Rhythm of the β-cell oscillator is not governed by a single regulator: multiple systems contribute to oscillatory behavior

Heart, Emma; Smith, Peter J. S.

doi:10.1152/ajpendo.00648.2006

Cited by 25 publications

(25 citation statements)

References 47 publications

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“…Our study has three main findings. First, we have shown that palmitate causes cytosolic Ca 2ϩ signals in primary human islet ␤-cells and MIN6 cells, in agreement with previous findings in other ␤-cell lines and primary mouse islets (19,22). Second, we have demonstrated that these Ca 2ϩ signals are generated by a combination of extracellular Ca 2ϩ influx and Ca 2ϩ release from intracellular stores.…”

Section: Discussionsupporting

confidence: 91%

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

Gwiazda¹,

Yang²,

Lin³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

178

158

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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.

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Section: Discussionsupporting

confidence: 91%

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

Gwiazda¹,

Yang²,

Lin³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

178

158

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“…MMS induced ⌬ p and [Ca 2ϩ ] c oscillations in the rat islets indistinguishable from those produced by glucose, as well as a "classic" first-and secondphase insulin secretion, and the authors concluded that "systems other than glycolysis might control these oscillations" (213). The study was extended to methyl pyruvate and ␣-ketoisocaproate (KIC) (212). Both substrates supported regular "slow" [Ca 2ϩ ] c oscillations in single dissociated mouse islet cells.…”

Section: Is Glycolysis Needed For Slow Oscillations?mentioning

confidence: 98%

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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“…However, oscillations in [Ca 2+ ] i remained normal after 95-98% suppression of PFK-M activity in mouse islets (Richard et al, 2007). Moreover, oscillations of [Ca 2+ ] i are not only generated by glucose, but also by mitochondrial substrates like leucine (Grapengiesser et al, 1989b), α-ketoisocaproic acid (Martin et al, 1995;Heart and Smith, 2007) and methyl pyruvate (Heart and Smith, 2007) even in the absence of glycolytic flux (Heart and Smith, 2007), although some of these observations are controversial (Lenzen et al, 2000;Dahlgren et al, 2005). Since citrate oscillates in isolated islet mitochondria, it has also been proposed that there is an independent mitochondrial oscillator and that exported citrate may feedback-coordinate mitochondrial and glycolytic oscillations (MacDonald et al, 2003 (Detimary et al, 1998).…”

Section: Role Of Metabolism For Glucose-induced Insulin Secretionmentioning

confidence: 99%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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Rhythm of the β-cell oscillator is not governed by a single regulator: multiple systems contribute to oscillatory behavior

Abstract: Heart E, Smith PJS. Rhythm of the ␤-cell oscillator is not governed by a single regulator: multiple systems contribute to oscillatory behavior.

Cited by 25 publications

References 47 publications

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

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

The Pancreatic β-Cell: A Bioenergetic Perspective

Oscillatory control of insulin secretion

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Rhythm of the β-cell oscillator is not governed by a single regulator: multiple systems contribute to oscillatory behavior

Abstract: Heart E, Smith PJS. Rhythm of the ␤-cell oscillator is not governed by a single regulator: multiple systems contribute to oscillatory behavior.

Cited by 25 publications

References 47 publications

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

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

The Pancreatic β-Cell: A Bioenergetic Perspective

Oscillatory control of insulin secretion

Contact Info

Product

Resources

About

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

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