scholarly journals Chronic stimulation induces adaptive potassium channel activity that restores calcium oscillations in pancreatic islets in vitro

2020 ◽  
Vol 318 (4) ◽  
pp. E554-E563 ◽  
Author(s):  
Nathan C. Law ◽  
Isabella Marinelli ◽  
Richard Bertram ◽  
Kathryn L. Corbin ◽  
Cara Schildmeyer ◽  
...  
Keyword(s):  
Potassium Chloride ◽  
Chronic Exposure ◽  
Cell Activity ◽  
Calcium Oscillations ◽  
Β Cells ◽  
Β Cell ◽  
Compensatory Mechanisms ◽  
Adaptation Mechanism ◽  
Compensatory Response ◽  
Chronic Stimulation

Insulin pulsatility is important to hepatic response in regulating blood glucose. Growing evidence suggests that insulin-secreting pancreatic β-cells can adapt to chronic disruptions of pulsatility to rescue this physiologically important behavior. We determined the time scale for adaptation and examined potential ion channels underlying it. We induced the adaptation both by chronic application of the ATP-sensitive K+ [K(ATP)] channel blocker tolbutamide and by application of the depolarizing agent potassium chloride (KCl). Acute application of tolbutamide without pretreatment results in elevated Ca2+ as measured by fura-2AM and the loss of endogenous pulsatility. We show that after chronic exposure to tolbutamide (12–24 h), Ca2+ oscillations occur with subsequent acute tolbutamide application. The same experiment was conducted with potassium chloride (KCl) to directly depolarize the β-cells. Once again, following chronic exposure to the cell stimulator, the islets produced Ca2+ oscillations when subsequently exposed to tolbutamide. These experiments suggest that it is the chronic stimulation, and not tolbutamide desensitization, that is responsible for the adaptation that rescues oscillatory β-cell activity. This compensatory response also causes islet glucose sensitivity to shift rightward following chronic tolbutamide treatment. Mathematical modeling shows that a small increase in the number of K(ATP) channels in the membrane is one adaptation mechanism that is compatible with the data. To examine other compensatory mechanisms, pharmacological studies provide support that Kir2.1 and TEA-sensitive channels play some role. Overall, this investigation demonstrates β-cell adaptability to overstimulation, which is likely an important mechanism for maintaining glucose homeostasis in the face of chronic stimulation.

Life and death decisions of the pancreatic β-cell: the role of fatty acids

2006 ◽  
Vol 112 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Philip Newsholme ◽  
Deirdre Keane ◽  
Hannah J. Welters ◽  
Noel G. Morgan
Keyword(s):  
Fatty Acids ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Endogenous Fatty Acid ◽  
Gene And Protein Expression ◽  
Β Cell Function

Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion, followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. Therefore changes in the levels of NEFAs are likely to be important for the regulation of β-cell function and viability under physiological conditions. In addition, the switching between endogenous fatty acid synthesis or oxidation in the β-cell, together with alterations in neutral lipid accumulation, may have critical implications for β-cell function and integrity. Long-chain acyl-CoA (formed from either endogenously synthesized or exogenous fatty acids) controls several aspects of β-cell function, including activation of specific isoenzymes of PKC (protein kinase C), modulation of ion channels, protein acylation, ceramide formation and/or NO-mediated apoptosis, and transcription factor activity. In this review, we describe the effects of exogenous and endogenous fatty acids on β-cell metabolism and gene and protein expression, and have explored the outcomes with respect to insulin secretion and β-cell integrity.

scholarly journals Bursting and calcium oscillations in pancreatic β-cells: specific pacemakers for specific mechanisms

2010 ◽  
Vol 299 (4) ◽  
pp. E517-E532 ◽  
Author(s):  
L. E. Fridlyand ◽  
N. Tamarina ◽  
L. H. Philipson
Keyword(s):  
Mathematical Models ◽  
Calcium Concentration ◽  
Calcium Oscillations ◽  
Cell Physiology ◽  
Cytoplasmic Calcium ◽  
Β Cells ◽  
Β Cell ◽  
Endoplasmic Reticulum Calcium ◽  
Key Aspects ◽  
Potential Interactions

Oscillatory phenomenon in electrical activity and cytoplasmic calcium concentration in response to glucose are intimately connected to multiple key aspects of pancreatic β-cell physiology. However, there is no single model for oscillatory mechanisms in these cells. We set out to identify possible pacemaker candidates for burst activity and cytoplasmic Ca2+ oscillations in these cells by analyzing published hypotheses, their corresponding mathematical models, and relevant experimental data. We found that although no single pacemaker can account for the variety of oscillatory phenomena in β-cells, at least several separate mechanisms can underlie specific kinds of oscillations. According to our analysis, slowly activating Ca2+-sensitive K+ channels can be responsible for very fast Ca2+ oscillations; changes in the ATP/ADP ratio and in the endoplasmic reticulum calcium concentration can be pacemakers for both fast bursts and cytoplasmic calcium oscillations, and cyclical cytoplasmic Na+ changes may underlie patterning of slow calcium oscillations. However, these mechanisms still lack direct confirmation, and their potential interactions raises new issues. Further studies supported by improved mathematical models are necessary to understand oscillatory phenomena in β-cell physiology.

Modeling of Ca2+ flux in pancreatic β-cells: role of the plasma membrane and intracellular stores

2003 ◽  
Vol 285 (1) ◽  
pp. E138-E154 ◽  
Author(s):  
Leonid E. Fridlyand ◽  
Natalia Tamarina ◽  
Louis H. Philipson
Keyword(s):  
Plasma Membrane ◽  
Calcium Oscillations ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Ionic Flux ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca ◽  
Uptake And Release

We have developed a detailed mathematical model of ionic flux in β-cells that includes the most essential channels and pumps in the plasma membrane. This model is coupled to equations describing Ca2+, inositol 1,4,5-trisphosphate (IP3), ATP, and Na+ homeostasis, including the uptake and release of Ca2+ by the endoplasmic reticulum (ER). In our model, metabolically derived ATP activates inward Ca2+ flux by regulation of ATP-sensitive K+ channels and depolarization of the plasma membrane. Results from the simulations support the hypothesis that intracellular Na+ and Ca2+ in the ER can be the main variables driving both fast (2–7 osc/min) and slow intracellular Ca2+ concentration oscillations (0.3–0.9 osc/min) and that the effect of IP3 on Ca2+ leak from the ER contributes to the pattern of slow calcium oscillations. Simulations also show that filling the ER Ca2+ stores leads to faster electrical bursting and Ca2+ oscillations. Specific Ca2+ oscillations in isolated β-cell lines can also be simulated.

scholarly journals Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress

2007 ◽  
Vol 38 (1) ◽  
pp. 147-158 ◽  
Author(s):  
Carmela Santangelo ◽  
Paola Matarrese ◽  
Roberta Masella ◽  
Maria Chiara Di Carlo ◽  
Angela Di Lillo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Protective Effect ◽  
Chronic Exposure ◽  
Β Cells ◽  
Β Cell ◽  
Rinm5f Cell ◽  
Induced Apoptosis ◽  
Hepatocyte Growth

Type 2 diabetes is characterized by peripheral insulin resistance, pancreatic β-cells dysfunction, and decreased β-cell mass with increased rate of apoptosis. Chronic exposure to high levels of free fatty acids (FFAs) has detrimental effects on β-cell function and survival. FFAs have adverse effects on mitochondrial function, with a consequent increase in the production of reactive oxygen species. Hepatocyte growth factor (HGF) plays a critical role in promoting β-cell survival. In the present study, we investigated whether HGF was capable of protecting β-cells from death induced by prolonged exposure to FFAs. RINm5F cell line was cultured in the presence of FFAs (oleate:palmitate 2:1) for 72 h in order to induce apoptosis. Simultaneous administration of HGF and FFAs significantly suppressed the impaired insulin secretion and FFA-induced apoptosis. Specifically, HGF exerted its protective effect by counteracting: (i) the overproduction of either hydrogen peroxide and superoxide anion, (ii) the reduction of intracellular γ-glutamylcysteinylglycine level, and (iii) the depolarization of mitochondrial membrane, induced by prolonged FFAs exposure. These effects appear to be mediated by bcl-2 and phosphatidylinositol 3 kinase (PI3K)/Akt pathways. Indeed, HGF increased mRNA and protein expression of bcl-2 downregulated by FFAs-treatment; moreover, pre-treatment with the specific PI3-kinase inhibitor LY294002, significantly abolished the protective effect of HGF. In conclusion, in rat insulin-producing RINm5F cells, HGF exerts its prosurvival effect by counteracting the increased intracellular oxidative stress and, consequently, by inhibiting apoptosis induced by chronic exposure to FFAs.

scholarly journals CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

2015 ◽  
Vol 112 (49) ◽  
pp. E6818-E6824 ◽  
Author(s):  
Mario Rossi ◽  
Inigo Ruiz de Azua ◽  
Luiz F. Barella ◽  
Wataru Sakamoto ◽  
Lu Zhu ◽  
...  
Keyword(s):  
Insulin Release ◽  
Cell Activity ◽  
Negative Regulator ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Release In Vitro

G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic β-cells. β-Cell M3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of β-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic β-cells, knockdown of CK2α expression, or genetic deletion of CK2α in β-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonist-induced phosphorylation of β-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent novel therapeutic targets.

scholarly journals Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+ responses to glucose in pancreatic β-cells

2008 ◽  
Vol 197 (2) ◽  
pp. 221-229 ◽  
Author(s):  
Masaru Koizumi ◽  
Toshihiko Yada
Keyword(s):  
Glucocorticoid Receptor ◽  
Mineralocorticoid Receptor ◽  
Term Treatment ◽  
Β Cells ◽  
Β Cell ◽  
Chronic Stimulation ◽  
Glucose Signaling ◽  
Ru 486 ◽  
Long Term Treatment

The development of diabetes associated with stress, obesity, and metabolic syndrome involves elevated plasma glucocorticoid levels. It has been shown that short-term (<1 day) exposure to glucocorticoids reduces insulin secretion from pancreatic islets by affecting several steps of glucose signaling in β-cells. However, longer term direct effects of glucocorticoids on β-cells remain to be established. In this study, single β-cells isolated from rat islets were treated with glucocorticoids, mineralocorticoids, and their receptor agonists/antagonists for 3 days in culture, followed by assessment of the β-cell responsiveness to glucose by measuring cytosolic Ca2+ concentration ([Ca2+]i) using fura-2. Following treatment with corticosterone at 10–500 ng/ml for 3 days, the first-phase [Ca2+]i response to 8.3 mM glucose in β-cells was suppressed. Simultaneous administration of RU-486, a glucocorticoid receptor (GR) antagonist, prevented this suppression. RU-486 by itself promoted the β-cell [Ca2+]i response to glucose. Conversely, dexamethasone (1000 ng/ml), a highly selective GR agonist, impaired β-cell [Ca2+]i responses to glucose. A mineralocorticoid receptor (MR) antagonist spironolactone, co-administered with corticosterone, further depressed [Ca2+]i responses to glucose, while an MR ligand aldosterone attenuated the corticosterone inhibition of [Ca2+]i responses. Neither spironolactone nor aldosterone by itself affected [Ca2+]i responses. These results indicate that long-term treatment with corticosterone impairs β-cell [Ca2+]i responses to glucose. This effect is mediated by GR and attenuated partially by simultaneous MR stimulation by corticosterone. The results show a novel function of MR to protect islet β-cells against deteriorating glucocorticoid action via GR.

scholarly journals Long-chain Saturated Fatty Acid Species Are Not Toxic to Human Pancreatic Β-cells and May Offer Protection Against Pro-inflammatory Cytokine Induced β-cell Death

2020 ◽  
Author(s):  
Patricia Thomas ◽  
Kaiyven A Leslie ◽  
Hannah J Welters ◽  
Noel G Morgan
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Chain Length ◽  
Inflammatory Cytokines ◽  
Chronic Exposure ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Long Chain ◽  
Pro Inflammatory Cytokines

Abstract Obesity is a major risk factor for type 2 diabetes (T2D) although the causal links remain unclear. A feature shared by both conditions however is systemic inflammation and raised levels of circulating fatty acids (FFA). It is widely believed that in obese individuals genetically prone to T2D, elevated levels of plasma FFA may contribute towards the death and dysfunction of insulin-producing pancreatic β-cells in a process of (gluco)lipotoxicity. In support of this, in vitro studies have shown consistently that long-chain saturated fatty acids (LC-SFA) are toxic to rodent β-cells during chronic exposure (>24h). Conversely, shorter chain SFA and unsaturated species are well tolerated, suggesting that toxicity is dependent on carbon chain length and/or double bond configuration. Despite the wealth of evidence implicating lipotoxicity as a means of β-cell death in rodents, the evidence that a similar process occurs in humans is much less substantial. Therefore, the present study has evaluated the effects of chronic exposure to fatty acids of varying chain length and degree of saturation, on the viability of human β-cells in culture. We have also studied the effects of a combination of fatty acids and pro-inflammatory cytokines. Strikingly, we find that LC-FFA do not readily promote the demise of human β-cells and that they may even offer a measure of protection against the toxic effects of pro-inflammatory cytokines. Therefore, these findings imply that a model in which elevated circulating LC-FFA play a direct role in mediating β-cell dysfunction and death in humans, may be overly simplistic.

Glucose homeostasis with infinite gain: further lessons from the Daisyworld parable?

1997 ◽  
Vol 154 (2) ◽  
pp. 187-192 ◽  
Author(s):  
J H Koeslag ◽  
P T Saunders ◽  
J A Wessels
Keyword(s):  
Blood Glucose ◽  
Blood Glucose Level ◽  
Glucose Level ◽  
Cell Activity ◽  
Β Cells ◽  
Β Cell ◽  
Set Point ◽  
Black And White ◽  
Wide Range ◽  
Glucagon And Insulin

Abstract A major unresolved physiological problem is how the rate of hepatic glucose production is increased to match the increased rate of glucose utilization during exercise without a change in arterial blood glucose level. A homeostat with such capabilities is said to have infinite gain. Daisyworld is an imaginary planet orbiting a variable star. The only life is black and white daisies. Black daisies retain heat, slightly warming the planet; white daisies cool it. When the two types of daisies grow best at slightly different temperatures, variations in solar luminosity (over a wide range) cause the ratio of white:black daisies to vary in a manner that keeps the planetary temperature constant. This model therefore achieves infinite gain by having two opposing but interdependent controllers. Here we suggest that the pancreatic islet α- and β-cells might act as black and white daisies. For the analogy to apply, glucagon and insulin must not only have opposing effects on the blood sugar concentration, but the secretion of the one has, at some quantum level, to be at the expense of the other. Electrical coupling between heterocellular groups of α- and β-cells within the pancreatic islets suggests that this might indeed be the case. α-Cell activity must, furthermore, promote secretory activity in other α-cells; similarly with β-cells. This is probably mediated via pancreastatin and γ-amino butyric acid (GABA) which are paracrinically co-secreted with glucagon and insulin, respectively. α-Cell activity spreads (at the expense of β-cell activity) when the blood glucose level is below set point, while β-cell activity progressively replaces α-cell activity above set point. At set point changes in the ratio of α:β-cell activity are inhibited. Journal of Endocrinology (1997) 154, 187–192

scholarly journals The Pancreatic ß-cell Response to Secretory Demands and Adaption to Stress

Endocrinology ◽  
2021 ◽  
Vol 162 (11) ◽  
Author(s):  
Michael A Kalwat ◽  
Donalyn Scheuner ◽  
Karina Rodrigues-dos-Santos ◽  
Decio L Eizirik ◽  
Melanie H Cobb
Keyword(s):  
Unfolded Protein Response ◽  
Cell Function ◽  
Protein Translation ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Compensatory Mechanisms ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Pancreatic β cells dedicate much of their protein translation capacity to producing insulin to maintain glucose homeostasis. In response to increased secretory demand, β cells can compensate by increasing insulin production capability even in the face of protracted peripheral insulin resistance. The ability to amplify insulin secretion in response to hyperglycemia is a critical facet of β-cell function, and the exact mechanisms by which this occurs have been studied for decades. To adapt to the constant and fast-changing demands for insulin production, β cells use the unfolded protein response of the endoplasmic reticulum. Failure of these compensatory mechanisms contributes to both type 1 and 2 diabetes. Additionally, studies in which β cells are “rested” by reducing endogenous insulin demand have shown promise as a therapeutic strategy that could be applied more broadly. Here, we review recent findings in β cells pertaining to the metabolic amplifying pathway, the unfolded protein response, and potential advances in therapeutics based on β-cell rest.

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