scholarly journals Potential Mechanisms Underlying Hypoxia-Induced Diabetes in a Rodent Model: Implications for COVID-19

Children ◽  
2021 ◽  
Vol 8 (12) ◽  
pp. 1178
Author(s):  
Eung-Kwon Pae ◽  
Ronald M. Harper
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Fasting Blood Glucose ◽  
Chloride Ion ◽  
Oxygen Desaturation ◽  
Β Cells ◽  
Glucose Levels ◽  
Rat Pups ◽  
Blood Glucose Levels ◽  
Β Cell Function

Previous studies reported that repetitive hypoxia in rat pups reduces insulin secretion and elevates fasting blood glucose levels; these sequelae persisted for several months. This report describes how episodic hypoxic events elevate a chloride ion exporter, K+-Cl− cotransporter-2 (KCC2), in the plasma membrane of insulin-secreting pancreatic β-cells. We assume that acute diabetic symptoms observed in rat pups with periodic oxygen desaturation could result from a lack of blood insulin levels due to disturbed β-cell function. This acute hypo-insulinemia may result from a disruption in chloride balance in β-cells arising from an imbalanced KCC2-NKCC1 (chloride exporter-importer) density as a consequence of periodic oxygen desaturation. Mechanistically, we postulate that a reduced insulin secretion due to the KCC2-NKCC1 imbalance subsequent to acute oxygen desaturation could result in hyperglycemia in rat pups, paralleling symptoms shown in patients with COVID-19 who experienced acute respiratory distress.

scholarly journals Notable Underlying Mechanism for Pancreatic β-Cell Dysfunction and Atherosclerosis: Pleiotropic Roles of Incretin and Insulin Signaling

2020 ◽  
Vol 21 (24) ◽  
pp. 9444
Author(s):  
Hideaki Kaneto ◽  
Atsushi Obata ◽  
Tomohiko Kimura ◽  
Masashi Shimoda ◽  
Junpei Sanada ◽  
...  
Keyword(s):  
Cell Function ◽  
Early Stage ◽  
Receptor Expression ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Cell Dysfunction ◽  
Blood Glucose Levels ◽  
Β Cell Function

Under healthy conditions, pancreatic β-cells produce and secrete the insulin hormone in response to blood glucose levels. Under diabetic conditions, however, β-cells are compelled to continuously secrete larger amounts of insulin to reduce blood glucose levels, and thereby, the β-cell function is debilitated in the long run. In the diabetic state, expression levels of insulin gene transcription factors and incretin receptors are downregulated, which we think is closely associated with β-cell failure. These data also suggest that it would be better to use incretin-based drugs at an early stage of diabetes when incretin receptor expression is preserved. Indeed, it was shown that incretin-based drugs exerted more protective effects on β-cells at an early stage. Furthermore, it was shown recently that endothelial cell dysfunction was also associated with pancreatic β-cell dysfunction. After ablation of insulin signaling in endothelial cells, the β-cell function and mass were substantially reduced, which was also accompanied by reduced expression of insulin gene transcription factors and incretin receptors in β-cells. On the other hand, it has been drawing much attention that incretin plays a protective role against the development of atherosclerosis. Many basic and clinical data have underscored the importance of incretin in arteries. Furthermore, it was shown recently that incretin receptor expression was downregulated in arteries under diabetic conditions, which likely diminishes the protective effects of incretin against atherosclerosis. Furthermore, a series of large-scale clinical trials (SPAED-A, SPIKE, LEADER, SUSTAIN-6, REWIND, PIONEER trials) have shown that various incretin-related drugs have beneficial effects against atherosclerosis and subsequent cardiovascular events. These data strengthen the hypothesis that incretin plays an important role in the arteries of humans, as well as rodents.

scholarly journals Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Dina Mostafa ◽  
Akiko Yanagiya ◽  
Eleni Georgiadou ◽  
Yibo Wu ◽  
Theodoros Stylianides ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Cell Maturation ◽  
Β Cells ◽  
Β Cell ◽  
Cell Identity ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Β Cell Function ◽  
And Function

AbstractPancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4–NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.

scholarly journals Effect of Probiotics on the Glucose Levels of Pregnant Women: A Meta-Analysis of Randomized Controlled Trials

Medicina ◽  
2018 ◽  
Vol 54 (5) ◽  
pp. 77 ◽  
Author(s):  
Tzu-Rong Peng ◽  
Ta-Wei Wu ◽  
You-Chen Chao
Keyword(s):  
Blood Glucose ◽  
Randomized Controlled Trials ◽  
Pregnant Women ◽  
Cell Function ◽  
Fasting Blood Glucose ◽  
Controlled Trials ◽  
Model Assessment ◽  
Glucose Levels ◽  
Randomized Controlled ◽  
Blood Glucose Levels

Background: Gestational diabetes mellitus (GDM) is a condition, in which women develop high blood sugar levels during pregnancy without having diabetes. Evidence on the effects of probiotics on the blood glucose levels of women with GDM is inconsistent. Objective: The present study aimed to investigate the effects of probiotics on the blood glucose levels of pregnant women. Methods: Online databases, such as PubMed, Cochrane, and Excerpta Medica Database (EMBASE) were searched for randomized controlled trials (RCTs) published before July 2018. Trials had to meet the inclusion criteria of our study. Methodological quality and risk bias were independently assessed by two reviewers. Data were pooled using a random effects model and were expressed as the mean difference (MD) and 95% confidence interval (CI). Heterogeneity was evaluated and quantified as I2. Results: In total, 12 RCTs were included in this study. Studies have shown that the use of probiotics significantly reduced the fasting blood glucose (FBG) level (MD: −0.10 mmol/L; 95% CI: −0.19, −0.02), insulin concentration (MD: −2.24 μIU/mL; 95% CI: −3.69, −0.79), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score (MD: −0.47; 95% CI: −0.74, −0.21), and Homeostasis model of assessment-estimated β cell function (HOMA-B) score (MD: −20.23; 95% CI: −31.98, −8.49) of pregnant women. In a subgroup analysis, whether the blood glucose-lowering effect of probiotics influenced the diagnosis of pregnant women with GDM was assessed. The results showed that probiotics had significantly reduced the fasting blood glucose (FBG) level (MD: −0.10 mmol/L; 95% CI: −0.17, −0.04) and HOMA-IR score (MD: −0.37; 95% CI: −0.72, −0.02) of pregnant women who were not diagnosed with GDM. Conclusion: Probiotics reduce the blood glucose level of pregnant women, especially without GDM diagnosis. However, further research using RCTs must be conducted to validate the results of the present study.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

scholarly journals Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity

2014 ◽  
Vol 223 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Michael Rouse ◽  
Antoine Younès ◽  
Josephine M Egan
Keyword(s):  
Insulin Secretion ◽  
Cell Lines ◽  
Cell Function ◽  
Human Islets ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pde Inhibitors ◽  
Β Cell Function

Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1–10 μmol/l) and CUR (1–100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.

TWO ABNORMALITIES OF GLUCOSE-INDUCED INSULIN SECRETION: DOSE-RESPONSE CHARACTERISTICS AND INSULIN SENSITIVITY

1979 ◽  
Vol 92 (1) ◽  
pp. 148-165 ◽  
Author(s):  
R. C. Turner ◽  
E. Harris ◽  
M. Ounsted ◽  
C. Ponsford
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Insulin Response ◽  
Β Cells ◽  
Normal Range ◽  
Response Characteristics ◽  
Abnormal Metabolism ◽  
Β Cell Function ◽  
First Phase Insulin Response ◽  
Secretory Capacity

ABSTRACT To characterize the defect of insulin secretion in diabetes, the response to different iv glucose loads has been studied in women who have had gestational diabetes and are, by definition, latent diabetic (LD). Women who have produced a large-for-dates baby, but who were not known to have been diabetic (LFD), have been investigated to determine if they have abnormal metabolism. Both groups were found to have raised fasting plasma glucose concentrations. Only the LD had glucose intolerance, which was associated with a reduced first phase insulin response to all glucose loads with a decreased maximal secretory capacity (low V max). The LFD women appeared to include a distinct abnormality in which the β cells had decreased sensitivity to glucose (high Km), with diminished secretory response to small but normal response to large loads. Whereas the LD probably have disordered μ cell function, some of the LFD women may represent the upper end of the normal range of the glucose "set" of β cell function. Neither group had insulin resistance, as measured by the hypoglycaemic response to an iv insulin bolus. A woman who has produced a LFD, but who was not known to be diabetic, does not necessarily have a diabetic tendency.

scholarly journals Antagonistic epistasis of Hnf4α and FoxO1 networks through enhancer interactions in β-cell function

2020 ◽  
Author(s):  
Taiyi Kuo ◽  
Wen Du ◽  
Yasutaka Miyachi ◽  
Prasanna K. Dadi ◽  
David A. Jacobson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Functional Restoration ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Gene Environment ◽  
Genome Wide ◽  
Β Cell Function ◽  
Acquired Abnormalities

AbstractGenetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components, and are known to act through β-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature β-cells leads to increased selection of FoxO1 enhancers by Hnf4α. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues, was completely reversed in double mutants. Gene expression analyses revealed the reversal of β-cell dysfunction with an antagonistic network regulating glycolysis, including β-cell “disallowed” genes; and that a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.

scholarly journals Emerging role of testosterone in pancreatic β cell function and insulin secretion

2019 ◽  
Vol 240 (3) ◽  
pp. R97-R105 ◽  
Author(s):  
Weiwei Xu ◽  
Jamie Morford ◽  
Franck Mauvais-Jarvis
Keyword(s):  
Insulin Secretion ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Visceral Obesity ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.

scholarly journals Oxytocin signal contributes to the adaptative growth of islets during gestation

2021 ◽  
Author(s):  
Ping Gu ◽  
Yuege Lin ◽  
Qi Wan ◽  
Dongming Su ◽  
Qun Shu
Keyword(s):  
Insulin Secretion ◽  
Pregnant Women ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Β Cell Function ◽  
Insulinoma Cells

Background: Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or in gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. Methods: The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. Results: The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A three-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. Conclusions: These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and lack of oxytocin could be associated with the risk of GDM.

The effects of aging on male mouse pancreatic β-cell function involve multiple events in the regulation of secretion: influence of insulin sensitivity

2021 ◽  
Author(s):  
Eva Tudurí ◽  
Sergi Soriano ◽  
Lucía Almagro ◽  
Anabel García-Heredia ◽  
Alex Rafacho ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Aged Mouse ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Insulin Sensitivity ◽  
Increased Risk ◽  
Β Cell Function ◽  
Effects Of Aging

Abstract Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β-cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of β-cell adaptations and/or alterations during aging are still a matter of debate. In this study, we investigated the effects of aging on β-cell function from control (3-month-old) and aged (20-month-old) mice. Aged animals were further categorized in two groups: high insulin sensitive (aged-HIS) and low insulin sensitive (aged-LIS). Aged-LIS mice were hyperinsulinemic, glucose intolerant and displayed impaired glucose-stimulated insulin and C-peptide secretion, whereas aged-HIS animals showed characteristics in glucose homeostasis similar to controls. In isolated β-cells, we observed that glucose-induced inhibition of KATP channel activity was reduced with aging, particularly in the aged-LIS group. Glucose-induced islet NAD(P)H production was decreased in aged mice, suggesting impaired mitochondrial function. In contrast, voltage-gated Ca 2+ currents were higher in aged-LIS β-cells, and pancreatic islets of both aged groups displayed increased glucose-induced Ca 2+ signaling and augmented insulin secretion compared with controls. Morphological analysis of pancreas sections also revealed augmented β-cell mass with aging, especially in the aged-LIS group, as well as ultrastructural β-cell changes. Altogether, these findings indicate that aged mouse β-cells compensate for the aging-induced alterations in the stimulus-secretion coupling, particularly by adjusting their Ca 2+ influx to ensure insulin secretion. These results also suggest that decreased peripheral insulin sensitivity exacerbates the effects of aging on β-cells.

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