of ◽  
Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

Arachidonic acid fights palmitate: new insights into fatty acid toxicity in β-cells

2010 ◽  
Vol 120 (5) ◽  
pp. 179-181 ◽  
Author(s):  
Henrik Ortsäter
Keyword(s):  
Type 2 Diabetes ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Saturated Fatty Acids ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Self Protection

Saturated fatty acids are toxic to pancreatic β-cells. By inducing apoptosis, they contribute to a decrease in β-cell mass, a hallmark of Type 2 diabetes. In the present issue of Clinical Science, Keane and co-workers show that the polyunsaturated fatty acid arachidonic acid protects the β-cell against the toxic effects of palmitate. As Type 2 diabetes is characterized by subclinical inflammation, and arachidonic acid and metabolites thereof are produced during states of inflammation, it is possible that pancreatic β-cells use arachidonic acid as a compound for self-protection.

scholarly journals Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer

2009 ◽  
Vol 55 (3) ◽  
pp. 425-438 ◽  
Author(s):  
Javier A Menendez ◽  
Alejandro Vazquez-Martin ◽  
Francisco Jose Ortega ◽  
Jose Manuel Fernandez-Real
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
De Novo ◽  
Genetic Alterations ◽  
Insulin Resistant

Abstract Background: An emerging paradigm supports the notion that deregulation of fatty acid synthase (FASN)-catalyzed de novo FA biogenesis could play a central role in the pathogenesis of metabolic diseases sharing the hallmark of insulin-resistance. Content: We reviewed pharmacological and genetic alterations of FASN activity that have been shown to significantly influence energy expenditure rates, fat mass, insulin sensitivity, and cancer risk. This new paradigm proposes that insulin-resistant conditions such as obesity, type 2 diabetes, and cancer arise from a common FASN-driven “lipogenic state”. An important question then is whether the development or the progression of insulin-related metabolic disorders can be prevented or reversed by the modulation of FASN status. If we accept the paradigm of FASN dysfunction as a previously unrecognized link between insulin resistance, type 2 diabetes, and cancer, the use of insulin sensitizers in parallel with forthcoming FASN inhibitors should be a valuable therapeutic approach that, in association with lifestyle interventions, would concurrently improve energy-flux status, ameliorate insulin sensitivity, and alleviate the risk of lipogenic carcinomas. Conclusions: Although the picture is currently incomplete and researchers in the field have plenty of work ahead, the latest clinical and experimental evidence that we discuss illuminates a functional and drug-modifiable link that connects FASN-driven endogenous FA biosynthesis, insulin action, and glucose homeostasis in the natural history of insulin-resistant pathologies.

BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner

2009 ◽  
Vol 296 (2) ◽  
pp. C346-C354 ◽  
Author(s):  
Fan Zhang ◽  
Deben Dey ◽  
Robert Bränström ◽  
Lars Forsberg ◽  
Ming Lu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
High Glucose ◽  
Cell Function ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic β-cells. We have investigated the influence of the drug on β-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+]i) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the β-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in β-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+]i mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on β-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

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.

β-Cell compensation concomitant with adaptive endoplasmic reticulum stress and β-cell neogenesis in a diet-induced type 2 diabetes model

2019 ◽  
Vol 44 (12) ◽  
pp. 1355-1366 ◽  
Author(s):  
Hui Huang ◽  
Kaiyuan Yang ◽  
Rennian Wang ◽  
Woo Hyun Han ◽  
Sharee Kuny ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Temporal Association ◽  
Adaptive Responses ◽  
Β Cells ◽  
Β Cell

Insulin-secreting pancreatic β-cells adapt to obesity-related insulin resistance via increases in insulin secretion and β-cell mass. Failed β-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of β-cell compensation are not fully understood. Our previous study reported changes in β-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other β-cell adaptive responses, including glucose metabolism and β-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of β-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in β-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative β-cell growth as a mechanism of β-cell mass adaptation. In contrast, decreased neogenesis and β-cell dedifferentiation were observed in β-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of β-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for β-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. β-Cell neogenesis but not proliferation contributes to β-cell mass adaptation.

scholarly journals TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Chen Liu ◽  
Wu QiNan ◽  
Lei XiaoTian ◽  
Yang MengLiu ◽  
Gan XiaGuang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Leucine Zipper ◽  
Diabetic Mice ◽  
Β Cells ◽  
Akt Phosphorylation ◽  
Key Steps

Islet β cell apoptosis plays an important role in type 2 diabetes. We previously reported that Par-4-mediated islet β cell apoptosis is induced by high-glucose/fatty acid levels. In the present study, we show that Par-4, which is induced by high-glucose/fatty acid levels, interacts with and inhibits TERT in the cytoplasm and then translocates to the nucleus. Par-4 also inhibited Akt phosphorylation, leading to islet β cell apoptosis. We inhibited Par-4 in islet β cells under high-glucose/fatty acid conditions and knocked out Par-4 in diabetic mice, which led to the up-regulation of TERT and an improvement in the apoptosis rate. We inhibited Akt phosphorylation in islet β cells and diabetic mice, which led to aggressive apoptosis. In addition, the biological film interference technique revealed that Par-4 bound to TERT via its NLS and leucine zipper domains. Our research suggests that Par-4 activation and binding to TERT are key steps required for inducing the apoptosis of islet β cells under high-glucose/fatty acid conditions. Inhibiting Akt phosphorylation aggravated apoptosis by activating Par-4 and inhibiting TERT, and Par-4 inhibition may be an attractive target for the treatment of islet β cell apoptosis.

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