scholarly journals Pancreatic α and β cells are globally phase-locked

2021 ◽  
Author(s):  
Huixia Ren ◽  
Yanjun Li ◽  
Chensheng Han ◽  
Yi Yu ◽  
Bowen Shi ◽  
...  
Keyword(s):  
Phase Shift ◽  
Fixed Time ◽  
Cell Interaction ◽  
Oscillation Period ◽  
Β Cells ◽  
Cell Level ◽  
Glucose Stimulation ◽  
Transient Period ◽  
Paracrine Interaction ◽  
Glucagon And Insulin

Abstract The Ca2+ modulated pulsatile secretion of glucagon and insulin by pancreatic α and β cells plays a key role in glucose homeostasis. However, how α and β cells coordinate via paracrine interaction to produce various Ca2+ oscillation patterns is still elusive. Using a microfluidic device and transgenic mice in which α and β cells were labeled with different colors, we were able to record islet Ca2+ signals at single cell level for long times. Upon glucose stimulation, we observed heterogeneous Ca2+ oscillation patterns intrinsic to each islet. After a transient period, the oscillations of α and β cells were globally phase-locked, i.e., the two types of cells in an islet each oscillate synchronously but with a phase shift between the two. While the activation of α cells displayed a fixed time delay of ~20 s to that of β cells, β cells activated with a tunable delay after the α cells. As a result, the tunable phase shift between α and β cells set the islet oscillation period and pattern. Furthermore, we demonstrated that the phase shift can be modulated by glucagon. A mathematical model of islet Ca2+ oscillation taking into consideration of the paracrine interaction was constructed, which quantitatively agreed with the experimental data. Our study highlights the importance of cell-cell interaction to generate stable but tunable islet oscillation patterns.

Cell Interaction in B/W Mice: A Reversible Defect at the T-Cell Level

1976 ◽  
pp. 273-282
Author(s):  
John C. Roder ◽  
David A. Bell ◽  
Sharwan K. Singhal
Keyword(s):  
T Cell ◽  
Cell Interaction ◽  
Cell Level ◽  
Reversible Defect

scholarly journals Pancreatic α and β cells are globally phase-locked

2020 ◽  
Author(s):  
Huixia Ren ◽  
Yanjun Li ◽  
Chengsheng Han ◽  
Yi Yu ◽  
Bowen Shi ◽  
...  
Keyword(s):  
Islet Cells ◽  
Cell Types ◽  
Phase Oscillators ◽  
Β Cells ◽  
Oscillation Modes ◽  
Different Types ◽  
Glucagon And Insulin ◽  
Different Cell Types

ABSTRACTThe Ca2+ modulated pulsatile secretions of glucagon and insulin by pancreatic α and β cells play a key role in glucose metabolism and homeostasis. However, how different types of islet cells couple and coordinate via paracrine interactions to produce various Ca2+ oscillation patterns are still elusive. By designing a microfluidic device to facilitate long-term recording of islet Ca2+ activity at single cell level and simultaneously identifying different cell types in live islet imaging, we show heterogeneous but intrinsic Ca2+ oscillation patterns of islets upon glucose stimulation. The α and β cells oscillate in antiphase and are globally phase locked to various phase delays, causing fast, slow or mixed oscillations. A mathematical model of coupled phase oscillators quantitatively agrees with experiments and reveals the essential role of paracrine regulations in tuning the oscillation modes. Our study highlights the importance of cell-cell interactions to generate stable but tunable islet oscillation patterns.

scholarly journals SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans

2020 ◽  
Vol 42 ◽  
pp. 101071
Author(s):  
Heeyoung Chae ◽  
Robert Augustin ◽  
Eva Gatineau ◽  
Eric Mayoux ◽  
Mohammed Bensellam ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Glucagon And Insulin

scholarly journals Requirement for three signals in B cell responses. II. Analysis of antigen- and Ia-restricted T helper cell-B cell interaction.

1982 ◽  
Vol 156 (2) ◽  
pp. 415-429 ◽  
Author(s):  
R H Zubler ◽  
O Kanagawa
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Interaction ◽  
T Helper Cell ◽  
Helper Cell ◽  
B Cell Differentiation ◽  
T Helper ◽  
Cell Level ◽  
Cell Responses ◽  
Helper Factor

We have recently reported that resting B cells must receive at least three different signals in a T helper cell (TH)-dependent as well as in a lipopolysaccharide (LPS)-induced B cell response (3), i.e., a specific TH signal (that can be bypassed by LPS), a nonspecific TH signal (mediated by Ia or antigen-nonspecific B cell helper factor), and an antigen (hapten) signal. In a system using male (H-Y) antigen-specific cloned TH of C57BL/6 origin and male (or female) B cells, we now confirm and extend these findings by demonstrating that H-Y-specific TH must see both H-Y and Ia determinants on the B cells (and not only on macrophages) to provide the first specific TH signal required for a plaque-forming cell (PFC) response. This signal was interfered with by a monoclonal anti-I-Ab antibody at the B cell level, was not mediated by detectable soluble factors (in contrast to the nonspecific signal also provided by the TH), and could be bypassed by LPS, in which case anti-I-Ab antibody had no effect. However, although the H-Y-specific TH induced a polyclonal PFC response (B cell differentiation) in the apparent absence of an antigen seen by the B cells, significant clonal expansion of PFC precursors occurred only when the B cells also recognized an antigen (hapten).

scholarly journals Glucose regulates microtubule disassembly and the dose of insulin secretion via tau phosphorylation

2020 ◽  
Author(s):  
Ada Admin ◽  
Kung-Hsien Ho ◽  
Xiaodun Yang ◽  
Anna B. Osipovich ◽  
Over Cabrera ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
High Glucose ◽  
Tau Phosphorylation ◽  
Β Cells ◽  
Glucose Stimulation ◽  
Microtubule Network ◽  
Mouse Islet ◽  
Protein Tau ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

The microtubule cytoskeleton of pancreatic islet β-cells regulates glucose-stimulated insulin secretion (GSIS). We have reported that the microtubule-mediated movement of insulin vesicles away from the plasma membrane limits insulin secretion. High glucose-induced remodeling of microtubule network facilitates robust GSIS. This remodeling involves disassembly of old microtubules and nucleation of new microtubules. Here, we examine the mechanisms whereby glucose stimulation decreases microtubule lifetimes in β-cells. Using real-time imaging of photoconverted microtubules, we demonstrate that high levels of glucose induce rapid microtubule disassembly preferentially in the periphery of individual β-cells, and this process is mediated by the phosphorylation of microtubule-associated protein tau. Specifically, high glucose induces tau hyper-phosphorylation via glucose-responsive kinases GSK3, PKA, PKC, and CDK5. This causes dissociation of tau from and subsequent destabilization of microtubules. Consequently, tau-knockdown in mouse islet β-cells facilitates microtubule turnover, causing increased basal insulin secretion, depleting insulin vesicles from the cytoplasm, and impairing GSIS. More importantly, tau-knockdown uncouples microtubule destabilization from glucose stimulation. These findings suggest that tau suppresses peripheral microtubules turning-over to restrict insulin over-secretion at basal conditions and preserve the insulin pool that can be released in following stimulation; high glucose promotes tau phosphorylation to enhance microtubule disassembly to acutely enhance GSIS.

scholarly journals Microtubules and Gαo-signaling independently regulate the preferential secretion of newly synthesized insulin granules in pancreatic islet β cells

2020 ◽  
Author(s):  
Ruiying Hu ◽  
Xiaodong Zhu ◽  
Mingyang Yuan ◽  
Kung-Hsien Ho ◽  
Irina Kaverina ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulation ◽  
Potential Models ◽  
Insulin Granules ◽  
High Insulin ◽  
Underlying Mechanisms ◽  
Glucose Stimulated Insulin Secretion

AbstractFor sustainable function, each pancreatic islet β cell maintains thousands of insulin granules (IGs) at all times. Glucose stimulation induces the secretion of a small portion of these IGs and simultaneously triggers IG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, newly synthesized IGs are more likely secreted during glucose-stimulated insulin secretion. The older IGs tend to lose releasability and be degraded, which represents a futile metabolic load that can sensitize β cells to workload-induced dysfunction and even death. Here, we examine the factor(s) that allows the preferential secretion of younger IGs. We show that β cells without either microtubules (MTs) or Gαo signaling secrete a bigger portion of older IGs, which is associated with increased IG docking on plasma membrane. Yet Gαo inactivation does not alter the β-cell MT network. These findings suggest that Gαo and MT regulate the preferential release of newer IGs via parallel pathways and provide two potential models to further explore the underlying mechanisms and physiological significance of this regulation in functional β cells.

scholarly journals Impaired glucose tolerance, glucagon, and insulin responses in mice lacking the loop diuretic-sensitive Nkcc2a transporter

2019 ◽  
Vol 317 (4) ◽  
pp. C843-C856 ◽  
Author(s):  
Lisa Kelly ◽  
Mohammed M. Almutairi ◽  
Shams Kursan ◽  
Romario Pacheco ◽  
Eduardo Dias-Junior ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Β Cells ◽  
Islet Size ◽  
Low Levels ◽  
Glucagon And Insulin ◽  
Cell Expression ◽  
Insulin Responses ◽  
Gluconeogenic Substrate

The Na+K+2Cl− cotransporter-2 ( Nkcc2, Slc12a1) is abundantly expressed in the kidney and its inhibition with the loop-diuretics bumetanide and furosemide has been linked to transient or permanent hyperglycemia in mice and humans. Notably, Slc12a1 is expressed at low levels in hypothalamic neurons and in insulin-secreting β-cells of the endocrine pancreas. The present study was designed to determine if global elimination of one of the Slc12a1 products, i.e., Nkcc2 variant a ( Nkcc2a), the main splice version of Nkcc2 found in insulin-secreting β-cells, has an impact on the insulin and glucagon secretory responses and fuel homeostasis in vivo. We have used dynamic tests of glucose homeostasis in wild-type mice and mice lacking both alleles of Nkcc2a ( Nkcc2aKO) and assessed their islet secretory responses in vitro. Under basal conditions, Nkcc2aKO mice have impaired glucose homeostasis characterized by increased blood glucose, intolerance to the sugar, delayed/blunted in vivo insulin and glucagon responses to glucose, and increased glycemic responses to the gluconeogenic substrate alanine. Further, we provide evidence of conserved quantitative secretory responses of Nkcc2aKO islets within a context of increased islet size related to hyperplastic/hypertrophic glucagon- and insulin-positive cells (α-cells and β-cells, respectively), normal total islet Cl− content, and reduced β-cell expression of the Cl− extruder Kcc2.

Sustained exposure of toxically damaged mouse pancreatic islets to high glucose does not increase β-cell dysfunction

1989 ◽  
Vol 123 (1) ◽  
pp. 47-51 ◽  
Author(s):  
D. L. Eizirik ◽  
S. Sandler
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
High Glucose ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulation ◽  
Cell Dysfunction ◽  
Mouse Pancreatic Islets ◽  
Insulin Secretory Response

ABSTRACT The aim of this study was to clarify whether prolonged in-vitro exposure of either normal or damaged β cells to a high glucose environment can be toxic to these cells. For this purpose NMRI mice were injected intravenously with a diabetogenic dose of streptozotocin (SZ; 160 mg/kg) or vehicle alone (controls). Their islets were isolated 15 min after the injection and subsequently maintained in culture for 21 days in the presence of 11·1 or 28 mmol glucose/l. After this period, during acute glucose stimulation, the control islets showed a marked increase in their insulin release in response to a high glucose stimulus. In the SZ-exposed islets there was a decrease in DNA and insulin contents, and a deficient insulin secretory response to glucose. However, in the SZ-damaged islets as well as in the control islets, culture with 28 mmol glucose/l compared with 11·1 mmol glucose/l did not impair islet retrieval after culture, islet DNA content or glucose-induced insulin release. Thus, the degree of damage was similar in the SZ-treated islets cultured at the two concentrations of glucose. These results suggest that glucose is not toxic to normal or damaged mouse pancreatic islets over a prolonged period in tissue culture. Journal of Endocrinology (1989) 123, 47–51

scholarly journals Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

2014 ◽  
Vol 27 (1) ◽  
pp. 48-62 ◽  
Author(s):  
Laura Marroquí ◽  
Paloma Alonso-Magdalena ◽  
Beatriz Merino ◽  
Esther Fuentes ◽  
Angel Nadal ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Diabetic Patients ◽  
Β Cells ◽  
Glucagon Receptor ◽  
Nutrient Regulation ◽  
New Information ◽  
Experimental Approaches ◽  
Glucagon And Insulin

Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic α- and β-cells, respectively. While β-cells have been the focus of intense research, less is known about α-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of α-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and α-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in α-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

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