Neurotransmitter control of islet hormone pulsatility

Gylfe, Erik; Tengholm, Anders

doi:10.1111/dom.12345

Cited by 60 publications

(61 citation statements)

References 79 publications

(139 reference statements)

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“…Such oscillations would not be possible unless the delta cells were stimulated by the beta cells, possibly through GABA or ATP [75] as the delta cells, like the alpha cells, are not coupled to each other. Another islet hormone, amylin, which is co-stored in the beta cell with insulin in large dense core granules also shows pulsatile secretion, with a mean period of around 5 minutes [76].…”

Section: Introductionmentioning

confidence: 99%

Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Satin

Butler

et al. 2015

Molecular Aspects of Medicine

203

201

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Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM.

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Section: Introductionmentioning

confidence: 99%

Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Satin

Butler

et al. 2015

Molecular Aspects of Medicine

203

201

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“…It has been recently proposed that “glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes”. 1,2 For these reasons, there is a growing interest in the development of rapid analytical methods for the determination of glucagon. Typically, glucagon has been determined by complex indirect assays that require its labeling with optical 3,4 or radioactive tags.…”

Section: Introductionmentioning

confidence: 99%

Hormone glucagon: electrooxidation and determination at carbon nanotubes

Karra

Griffith

Kennedy

et al. 2016

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The oxidation of glucagon, which is one of the key hormones in glucose homeostasis, was studied at electrodes modified with carbon nanotubes (CNT) that were dispersed in a polysaccharide adhesive chitosan (CHIT). Such electrodes displayed improved resistance to fouling, which allowed for the investigation of both the electrolysis/mass spectrometry and electroanalysis of glucagon. The off-line electrospray ionization and tandem mass spectrometric analyses showed that the -4 Da mass change to glucagon upon electrolysis at CNT was due to the electrooxidation of its tryptophan (W25) and dityrosine (Y10, Y13) residues. The methionine residue of glucagon did not contribute to its oxidation. The amperometric determination of glucagon yielded the limit of detection equal to ~20 nM (E = 0.800 V, pH 7.40, S/N = 3), sensitivity of 0.46 A M−1 cm−2, linear dynamic range up to 2.0 μM (R2 = 0.998), response time <5 s, and good signal stability. Free tryptophan and tyrosine yielded comparable analytical figures of merit. The direct amperometric determination of unlabeled glucagon at CHIT-CNT electrodes is the first example of a rapid alternative to the complex analytical assays of this peptide.

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Section: +mentioning

confidence: 99%

“…The endocrine cells are not the only source of purine nucleotides as ATP is also released from nerve endings [23]. In mouse islets, transient and self-regenerating release of ATP from beta cells serves as a complement to gap junctions for synchronising cytosolic Ca 2+ oscillations between beta cells to generate pulsatile insulin secretion [9,23]. Similarly, neurally derived ATP may help to synchronise oscillations between islets in different parts of the pancreas to generate insulin pulses in the circulation [13,23].…”

Section: +mentioning

confidence: 99%

“…In mouse islets, transient and self-regenerating release of ATP from beta cells serves as a complement to gap junctions for synchronising cytosolic Ca 2+ oscillations between beta cells to generate pulsatile insulin secretion [9,23]. Similarly, neurally derived ATP may help to synchronise oscillations between islets in different parts of the pancreas to generate insulin pulses in the circulation [13,23]. In both rodent [24,25] and human [26] islets, pulses of insulin occur in phase with pulses of somatostatin but in opposite phase with peaks of glucagon.…”

Section: +mentioning

confidence: 99%

See 1 more Smart Citation

Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells

Tengholm

2014

Diabetologia

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Insulin secretory vesicles contain high concentrations of adenine nucleotides, which are co-released with insulin during exocytosis. There is strong evidence that ATP and ADP serve as autocrine messengers in pancreatic beta cells, but the functional effects and detailed mechanisms of action are under debate. In this issue of Diabetologia, Khan and colleagues (DOI: 10.1007/s00125-014-3368-8) present the results of their study of autocrine purinergic signalling in isolated human beta cells. Using a combination of electrophysiological techniques, Ca 2+ imaging and measurements of insulin secretion, it is demonstrated that voltage-dependent Ca 2+ influx triggers release of ATP/ADP, which activates purinergic receptors of the G q/11 -coupled P2Y 1 isoform. Activation of these receptors leads to membrane depolarisation and phospholipase C-mediated mobilisation of Ca 2+ from endoplasmic reticulum stores, which amplifies the exocytosis-triggering Ca 2+ signal. In contrast, there is little evidence for involvement of ionotropic P2X receptors in the autocrine stimulation of human beta cells. This commentary discusses these findings as well as various functional and therapeutic implications of the complex purinergic signalling network in the pancreatic islet. . The nucleotides are co-released with insulin during vesicle exocytosis and the local concentration of ATP at the beta cell surface may then reach micromolar levels [5]. The small size of ATP and related nucleotides allows them to escape through the granule fusion pore before insulin is released, and sometimes even without concomitant protein secretion [6]. The purine nucleotides exert auto-and paracrine actions on beta cells, and although there is extensive literature on the subject (reviewed in [7,8]), the precise receptors and molecular mechanisms involved have not been clarified.Two classes of purinergic P2 receptors mediate the effects of ATP and ADP: ionotropic P2X receptors and G-proteincoupled P2Y receptors. The P2X receptors constitute a group of seven isoforms that act as ATP-gated cation channels, several of which are expressed in beta cells [7,8]. Many of the eight P2Y family members are also present in beta cells, with a dominant role of the G q/11 -coupled P2Y 1 receptor [7,9]. Extracellular ATP has been found to amplify glucosestimulated insulin secretion in both rodent and human studies [7], but inhibitory effects have also been demonstrated, at least in the mouse [10,11]. A negative effect of ATP is also supported by the observation that glucose-induced insulin secretion is enhanced in P2Y 1 -knockout mice [12] and that a P2Y 1 receptor antagonist increases insulin secretion in the perfused rat pancreas [13]. However, recent studies support a stimulatory autocrine effect in human beta cells, although

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Neurotransmitter control of islet hormone pulsatility

Cited by 60 publications

References 79 publications

Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Hormone glucagon: electrooxidation and determination at carbon nanotubes

Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells

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