Human islet expression levels of Prostaglandin E2 synthetic enzymes, but not prostaglandin EP3 receptor, are positively correlated with markers of β-cell function and mass in non-diabetic obesity

AbstractWe and others previously reported increased signaling through the Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor (GPCR) for the arachidonic acid metabolite, prostaglandin E2 (PGE2), is associated with β-cell dysfunction of type 2 diabetes (T2D). Yet, the relationship between PGE2 production and signaling and β-cell function during the progression to T2D remains unclear. In this work, we assessed gene expression from a panel of cadaveric human islets from 40 non-diabetic donors with BMI values spanning the spectrum from lean to high-risk obesity. Interleukin-6 (gene symbol: IL6) and cyclooxygenase-2 (COX-2) (gene symbol: PTGS2) mRNA levels were positively correlated with donor body mass index (BMI), while EP3 (gene symbol: PTGER3) was not. IL6 was itself strongly correlated with PTGS2 and all but one of the other PGE2 synthetic pathway genes tested. About half of the islet preparations were used in glucose-stimulated- and incretin-potentiated insulin secretion assays using an EP3-specific antagonist, confirming functionally-relevant up-regulation of PGE2 production. Islets from obese donors showed no inherent β-cell dysfunction and were at least equally as glucose- and incretin-responsive as islets from non-obese donors. Furthermore, insulin content, a marker of islet size known to be associated with donor BMI, was also significantly and positively correlated with islet PTGS2 expression. We conclude up-regulated islet PGE2 production and signaling may be a necessary part of the β-cell adaption response, compensating for obesity and insulin resistance. Analysis of plasma PGE2 metabolite levels from a clinical cohort reveal these findings are not in conflict with the concept of further elevations in PGE2 production contributing to T2D-related β-cell dysfunction where islet EP3 expression has also been up-regulated.Graphical Abstract

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Effects of glucose and d-3-hydroxybutyrate on human pancreatic islet cell function

Clinical Science ◽

10.1042/cs0680567 ◽

1985 ◽

Vol 68 (5) ◽

pp. 567-572 ◽

Cited By ~ 6

Author(s):

C. J. Rhodes ◽

I. L. Campbell ◽

T. M. Szopa ◽

T. J. Biden ◽

P. D. Reynolds ◽

...

Keyword(s):

Insulin Release ◽

Human Tissue ◽

Islet Cell ◽

Cell Function ◽

Human Islets ◽

Β Cell ◽

Pancreatic Islet Cell ◽

Sigmoidal Curve ◽

Β Cell Function ◽

Islet Cell Function

1. β-Cell function in human islets derived from a number of kidney donors was investigated by using various types of islet preparations. 2. With fresh islets, both insulin release and biosynthesis were increased by raising glucose concentrations, although the response was a variable one. 3. In fresh islets, the effects of 5 mmol of glucose/l on release were potentiated by 10 mmol of d-3-hydroxybutyrate/l. 4. Insulin release at 20 mmol of glucose/l was inhibited by adrenaline (0.1 mmol/l), and potentiated by theophylline (10 mmol/l) in the presence of 5 mmol of glucose/l, in islets cultured for 4 days. 5. After culture for 8 days, islets still showed an increase in insulin release and biosynthesis in response to glucose. 6. Pancreas slices derived from fresh human tissue also responded to increasing concentrations of glucose with a sigmoidal curve for insulin release.

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Impaired Pancreatic β-Cell Function in Critically Ill Children

Frontiers in Pediatrics ◽

10.3389/fped.2021.603361 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shereen A. Mohamed ◽

Nora E. Badawi ◽

Hoiyda A. AbdelRasol ◽

Hossam M. AbdelAziz ◽

Nirvana A. Khalaf ◽

...

Keyword(s):

Cell Function ◽

Multivariate Logistic Regression Analysis ◽

Pediatric Intensive Care ◽

Glucose Production ◽

Critically Ill Children ◽

Model Assessment ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction ◽

Β Cell Function

Critical illness hyperglycemia (CIH) is common in the pediatric intensive care unit (PICU). Increased glucose production, insulin resistance (IR), and pancreatic β-cell dysfunction are responsible mechanisms. We aimed to investigate β-cell function in the PICU and to uncover its relation to clinical and laboratory variables and ICU mortality. We prospectively recruited 91 children. Pancreatic β-cell function was assessed by using a homeostasis model assessment (HOMA)-β. Patients with β-cell function <40.0% had significantly higher Pediatric Risk of Mortality III (PRISM III) scores, higher rates of a positive C-reactive protein (CRP), lower IR, and a longer hospital stay. The patients with 40–80% β-cell function had the highest IR. Intermediate IR was found when the β-cell function was >80%. ICU survivors had better β-cell function than ICU non-survivors. A multivariate logistic regression analysis revealed that higher PRISM III score and HOMA-β <80.0% were significant predictors of mortality. In conclusion, β-cell dysfunction is prevalent among PICU patients and influences patient morbidity and mortality.

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Detailed protocol for evaluation of dynamic perifusion of human islets to assess β-cell function

Islets ◽

10.4161/isl.3.5.15938 ◽

2011 ◽

Vol 3 (5) ◽

pp. 284-290 ◽

Cited By ~ 15

Author(s):

Kwamina Bentsi-Barnes ◽

Máire E. Doyle ◽

Danny Abad ◽

Fouad Kandeel ◽

Ismail Al-Abdullah

Keyword(s):

Cell Function ◽

Human Islets ◽

Β Cell ◽

Β Cell Function ◽

Detailed Protocol

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Association between Genetic Polymorphisms of β-Cell Differentiation Genes and Insulin Resistance (β-Cell Dysfunction) in Childhood Acute Lymphoblastic Leukemia (ALL) Survivors.

Blood ◽

10.1182/blood.v110.11.4281.4281 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4281-4281

Author(s):

Pacharapan Surapolchai ◽

Suradej Hongeng ◽

Samart Pakakasama ◽

Pat Mahachoklertwattana ◽

Angkana Winaichatsak ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Cell Function ◽

Sensitivity Index ◽

Insulin Sensitivity Index ◽

Β Cell ◽

Childhood All ◽

Cell Dysfunction ◽

Β Cell Function

Abstract Background: The purposes of the study were to determine β-cell function and insulin sensitivity after ALL therapy cessation and the association between genetic polymorphisms of β-cell differentiation genes, TCF7L2 and PAX4, with insulin resistance (β-cell dysfunction) in childhood ALL survivors. Methods: Childhood ALL patients diagnosed during 1997–2004 finished the treatment for at least 6 months. The oral glucose tolerance test and lipid screening were performed. Impaired glucose tolerance and diabetes mellitus (DM) were defined according to WHO criteria. β-cell function was estimated by homeostasis model assessment β-cell (HOMA β-cell) and insulinogenic index (IGI) and insulin sensitivity was estimated by whole body insulin sensitivity index (WBISI). The polymorphisms of TCF7L2 (rs12255372 and rs7903146) and PAX4 (A1186C) were genotyped and assessed for the association between these polymorphisms and the β-cell function and the insulin sensitivity. Results: 126 patients were studied (52 females, 74 males and age at the time of study; 4–20 yrs). 116 patients (92%) had normal glucose tolerance (NGT) while the others 10 patients (8%) had impaired glucose tolerance (IGT). Comparing between IGT and NGT groups respectively, we found statistically significant differences in age at the diagnosis (7.5 and 5.2 yrs, p=0.041), age at the study (14 and 10.3 yrs, p=0.001), the duration of post ALL therapy cessation (43 and 26 months, p=0.015), and insulin sensitivity index (WBISI) (5.75 and 9.52, p<0.001). HOMA β-cell and IGI were not different between NGT and IGT group (190.8 and 139.5, p=0.332; 23.6 and 15.8, p=0.310, respectively). Moreover, 32 of 126 patients (25%) had insulin resistance (modified from the criteria of WBISI in obese children and adolescents). These 32 patients who had insulin resistance demonstrated significant pictures of metabolic syndrome i.e. hypertriglyceridemia (116.6 and 85.4 mg/dL, p=0.036), low HDL-C (43.0 and 48.3 mg/dL, p=0.015), obesity (BMI SDS 1.03 and 0.38, p=0.044) and were also older age at the study (12.8 and 9.9 yrs, p<0.001). The genotype frequencies and allele frequencies of polymorphisms of TCF7L2 and PAX4 genes between IGT and NGT groups and between insulin resistance and nonresistance were not difference (p>0.05). Conclusion: The childhood ALL survivors who had IGT were associated with the longer duration of ALL therapy cessation, the older age at diagnosis and at the time of study, and insulin resistance while β-cell function was still relatively preserved. Long-term childhood ALL survivors have potential risks of IGT, insulin resistance and metabolic syndrome. Our findings with such small representatives are not yet applicable to associate TCF7L2 and PAX4 polymorphisms with the insulin resistance (β-cell dysfunction) in the childhood ALL survivors.

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

Journal of Endocrinology ◽

10.1530/joe-14-0335 ◽

2014 ◽

Vol 223 (2) ◽

pp. 107-117 ◽

Cited By ~ 53

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.

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Insulin Resistance and Beta Cell Dysfunction in Severe Falciparum Malaria with Multi Organ Dysfunction Syndrome (MODS)

Volume 5 - 2020, Issue 9 - September - International Journal of Innovative Science and Research Technology ◽

10.38124/ijisrt20aug309 ◽

2020 ◽

Vol 5 (8) ◽

pp. 1756-1759

Author(s):

Manoj Kumar Mohapatra ◽

Muralidhar Anantrao Sangle ◽

Prafulla Kumar Bariha

Keyword(s):

Insulin Resistance ◽

Falciparum Malaria ◽

Organ Dysfunction ◽

Cell Function ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

Β Cell ◽

Cell Dysfunction ◽

Β Cell Function ◽

Severe Falciparum Malaria

Insulin Resistance is a major factor among patients with critical illness due to various causes. Severe falciparum malaria with MODS diagnosed as per the criteria of MSS and admitted to the Medical ward of our hospital were assessed for IR and β cell function by using homeostasis model assessment. 75 consecutive patients of SFM admitted to the Medical ward of our hospital were included in this study. Malaria was diagnosed as per criteria of WHO and organ dysfunction was diagnosed as per Malaria Severity Score. Insulin Resistance and β cell function was assessed by using homeostasis model assessment on Day-1 and Day-7. Out of 75 patients of severe falciparum malaria with MODS 2, 3, 4, and 5 organ dysfunctions constituted 16 (21.3%), 34 (45.3%), 16 (21.3%), and 9 (12.0%) patients, respectively.Hepatic failure was the most common organ system failure (n=58; 77.3%), followed by neurological (n=50;66.6%) ,renal (n=40;53.3%), hematological (n=30; 40.0%), and, respiratory failure ( n=15; 20.0%). Hyperglycemia was present in 25 (33.3%) cases where as normoglycemia was present in 50 (66.6%) cases. The values of FBS, Tg, insulin, IR, and β cell function decreased on Day-7 compared to Day-1 after recovery from critically ill state. The patients who died had a high insulin value, IR, but low β cell dysfunction compared to the survivors. This study showed that IR and β cell dysfunction were associated with severe malaria with MODS with increased mortality.

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Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males

10.1101/2020.06.29.177527 ◽

2020 ◽

Author(s):

Emily M. Walker ◽

Jeeyeon Cha ◽

Xin Tong ◽

Min Guo ◽

Jin-Hua Liu ◽

...

Keyword(s):

Cell Function ◽

Premature Aging ◽

Calcium Handling ◽

Secretory Proteins ◽

Dependent Manner ◽

Β Cell ◽

Functional Changes ◽

Protein Levels ◽

Cell Dysfunction ◽

Β Cell Function

AbstractA heterozygous missense mutation producing a variant of the islet β-cell-enriched MAFA transcription factor (Ser(S)64Phe(F) MAFA) was identified in humans who developed adult-onset, β-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this variant impacts β cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only heterozygous males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in calcium signaling, DNA damage, aging, and senescence. Functional changes in islet calcium handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, S64F MAFA expression in human, male EndoC-βH2 β cells accelerated cellular senescence and increased production of senescence-associated secretory proteins compared to cells expressing wild-type MAFA. Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in S64F MAFA carriers in a sex-dependent manner.

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

10.1101/2020.07.04.187864 ◽

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.

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Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

10.1101/761007 ◽

2019 ◽

Author(s):

Xin Tong ◽

Zunaira Chaudry ◽

Chih-Chun Lee ◽

Robert N. Bone ◽

Sukrati Kanojia ◽

...

Keyword(s):

Oxidative Stress ◽

Smoking Cessation ◽

Weight Gain ◽

Cell Function ◽

Ex Vivo ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction ◽

Β Cell Function ◽

Ceramide Accumulation

ABSTRACTObjectivesEpidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.MethodsBeginning at 8 weeks of age, C57BL/6J mice were concurrently fed high fat-diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD exposure. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured β-cells (INS-1) and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide in lungs cells and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.ResultsCompared to HFD-fed ambient air-exposed mice, HFD-fed and CS- exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and a significantly greater increase in glucose intolerance compared to non-smoking control mice. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p=0.02), and reduced β-cell proliferation (p=0.006), and increased islet ceramide accumulation. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide accumulation, reduce insulin gene expression and glucose-stimulated insulin secretion, and increase β-cell oxidative and ER stress. Treatment with the antioxidant N-acetylcysteine, markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.ConclusionsOur results indicate that CS exposure inhibits insulin production, processing, and secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

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