scholarly journals Caloric Restriction recovers impaired β-cell-β-cell coupling, calcium oscillation coordination and insulin secretion in prediabetic mice

2020 ◽  
Author(s):  
Maria Esméria Corezola do Amaral ◽  
Vira Kravets ◽  
JaeAnn M. Dwulet ◽  
Nikki L. Farnsworth ◽  
Robert Piscopio ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Weight Gain ◽  
Gap Junction ◽  
Caloric Restriction ◽  
Glucose Homeostasis ◽  
Fasting Glucose ◽  
Β Cell ◽  
Insulin Levels ◽  
Gap Junction Coupling ◽  
Junction Coupling

AbstractCaloric restriction has been shown to decrease the incidence of metabolic diseases such as obesity and type 2 diabetes mellitus (T2DM). The mechanisms underlying the benefits of caloric restriction involved in insulin secretion and glucose homeostasis and are not fully understood. Intercellular communication within the islets of Langerhans, mediated by Connexin36 (Cx36) gap junctions, regulates insulin secretion dynamics and glucose homeostasis. The goal of this study was to determine if caloric restriction can protect against decreases in Cx36 gap junction coupling and altered islet function induced in models of obesity and prediabetes. C57BL6 mice were fed with a high fat diet (HFD), showing indications of prediabetes after 2 months, including weight gain, insulin resistance, and elevated fasting glucose and insulin levels. Subsequently, mice were submitted to one month of 40% caloric restriction (2g/day of HFD). Mice under 40% caloric restriction showed reversal in weight gain and recovered insulin sensitivity, fasting glucose and insulin levels. In islets of mice fed the HFD, caloric restriction protected against obesity-induced decreases in gap junction coupling and preserved glucose-stimulated calcium signaling, including Ca2+ oscillation coordination and oscillation amplitude. Caloric restriction also promoted a slight increase in glucose metabolism, as measured by increased NAD(P)H autofluorescence, as well as recovering glucose-stimulated insulin secretion. We conclude that declines in Cx36 gap junction coupling that occur in obesity can be completely recovered by caloric restriction and obesity reversal, improving Ca2+ dynamics and insulin secretion regulation. This suggests a critical role for caloric restriction in the context of obesity to prevent islet dysfunction.

scholarly journals Caloric restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice

2020 ◽  
Vol 319 (4) ◽  
pp. E709-E720
Author(s):  
Maria Esméria Corezola do Amaral ◽  
Vira Kravets ◽  
JaeAnn M. Dwulet ◽  
Nikki L. Farnsworth ◽  
Robert Piscopio ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Weight Gain ◽  
Gap Junction ◽  
Caloric Restriction ◽  
Glucose Homeostasis ◽  
Fasting Glucose ◽  
Β Cell ◽  
Insulin Levels ◽  
Gap Junction Coupling ◽  
Junction Coupling

Caloric restriction can decrease the incidence of metabolic diseases, such as obesity and Type 2 diabetes mellitus. The mechanisms underlying the benefits of caloric restriction involved in insulin secretion and glucose homeostasis are not fully understood. Intercellular communication within the islets of Langerhans, mediated by Connexin36 (Cx36) gap junctions, regulates insulin secretion dynamics and glucose homeostasis. The goal of this study was to determine whether caloric restriction can protect against decreases in Cx36 gap junction coupling and altered islet function induced in models of obesity and prediabetes. C57BL6 mice were fed with a high-fat diet (HFD), showing indications of prediabetes after 2 mo, including weight gain, insulin resistance, and elevated fasting glucose and insulin levels. Subsequently, mice were submitted to 1 mo of 40% caloric restriction (2 g/day of HFD). Mice under 40% caloric restriction showed reversal in weight gain and recovered insulin sensitivity, fasting glucose, and insulin levels. In islets of mice fed the HFD, caloric restriction protected against obesity-induced decreases in gap junction coupling and preserved glucose-stimulated calcium signaling, including Ca2+ oscillation coordination and oscillation amplitude. Caloric restriction also promoted a slight increase in glucose metabolism, as measured by increased NAD(P)H autofluorescence, as well as recovering glucose-stimulated insulin secretion. We conclude that declines in Cx36 gap junction coupling that occur in obesity can be completely recovered by caloric restriction and obesity reversal, improving Ca2+ dynamics and insulin secretion regulation. This suggests a critical role for caloric restriction in the context of obesity to prevent islet dysfunction.

2076-P: Increased Gap Junction Coupling in the Islet of Langerhans following Caloric Restriction

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2076-P
Author(s):  
MARIA C. AMARAL ◽  
VIRA KRAVETS ◽  
JAEANN M. DWULET ◽  
NIKKI L. FARNSWORTH ◽  
ROBERT A. PISCOPIO ◽  
...  
Keyword(s):  
Gap Junction ◽  
Caloric Restriction ◽  
Islet Of Langerhans ◽  
Gap Junction Coupling ◽  
Junction Coupling

scholarly journals Small subpopulations of β-cells do not drive islet oscillatory [Ca2+] dynamics via gap junction communication

2021 ◽  
Vol 17 (5) ◽  
pp. e1008948
Author(s):  
JaeAnn M. Dwulet ◽  
Jennifer K. Briggs ◽  
Richard K. P. Benninger
Keyword(s):  
Gap Junction ◽  
Metabolic Activity ◽  
Oscillation Frequency ◽  
Cell Populations ◽  
Small Populations ◽  
Β Cells ◽  
Β Cell ◽  
Physiological Basis ◽  
Gap Junction Coupling ◽  
Junction Coupling

The islets of Langerhans exist as multicellular networks that regulate blood glucose levels. The majority of cells in the islet are excitable, insulin-producing β-cells that are electrically coupled via gap junction channels. β-cells are known to display heterogeneous functionality. However, due to gap junction coupling, β-cells show coordinated [Ca2+] oscillations when stimulated with glucose, and global quiescence when unstimulated. Small subpopulations of highly functional β-cells have been suggested to control [Ca2+] dynamics across the islet. When these populations were targeted by optogenetic silencing or photoablation, [Ca2+] dynamics across the islet were largely disrupted. In this study, we investigated the theoretical basis of these experiments and how small populations can disproportionality control islet [Ca2+] dynamics. Using a multicellular islet model, we generated normal, skewed or bimodal distributions of β-cell heterogeneity. We examined how islet [Ca2+] dynamics were disrupted when cells were targeted via hyperpolarization or populations were removed; to mimic optogenetic silencing or photoablation, respectively. Targeted cell populations were chosen based on characteristics linked to functional subpopulation, including metabolic rate of glucose oxidation or [Ca2+] oscillation frequency. Islets were susceptible to marked suppression of [Ca2+] when ~10% of cells with high metabolic activity were hyperpolarized; where hyperpolarizing cells with normal metabolic activity had little effect. However, when highly metabolic cells were removed from the model, [Ca2+] oscillations remained. Similarly, when ~10% of cells with either the highest frequency or earliest elevations in [Ca2+] were removed from the islet, the [Ca2+] oscillation frequency remained largely unchanged. Overall, these results indicate small populations of β-cells with either increased metabolic activity or increased frequency are unable to disproportionately control islet-wide [Ca2+] via gap junction coupling. Therefore, we need to reconsider the physiological basis for such small β-cell populations or the mechanism by which they may be acting to control normal islet function.

scholarly journals Pancreatic PYY Is Critical in the Control of Insulin Secretion and Glucose Homeostasis in Female Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (9) ◽  
pp. 3122-3136 ◽  
Author(s):  
Yan-Chuan Shi ◽  
Kim Loh ◽  
Mohammed Bensellam ◽  
Kailun Lee ◽  
Lei Zhai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Insulin Release ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Cell Phenotype ◽  
Β Cell ◽  
Insulin Levels ◽  
And Function ◽  
The Impact

Insulin secretion is tightly controlled through coordinated actions of a number of systemic and local factors. Peptide YY (PYY) is expressed in α-cells of the islet, but its role in control of islet function such as insulin release is not clear. In this study, we generated a transgenic mouse model (Pyytg/+/Rip-Cre) overexpressing the Pyy gene under the control of the rat insulin 2 gene promoter and assessed the impact of islet-released PYY on β-cell function, insulin release, and glucose homeostasis in mice. Our results show that up-regulation of PYY in islet β-cells leads to an increase in serum insulin levels as well as improved glucose tolerance. Interestingly, PYY-overproducing mice show increased lean mass and reduced fat mass with no significant changes in food intake or body weight. Energy expenditure is also increased accompanied by increased respiratory exchange ratio. Mechanistically, the enhanced insulin levels and improved glucose tolerance are primarily due to increased β-cell mass and secretion. This is associated with alterations in the expression of genes important for β-cell proliferation and function as well as the maintenance of the β-cell phenotype. Taken together, these data demonstrate that pancreatic islet-derived PYY plays an important role in controlling glucose homeostasis through the modulation of β-cell mass and function.

Investigation of the roles of Ca2+ and InsP3 diffusion in the coordination of Ca2+ signals between connected hepatocytes

2001 ◽  
Vol 114 (11) ◽  
pp. 1999-2007
Author(s):  
Caroline Clair ◽  
Cécile Chalumeau ◽  
Thierry Tordjmann ◽  
Josiane Poggioli ◽  
Christophe Erneux ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Significant Role ◽  
Signaling Molecules ◽  
Rat Hepatocyte ◽  
Inositol 1,4,5 Trisphosphate ◽  
Gap Junction Coupling ◽  
Junction Coupling ◽  
Insp3 Receptor

Glycogenolytic agonists induce coordinated Ca2+ oscillations in multicellular rat hepatocyte systems as well as in the intact liver. The coordination of intercellular Ca2+ signals requires functional gap-junction coupling. The mechanisms ensuring this coordination are not precisely known. We investigated possible roles of Ca2+ or inositol 1,4,5-trisphosphate (InsP3) as a coordinating messengers for Ca2+ spiking among connected hepatocytes. Application of ionomycin or of supra-maximal concentrations of agonists show that Ca2+ does not significantly diffuse between connected hepatocytes, although gap junctions ensure the passage of small signaling molecules, as demonstrated by FRAP experiments. By contrast, coordination of Ca2+ spiking among connected hepatocytes can be favored by a rise in the level of InsP3, via the increase of agonist concentrations, or by a shift in the affinity of InsP3 receptor for InsP3. In the same line, coordination cannot be achieved if the InsP3 is rapidly metabolized by InsP3-phosphatase in one cell of the multiplet. These results demonstrate that even if small amounts of Ca2+ diffuse across gap junctions, they most probably do not play a significant role in inducing a coordinated Ca2+ signal among connected hepatocytes. By contrast, coordination of Ca2+ oscillations is fully dependent on the diffusion of InsP3 between neighboring cells.

Abstract 336: A 14-3-3 Mode-1 Binding Motif Promotes Gap Junction Internalization During Acute Cardiac Ischemia

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
James W Smyth ◽  
Jose M Sanchez ◽  
Samy Lamouille ◽  
Ting-Ting Hong ◽  
Jacob M Vogan ◽  
...  
Keyword(s):  
Gap Junction ◽  
Protein Trafficking ◽  
Connexin 43 ◽  
Electrical Coupling ◽  
Acute Ischemia ◽  
Binding Motif ◽  
Wild Type ◽  
Gap Junction Coupling ◽  
Junction Coupling ◽  
Cell Cell

During each heartbeat, robust cell-cell electrical coupling via connexin 43 (Cx43) gap junctions allows billions of individual cardiomyocytes to contract in synchrony. Cx43 turns over rapidly, and altered Cx43 trafficking during disease contributes to the arrhythmias of sudden cardiac death. The overall phosphorylation status of the Cx43 protein is known to regulate gap junction coupling, but the role of many residue specific phosphorylation events remains unknown. One such residue, Ser373, forms a mode-1 14-3-3 binding motif upon phosphorylation. Given that 14-3-3 proteins are known to regulate protein trafficking, we hypothesized a role for Cx43 Ser373 phosphorylation in regulation of Cx43 gap junction coupling. Using Langendorff-perfused mouse hearts we find robust phosphorylation of Cx43 at Ser373 and Ser368 after 30 min of no-flow ischemia. In human cell lines, a S373A mutation ablated Cx43/14-3-3 complexing and 35 S pulse-chase revealed Cx43 S373A also experiences a longer half-life than wild-type Cx43. Previous reports have implicated phosphorylation of Cx43 Ser368 in PKC mediated Cx43 internalization. We find that upon activation of PKC, the Cx43 S373A mutant undergoes lower and more transient levels of phosphorylation at Ser368 than wild-type Cx43. Consistent with these data, siRNA-mediated ablation of 14-3-3 expression results in enlargement of gap junction plaque formation at cell-cell borders. In conclusion, we propose that phosphorylation of Cx43 Ser373 results in 14-3-3 binding which promotes and maintains phosphorylation of Cx43 Ser368 and the subsequent internalization of gap junction channels. These results identify for the first time a specific role for 14-3-3 proteins in regulation of Cx43 internalization during acute ischemia and contribute to the development of therapies aimed at preserving or enhancing gap junction coupling in the heart.

Sign in / Sign up

Export Citation Format

Share Document