Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

Oh, Yoon Sin; Bae, Gong Deuk; Baek, Dong Jae; Park, Eun‐Young; Jun, Hee-Sook

doi:10.3389/fendo.2018.00384

Cited by 236 publications

(200 citation statements)

References 110 publications

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“…Under physiological conditions, beta-cells can use NEFA as fuel; however, prolonged exposure to elevated levels of NEFA reduces insulin secretion by two different mechanisms, direct insulin transcriptional downregulation and beta-cell death [19][20][21]. This mechanism is not exclusive to beta-cells; it has also been observed diabetic cardiomyopathy and DN [22,23].…”

Section: Subcutaneous Abdominal Fatty Deposits and High Plasma Nefa Lmentioning

confidence: 99%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

210

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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Section: Subcutaneous Abdominal Fatty Deposits and High Plasma Nefa Lmentioning

confidence: 99%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

210

147

View full text Add to dashboard Cite

show abstract

“…Obesity is another example of a metabolic disorder associated with several co-morbidities, with an increasing prevalence every year [21]. Excessive lipid accumulation could be one of the causative factors for type II diabetes, as the accumulation of lipid in the pancreas causes dysfunction of insulin-producing pancreatic β-cells [22]. Recently, inhibitors of pancreatic lipase have attracted interest due to their ability to delay lipid digestion, and hence could act as promising anti-obesity drugs [23].…”

Section: Introductionmentioning

confidence: 99%

Phenolic Compounds from the Aerial Parts of Blepharis linariifolia Pers. and Their Free Radical Scavenging and Enzyme Inhibitory Activities

et al. 2019

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Background: Blepharis linariifolia Pers. (Family: Acanthaceae) is used in traditional medicines as a general tonic and for the treatment of various health problems in Sudan. The main aim of this study was to isolate and identify the major chemical constituents from the aerial parts of B. linariifolia and evaluate their bioactivities. Methods: The dried aerial parts of the plant were extracted successively with 100% acetone and 50% acetone, and thereafter the combined extract was subjected to repeated column chromatography to isolate the main components. Free radical scavenging activity was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical method, and in vitro enzyme inhibitory activities against α-glucosidase, pancreatic lipase, and mushroom tyrosinase were evaluated. Results: From the detailed chemical analysis, verbascoside (1), vanillic acid (2), apigenin (3), and 6″-O-p-coumaroylprunin (4), were isolated and their structures were identified on the basis of their nuclear magnetic resonance (NMR) spectral data. Among the isolated compounds, verbascoside (1) showed the most potent free radical scavenging activity (IC50 = 22.03 ± 0.04 μM). Apigenin (3) and 6″-O-p-coumaroylprunin (4) showed promising inhibitory activities against all tested enzymes. Apigenin (3) showed the most potent inhibitory activity against α-glucosidase and tyrosinase (IC50 = 34.73 ± 1.78 μM and 23.14 ± 1.83 μM, respectively), whereas 6″-O-p-coumaroylprunin (4) showed potent inhibition for lipase (IC50 = 2.25 ± 0.17 μM). Conclusions: Four phenolic compounds were isolated and identified from B. linariifolia acetone extract, which are reported for the first time from this plant. All compounds showed good DPPH free radical scavenging activities, with verbascoside (1) being the most potent. Apigenin (3) was the most active as α-glucosidase and mushroom tyrosinase inhibitor, while 6″-O-p-coumaroylprunin (4) showed potent inhibitory activity for pancreatic lipase.

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“…The markers of UPR include ER proteins PERK, IRE1α and ARF6, all of which are elevated in T2D. The activation of JNK is downstream of IRE1α to promote apoptosis [149]. IRE1α, when active, associates with TNFR-associated factor 2 (TRAF2), an adaptor protein, to activate the MAP3K ASK1, and ultimately JNK [144,[150][151][152][153].…”

Section: Activation Of Innate Immunity Receptorsmentioning

confidence: 99%

“…This is likely because the main JNK activators during saturated FFA exposure are ER stress, ceramides and innate immunity receptors, which are induced/stimulated mainly or exclusively by saturated fat. In β-cells, the ER is important in ensuring that insulin folds properly [149]. Thus, β-cells are especially sensitive to ER stress, and JNK stimulation by ER stress accounts for palmitate-induced IRS-1 serine phosphorylation [167], reduced insulin gene transcription [167], and apoptosis [144].…”

Section: β-Cell Lipotoxicitymentioning

confidence: 99%

Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes

Yung

Giacca

2020

Cells

151

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Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.

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Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

Cited by 236 publications

References 110 publications

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Phenolic Compounds from the Aerial Parts of Blepharis linariifolia Pers. and Their Free Radical Scavenging and Enzyme Inhibitory Activities

Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes

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