Increased Glucose Metabolism and Glycerolipid Formation by Fatty Acids and GPR40 Receptor Signaling Underlies the Fatty Acid Potentiation of Insulin Secretion

El-Azzouny, Mahmoud; Evans, Charles R.; Treutelaar, Mary K.; Kennedy, Robert T.; Burant, Charles F.

doi:10.1074/jbc.m113.531970

Cited by 57 publications

(58 citation statements)

References 42 publications

(69 reference statements)

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“…The free, unbound, fatty acid concentration under these conditions is only ϳ10 -20 nM (105,442). While the need for albumin binding is generally appreciated in the literature, molar ratios of 6:1 or even higher have been employed in vitro (144,285,332,472), producing unbound fatty acid concentrations close to 1 M, or 100 times higher than the normal physiological range (FIGURE 8A). One concern in such studies is the possibility that excessive fatty acid exposure in vitro may produce artifactual changes in metabolism, for example, due to nonspecific mitochondrial uncoupling (269,277), that might mask a physiologically relevant positive signaling or bioenergetic effect.…”

Section: E Fatty Acidsmentioning

confidence: 99%

“…Schnell et al (472) observed oleate-induced oscillations and a sustained increase in [Ca 2ϩ ] c in primary mouse ␤-cells in the presence of 5 mM glucose; however, a molar ratio of 6:1 seemed to be required. El-Azzouny et al (144) performed an exhaustive study of the bioenergetic and metabolic consequences of acute fatty acid exposure of INS-1 cells, including the use of a GPR40 antagonist, but again used a high 6:1 molar ratio. Ferdaoussi et al (152) compared islets from wild-type and Gpr40Ϫ/Ϫ mice, concluding that GPR40 was responsible for ϳ50% of the oleatemediated enhancement of second phase secretion (FIGURE 8B), but utilized a 5:1 molar ratio.…”

Section: Gpr40/ffa1mentioning

confidence: 99%

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The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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The pancreatic ␤-cell secretes insulin in response to elevated plasma glucose. This review applies an external bioenergetic critique to the central processes of glucose-stimulated insulin secretion, including glycolytic and mitochondrial metabolism, the cytosolic adenine nucleotide pool, and its interaction with plasma membrane ion channels. The control mechanisms responsible for the unique responsiveness of the cell to glucose availability are discussed from bioenergetic and metabolic control standpoints. The concept of coupling factor facilitation of secretion is critiqued, and an attempt is made to unravel the bioenergetic basis of the oscillatory mechanisms controlling secretion. The need to consider the physiological constraints operating in the intact cell is emphasized throughout. The aim is to provide a coherent pathway through an extensive, complex, and sometimes bewildering literature, particularly for those unfamiliar with the field.

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Section: E Fatty Acidsmentioning

confidence: 99%

Section: Gpr40/ffa1mentioning

confidence: 99%

The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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“…Studies using MIN6 and INS-1 insulin-producing cell lines have shown increases in insulin secretion induced by longchain FAs through GPR40 receptor activity [9,14]. Increase in insulin secretion was also observed in isolated mice pancreatic islets treated with polyunsaturated linoleic and α-linolenic acids [15].…”

Section: Introductionmentioning

confidence: 80%

“…Although the effects of FAs on pancreatic β-cell functions [3,11,[14][15][16][17][18][19][20] have been well documented, the molecular consequences of FA deficiency on pancreatic β-cell function remain to be clarified. Some studies have already reported the relationship of specific nutrient deficiencies with posterior high risk of diabetes and hyperglycemia 22-24, however; only few of them approach the cellular mechanisms of β-cell response to the deficiency conditions 25.…”

Section: Introductionmentioning

confidence: 99%

Culture Medium Fatty Acid Withdrawal Prompts Insulin Producing Cell Death

Mp¹,

Nunes²,

Lenzen³

et al. 2017

EMIJ

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Fatty acids (FAs) are important components of cell membranes and precursors of bioactive molecules. Deficiency of FA has been associated with development of diseases and tissue damage in animal models. FAs regulate several cell functions including insulin secretion. We investigated the effects of FA withdrawal in culture medium on insulin producing cell (RINm5F) metabolism, survival, and response to death stimuli. Cells were cultivated in lipid-reduced fetal bovine serum (LRS) medium for 24, 48 or 72 h. Cell proliferation was measured by BrdU incorporation and glucose metabolism by 14CO2 production. Production of reactive oxygen species (ROS) was determined using dichlorofluorescein diacetate assay. Cells were exposed to death inducers to evaluate the effect of FA deprivation on RINm5F cell survival and susceptibility to death induction. Loss of plasma membrane integrity, DNA fragmentation, phosphatidylserine externalization and activation of caspases were analyzed by flow cytometry. The removal of FAs from the culture medium increased the number of dead cells as assessed by loss of plasma membrane integrity and occurrence of DNA fragmentation. Cells cultured in LRS exhibited higher cell death rates as compared to those cultivated with conventional serum. Cultivation in LRS for 48 hours increased phosphatidylserine externalization, caspase activation, ROS production and glucose oxidation. FA deprivation induced RINm5F cell death through apoptosis and exacerbated the cell death response to death stimuli. Cell death was associated with changes in generation of ROS and glucose oxidation.

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“…Free fatty acids such as palmitate potentiate glucose-stimulated insulin secretion by altering b cell metabolism (El-Azzouny et al 2014). Islets from PWD mice secreted significantly more insulin in response to palmitate than B6 islets (Fig.…”

Section: Increased Glucose-stimulated Insulin Secretion From Pwd Isletsmentioning

confidence: 98%

PWD/PhJ mice have a genetically determined increase in nutrient-stimulated insulin secretion

Johnson

Clee

2015

Mamm Genome

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PWD/PhJ (PWD) is a wild-derived inbred mouse strain unrelated to commonly studied strains, such as C57BL/6J (B6). A chromosome substitution panel with PWD chromosomes transferred into the B6 background is commercially available and will facilitate genetic analysis of this strain. We have previously shown that the PWD strain is a model of primary fasting hyperinsulinemia. To identify more specific phenotypes affected by the genetic variation in PWD compared to B6 mice, we examined physiological mechanisms that may contribute to their elevated insulin levels. PWD mice had increased nutrient-stimulated insulin secretion due to factors inherent to their pancreatic islets. Insulin secretion responses to glucose, palmitate, and the metabolic intermediate α-ketoisocaproate were increased ~2-fold in islets from PWD mice compared to B6 islets. In contrast, there were no strain differences in processes affecting insulin secretion downstream of β cell depolarization. PWD mice tended to have larger but fewer islets than B6 mice, resulting in similar insulin-staining areas and insulin content per unit of pancreatic tissue. However, pancreata of PWD mice were smaller, resulting in reduced total β cell mass and pancreatic insulin content compared to B6 mice. Combined, these data suggest that the elevated fasting insulin levels in PWD mice result from increased generation of metabolic signals leading to β cell depolarization and insulin secretion. Identification of the genetic differences underlying the enhanced nutrient-stimulated insulin secretion in this model may lead to new approaches to appropriately modulate insulin secretion for the treatment of obesity and type 2 diabetes.

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Increased Glucose Metabolism and Glycerolipid Formation by Fatty Acids and GPR40 Receptor Signaling Underlies the Fatty Acid Potentiation of Insulin Secretion

Cited by 57 publications

References 42 publications

The Pancreatic β-Cell: A Bioenergetic Perspective

The Pancreatic β-Cell: A Bioenergetic Perspective

Culture Medium Fatty Acid Withdrawal Prompts Insulin Producing Cell Death

PWD/PhJ mice have a genetically determined increase in nutrient-stimulated insulin secretion

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