Electrical activity and exocytotic correlates of biphasic insulin secretion from β-cells of canine islets of Langerhans: Contribution of tuning two modes of Ca2+entry-dependent exocytosis to two modes of glucose-induced electrical activity

Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines.

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Granule docking and cargo release in pancreatic β-cells

Biochemical Society Transactions ◽

10.1042/bst0360294 ◽

2008 ◽

Vol 36 (3) ◽

pp. 294-299 ◽

Cited By ~ 9

Author(s):

Sebastian Barg ◽

Anders Lindqvist ◽

Stefanie Obermüller

Keyword(s):

Insulin Secretion ◽

Live Cell Imaging ◽

Cell Imaging ◽

Fusion Pore ◽

Β Cells ◽

Pancreatic Β Cells ◽

Isolated Pancreatic Islets ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion

Biphasic insulin secretion is required for proper insulin action and is observed not only in vivo, but also in isolated pancreatic islets and even single β-cells. Late events in the granule life cycle are thought to underlie this temporal pattern. In the last few years, we have therefore combined live cell imaging and electrophysiology to study insulin secretion at the level of individual granules, as they approach the plasma membrane, undergo exocytosis and finally release their insulin cargo. In the present paper, we review evidence for two emerging concepts that affect insulin secretion at the level of individual granules: (i) the existence of specialized sites where granules dock in preparation for exocytosis; and (ii) post-exocytotic regulation of cargo release by the fusion pore.

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Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

EBioMedicine ◽

10.1016/j.ebiom.2016.10.038 ◽

2016 ◽

Vol 13 ◽

pp. 168-180 ◽

Cited By ~ 7

Author(s):

Shinji Kume ◽

Motoyuki Kondo ◽

Shiro Maeda ◽

Yoshihiko Nishio ◽

Tsuyoshi Yanagimachi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Protein Kinase ◽

Β Cells ◽

Pancreatic Β Cells ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion ◽

Amp Activated Protein Kinase

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Calcium signaling and secretory granule pool dynamics underlie biphasic insulin secretion and its amplification by glucose: experiments and modeling

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00380.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. E475-E486 ◽

Cited By ~ 4

Author(s):

Morten Gram Pedersen ◽

Alessia Tagliavini ◽

Jean-Claude Henquin

Keyword(s):

Insulin Secretion ◽

Glucose Concentration ◽

Calcium Influx ◽

Secretory Granules ◽

Cytosolic Calcium ◽

Second Phase ◽

Calcium Dynamics ◽

Β Cells ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells is controlled by a triggering pathway that culminates in calcium influx and regulated exocytosis of secretory granules, and by a less understood amplifying pathway that augments calcium-induced exocytosis. In response to an abrupt increase in glucose concentration, insulin secretion exhibits a first peak followed by a lower sustained second phase. This biphasic secretion pattern is disturbed in diabetes. It has been attributed to depletion and subsequent refilling of a readily releasable pool of granules or to the phasic cytosolic calcium dynamics induced by glucose. Here, we apply mathematical modeling to experimental data from mouse islets to investigate how calcium and granule pool dynamics interact to control dynamic insulin secretion. Experimental calcium traces are used as inputs in three increasingly complex models of pool dynamics, which are fitted to insulin secretory patterns obtained using a set of protocols of glucose and tolbutamide stimulation. New calcium and secretion data for so-called staircase protocols, in which the glucose concentration is progressively increased, are presented. These data can be reproduced without assuming any heterogeneity in the model, in contrast to previous modeling, because of nontrivial calcium dynamics. We find that amplification by glucose can be explained by increased mobilization and priming of granules. Overall, our results indicate that calcium dynamics contribute substantially to shaping insulin secretion kinetics, which implies that better insight into the events creating phasic calcium changes in human β-cells is needed to understand the cellular mechanisms that disturb biphasic insulin secretion in diabetes.

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A subcellular model of glucose-stimulated pancreatic insulin secretion

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2008.0120 ◽

2008 ◽

Vol 366 (1880) ◽

pp. 3525-3543 ◽

Cited By ~ 40

Author(s):

Morten Gram Pedersen ◽

Alberto Corradin ◽

Gianna M Toffolo ◽

Claudio Cobelli

Keyword(s):

Insulin Secretion ◽

Glucose Concentration ◽

Rate Of Change ◽

Β Cells ◽

Biphasic Insulin ◽

Pancreatic Insulin ◽

Biphasic Insulin Secretion ◽

Qualitative Pattern ◽

Glucose Stimulated Insulin Secretion ◽

The Individual

When glucose is raised from a basal to stimulating level, the pancreatic islets respond with a typical biphasic insulin secretion pattern. Moreover, the pancreas is able to recognize the rate of change of the glucose concentration. We present a relatively simple model of insulin secretion from pancreatic β-cells, yet founded on solid physiological grounds and capable of reproducing a series of secretion patterns from perfused pancreases as well as from stimulated islets. The model includes the notion of distinct pools of granules as well as mechanisms such as mobilization, priming, exocytosis and kiss-and-run. Based on experimental data, we suggest that the individual β-cells activate at different glucose concentrations. The model reproduces most of the data it was tested against very well, and can therefore serve as a general model of glucose-stimulated insulin secretion. Simulations predict that the effect of an increased frequency of kiss-and-run exocytotic events is a reduction in insulin secretion without modification of the qualitative pattern. Our model also appears to be the first physiology-based one to reproduce the staircase experiment, which underlies ‘derivative control’, i.e. the pancreatic capacity of measuring the rate of change of the glucose concentration.

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Dynamics of glucose-induced insulin secretion in normal human islets

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00251.2015 ◽

2015 ◽

Vol 309 (7) ◽

pp. E640-E650 ◽

Cited By ~ 40

Author(s):

Jean-Claude Henquin ◽

Denis Dufrane ◽

Julie Kerr-Conte ◽

Myriam Nenquin

Keyword(s):

Insulin Secretion ◽

Stimulation Index ◽

Human Islets ◽

Diabetic Patients ◽

Second Phase ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion ◽

Normal Human ◽

Second Phases

The biphasic pattern of glucose-induced insulin secretion is altered in type 2 diabetes. Impairment of the first phase is an early sign of β-cell dysfunction, but the underlying mechanisms are still unknown. Their identification through in vitro comparisons of islets from diabetic and control subjects requires characterization and quantification of the dynamics of insulin secretion by normal islets. When perifused normal human islets were stimulated with 15 mmol/l glucose (G15), the proinsulin/insulin ratio in secretory products rapidly and reversibly decreased (∼50%) and did not reaugment with time. Switching from prestimulatory G3 to G6–G30 induced biphasic insulin secretion with flat but sustained (2 h) second phases. Stimulation index reached 6.7- and 3.6-fold for the first and second phases induced by G10. Concentration dependency was similar for both phases, with half-maximal and maximal responses at G6.5 and G15, respectively. First-phase response to G15–G30 was diminished by short (30–60 min) prestimulation in G6 (vs. G3) and abolished by prestimulation in G8, whereas the second phase was unaffected. After 1–2 days of culture in G8 (instead of G5), islets were virtually unresponsive to G15. In both settings, a brief return to G3–G5 or transient omission of CaCl2 restored biphasic insulin secretion. Strikingly, tolbutamide and arginine evoked immediate insulin secretion in islets refractory to glucose. In conclusion, we quantitatively characterized the dynamics of glucose-induced insulin secretion in normal human islets and showed that slight elevation of prestimulatory glucose reversibly impairs the first phase, which supports the view that the similar impairment in type 2 diabetic patients might partially be a secondary phenomenon.

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Assessment of the Metabolic Pathways Associated With Glucose-Stimulated Biphasic Insulin Secretion

Endocrinology ◽

10.1210/en.2013-1805 ◽

2014 ◽

Vol 155 (5) ◽

pp. 1653-1666 ◽

Cited By ~ 23

Author(s):

Mei Huang ◽

Jamie W. Joseph

Keyword(s):

Insulin Secretion ◽

Time Course ◽

Tricarboxylic Acid Cycle ◽

Global Analysis ◽

Tricarboxylic Acid ◽

Second Phase ◽

Data Set ◽

Negatively Associated ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion

Biphasic glucose-stimulated insulin secretion involves a rapid first phase followed by a prolonged second phase of insulin secretion. The biochemical pathways that control these 2 phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy-based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal β-cell line 832/13 cells showed that glycolytic, tricarboxylic acid, pentose phosphate pathway, and several amino acids were strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with l-valine, trans-4-hydroxy-l-proline, trans-3-hydroxy-l-proline, dl-3-aminoisobutyric acid, l-glutamine, sarcosine, l-lysine, and thymine and positively with l-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5′-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid, and palmitoleic acid. Tricarboxylic acid cycle intermediates pyruvate, α-ketoglutarate, and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, dl-3-aminobutyric acid, and l-norleucine were negatively associated metabolites with the second-phase of insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively or positively associated with biphasic insulin secretion. The insights provided by these data set create a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion.

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