iPLA2γ Ablation Alters Glucose Homeostasis and Insulin Secretion in Response to Fatty Acids

Leguina-Ruzzi, Alberto; Průchová, Pavla; Holendová, Blanka; Ježek, Petr; Jabůrek, Martin

doi:10.1016/j.freeradbiomed.2017.10.233

Cited by 2 publications

(5 citation statements)

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“…Ježek et al have identified FA β-oxidation, as one leg in the FASIS mechanism, the branch producing essential H 2 O 2 from the ETF:QOR-formed superoxide (36, 136); but also revealed a new amplifying mechanism for the GPR40 branch of insulin secretion (providing ∼60% FASIS): amplification by FAs cleaved from mitochondrial phospholipids by the H 2 O 2 -activated iPLA2γ (136), recently confirmed in islets (138, 139, 175) (Fig. 2).…”

Section: Oxidative Stress and Antioxidant Protection In Pancreatic β-mentioning

confidence: 93%

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Ježek

Jabůrek

Plecitá–Hlavatá

2019

Antioxidants & Redox Signaling

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Significance: Type 2 diabetes development involves multiple changes in β-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relationships among the dysregulated metabolism, impaired β-cell “well-being,” biogenesis, or cross talk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity, and glucotoxicity cannot be separated from numerous other cell pathology events, such as the attempted compensation of β-cell for the increased insulin demand and dynamics of β-cell biogenesis and its “reversal” at dedifferentiation, that is, from the concomitantly decreasing islet β-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. Critical Issues: At prediabetes, the compensation responses of β-cells, attempting to delay the pathology progression—when exaggerated—set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various secretagogues including glucose, may lead to excretion of cytokines or chemokines by β-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. Future Directions: Should bring an understanding of the β-cell self-checking and related redox signaling, including the putative stress signal to periphery. Strategies to cure or prevent type 2 diabetes could be based on the substitution of the “wrong” signal by the “correct” self-checking signal.

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Section: Oxidative Stress and Antioxidant Protection In Pancreatic β-mentioning

confidence: 93%

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Ježek

Jabůrek

Plecitá–Hlavatá

2019

Antioxidants & Redox Signaling

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“…In model β-cells and with isolated pancreatic islets (ex vivo, Jabůrek et al, unpublished, and preliminary data reported in [ 40 ]), a novel phenomenon of signal amplification for GPR40 has been reported [ 2 ]. Physiologically relevant concentrations of exogenous palmitic acid were not able or sufficient to directly activate the GPR40 to stimulate insulin secretion, but instead were metabolized by the mitochondrial β-oxidation.…”

Section: Physiological Involvement Of Lcfas In Insulin Secretionmentioning

confidence: 99%

“…With increasing glucose, the pathways of FASIS and GSIS act in concert. In experiments, FASIS may exceed GSIS [ 2 , 40 ]; however, the proportions of these two mechanisms, in response to various human diets, have to be further investigated.…”

Section: Physiological Involvement Of Lcfas In Insulin Secretionmentioning

confidence: 99%

“…When we recognize the existence of FASIS, despite the difficulties to quantify it experimentally in vivo [ 37 , 43 ], one may get a deeper insight into the interrelationships between the glucose and lipid metabolism. The net FASIS in model pancreatic β-cells, insulinoma INS-1E cells, provides >3 times more insulin than GSIS [ 1 , 2 , 40 ]. The similar pattern is valid when comparing the intraperitoneal (i.p.)…”

Section: Physiological Involvement Of Lcfas In Insulin Secretionmentioning

confidence: 99%

“… Predicted amount of insulin released by the mechanisms described in Figure 1 (based on References [ 2 , 40 ] and unpublished observations of GLP-1-induced insulin release in fasted mice, by Plecitá-Hlavatá et al), as follows: 1st column : Basal, very low, insulin secretion at fasting can be considered partly as originating from the FA stimulation of the intenstinal incretin release with subsequent GLP1R- and GIPR-mediated insulin release in β-cells. We predict that at the lipid overnutrition and metabolic syndrome ( 2nd column ), the elevated plasma FAs at fasting will significantly increase this insulin secretion by regular FASIS mechanisms, thus contributing to developed hyperinsulinemia.…”

Section: Figurementioning

confidence: 99%

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Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity

et al. 2018

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Fatty acid (FA)-stimulated insulin secretion (FASIS) is reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, all converging into insulin resistance. Focusing on pancreatic islet β-cells, we compare the physiological FA roles with the pathological ones. Considering FAs not as mere amplifiers of glucose-stimulated insulin secretion (GSIS), but as parallel insulin granule exocytosis inductors, partly independent of the KATP channel closure, we describe the FA initiating roles in the prediabetic state that is induced by retardations in the glycerol-3-phosphate (glucose)-promoted glycerol/FA cycle and by the impaired GPR40/FFA1 (free FA1) receptor pathway, specifically in its amplification by the redox-activated mitochondrial phospholipase, iPLA2γ. Also, excessive dietary FAs stimulate intestine enterocyte incretin secretion, further elevating GSIS, even at low glucose levels, thus contributing to diabetic hyperinsulinemia. With overnutrition and obesity, the FA overload causes impaired GSIS by metabolic dysbalance, paralleled by oxidative and metabolic stress, endoplasmic reticulum stress and numerous pro-apoptotic signaling, all leading to decreased β-cell survival. Lipotoxicity is exerted by saturated FAs, whereas ω-3 polyunsaturated FAs frequently exert antilipotoxic effects. FA-facilitated inflammation upon the recruitment of excess M1 macrophages into islets (over resolving M2 type), amplified by cytokine and chemokine secretion by β-cells, leads to an inevitable failure of pancreatic β-cells.

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iPLA2γ Ablation Alters Glucose Homeostasis and Insulin Secretion in Response to Fatty Acids

Cited by 2 publications

References 0 publications

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity

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