Role of the Saturated Nonesterified Fatty Acid Palmitate in Beta Cell Dysfunction

Maris, Michael; Robert, Sofie; Waelkens, Etienne; Derua, Rita; Hernangómez, Miriam; D’Hertog, Wannes; Cnop, Miriam; Mathieu, Chantal; Overbergh, Lutgart

doi:10.1021/pr300596g

Cited by 45 publications

(52 citation statements)

References 65 publications

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“…Obese and diabetic subjects have elevated plasma levels of nonesterified fatty acids (NEFAs) and hyperglycemia, which are believed to cause decreased insulin synthesis and impaired glucose responsiveness in pancreatic β-cells, also termed glucolipotoxicity [2], [3]. Chronic exposure of β-cells to high NEFAs and glucose concentrations results in β-cell dysfunction and loss by ER stress and oxidative stress [4]–[6] resulting in apoptosis [4], [7]–[9].…”

Section: Introductionmentioning

confidence: 99%

“…However, lipo- and glucolipotoxicity-induced ER stress dependent β-cell apoptosis is characterized by a late and more prolonged JNK activation, and blocking JNK activity with the JNK inhibitory small molecule SP600123 in vitro decreases lipotoxic- and glucolipotoxic β-cell apoptosis [9], [21]–[24]. Additionally, JNK activity is potentiated by glucolipotoxicity via oxidative stress and mitochondrial ROS formation [4], [6], [25], [26]. ER stress cross-talks to the mitochondrial or intrinsic death pathway via p53-upregulated modulator of apoptosis (Puma) and JNK-dependent upregulation of the Death protein (DP5) [27].…”

Section: Introductionmentioning

confidence: 99%

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JNK1 Protects against Glucolipotoxicity-Mediated Beta-Cell Apoptosis

et al. 2014

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Pancreatic β-cell dysfunction is central to type 2 diabetes pathogenesis. Prolonged elevated levels of circulating free-fatty acids and hyperglycemia, also termed glucolipotoxicity, mediate β-cell dysfunction and apoptosis associated with increased c-Jun N-terminal Kinase (JNK) activity. Endoplasmic reticulum (ER) and oxidative stress are elicited by palmitate and high glucose concentrations further potentiating JNK activity. Our aim was to determine the role of the JNK subtypes JNK1, JNK2 and JNK3 in palmitate and high glucose-induced β-cell apoptosis. We established insulin-producing INS1 cell lines stably expressing JNK subtype specific shRNAs to understand the differential roles of the individual JNK isoforms. JNK activity was increased after 3 h of palmitate and high glucose exposure associated with increased expression of ER and mitochondrial stress markers. JNK1 shRNA expressing INS1 cells showed increased apoptosis and cleaved caspase 9 and 3 compared to non-sense shRNA expressing control INS1 cells when exposed to palmitate and high glucose associated with increased CHOP expression, ROS formation and Puma mRNA expression. JNK2 shRNA expressing INS1 cells did not affect palmitate and high glucose induced apoptosis or ER stress markers, but increased Puma mRNA expression compared to non-sense shRNA expressing INS1 cells. Finally, JNK3 shRNA expressing INS1 cells did not induce apoptosis compared to non-sense shRNA expressing INS1 cells when exposed to palmitate and high glucose but showed increased caspase 9 and 3 cleavage associated with increased DP5 and Puma mRNA expression. These data suggest that JNK1 protects against palmitate and high glucose-induced β-cell apoptosis associated with reduced ER and mitochondrial stress.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

JNK1 Protects against Glucolipotoxicity-Mediated Beta-Cell Apoptosis

et al. 2014

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“…Saturated NEFAs are detrimental to beta-cell function. Their effect is exacerbated in the presence of high levels of glucose and may cause a condition called glucolipotoxicity (1). As fatty acids can stimulate insulin secretion, they have an important role in the mechanism of beta-cell compensation to insulin resistance (2).…”

Section: Introductionmentioning

confidence: 99%

Effects of supplementation with omega-3 on insulin sensitivity and non-esterified free fatty acid (NEFA) in type 2 diabetic patients

Farsi

Djazayery

Eshraghian

et al. 2014

Arq Bras Endocrinol Metab

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Objective: The aim of this study was to determine the role of omega-3 supplementation on NEFA concentration, insulin sensitivity and resistance, and glucose and lipid metabolism in type 2 diabetic patients. Subjects and methods: Forty-four type 2 diabetic patients were randomly recruited into two groups. Group A received 4 g/day omega-3 soft gels, and group B received a placebo for 10 wks. Blood samples were collected after 12-h fast. Physical activity records, three-day food records, and anthropometric measurements were obtained from all participants at the beginning and end of the study. Results: Omega-3 supplementation caused a significant reduction in NEFA in the intervention group compared with the placebo group (P = 0.009). Additionally, the administration of omega-3 resulted in significantly greater changes (Diff) for the intervention group in various parameters, such as insulin and Quicki indices compared with the placebo group (P < 0.05). Conclusions: Omega-3 fatty acid supplementation in type 2 diabetic patients improved insulin sensitivity, probably due to the decrease in NEFA concentrations. Arq Bras Endocrinol Metab. 2014;58(4):335-40

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“…For instance, Massa et al attempted to identify new autoantigen targets by blotting human pancreatic islet cells against sera from patients with T1D (*61). Finally, Maris et al used 2DGE/MS to highlight the changes in the β cell proteome induced by the fatty acid palmitate, implicating it as a cause of β cell dysfunction (62). …”

Section: Text Of Reviewmentioning

confidence: 99%

The pancreatic β-cell transcriptome and integrated-omics

Blodgett

Cura

Harlan

2014

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of Review β cells represent one of many cell types in heterogeneous pancreatic islets and play the central role in maintaining glucose homeostasis, such that disrupting β cell function leads to diabetes. This review summarizes methods for isolating and characterizing β cells, and describes integrated “omics” approaches used to define the β cell by its transcriptome and proteome. Recent Findings RNA Sequencing and mass spectrometry-based protein identification have now identified RNA and protein profiles for mouse and human pancreatic islets and β cells, and for β cell lines. Recent publications have outlined these profiles and, more importantly, have begun to assign the presence or absence of specific genes and regulatory molecules to β cell function and dysfunction. Overall, researchers have focused on understanding the pathophysiology of diabetes by connecting genome, transcriptome, proteome, and regulatory RNA profiles with findings from genome wide association studies (GWAS). Summary Studies employing these relatively new techniques promise to identify specific genes or regulatory RNAs with altered expression as β cell function begins to deteriorate in the spiral toward the development of diabetes. The ultimate goal is to identify potential therapeutic targets to prevent β cell dysfunction and thereby better treat the individual with diabetes.

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Role of the Saturated Nonesterified Fatty Acid Palmitate in Beta Cell Dysfunction

Cited by 45 publications

References 65 publications

JNK1 Protects against Glucolipotoxicity-Mediated Beta-Cell Apoptosis

JNK1 Protects against Glucolipotoxicity-Mediated Beta-Cell Apoptosis

Effects of supplementation with omega-3 on insulin sensitivity and non-esterified free fatty acid (NEFA) in type 2 diabetic patients

The pancreatic β-cell transcriptome and integrated-omics

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