scholarly journals Differential Effects of Prostaglandin E2Production and Signaling through the Prostaglandin EP3 Receptor on Human Beta-cell Compensation

2019 ◽  
Author(s):  
Nathan A. Truchan ◽  
Harpreet K. Sandhu ◽  
Rachel J. Fenske ◽  
Renee Buchanan ◽  
Jackson Moeller ◽  
...  
Keyword(s):  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Insulin Content ◽  
Organ Donors ◽  
Functional Responses ◽  
Human Organ ◽  
Cell Dysfunction ◽  
Beta Cell Compensation ◽  
Human Beta Cell

AbstractObjectiveSignaling through Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor for E series prostaglandins such as prostaglandin E2(PGE2), has been linked to the beta-cell dysfunction and loss of beta-cell mass in type 2 diabetes (T2D). In the beta-cell, EP3 is specifically coupled to the unique cAMP-inhibitory G protein, Gz. Divergent effects of EP3 agonists and antagonists or Gαzloss on beta-cell function, replication, and survival depending on whether islets are isolated from mice or humans in the lean and healthy, type 1 diabetic, or T2D state suggest a divergence in biological effects downstream of EP3/Gαzdependent on the physiological milieu in which the islets reside.MethodsWe determined the expression of a number of genes in the EP3/Gαzsignaling pathway; PGE2production pathway; and the beta-cell metabolic, proliferative, and survival responses to insulin resistance and its corresponding metabolic and inflammatory derangements in a panel of 80 islet preparations from non-diabetic human organ donors spanning a BMI range of approximately 20-45. In a subset of islet preparations, we also performed glucose-stimulated insulin secretion assays with and without the addition of an EP3 agonist, L798,106, and a glucagon-like peptide 1 receptor agonist, exendin-4, allowing us to compare the gene expression profile of each islet preparation with its (1) total islet insulin content (2), functional responses to glucose and incretin hormones, and (3) intrinsic influence of endogenous EP3 signaling in regulating these functional responses. We also transduced two independent islet preparations from three human organ donors with adenoviruses encoding human Gαzor a GFP control in order to determine the impact of Gαzhyperactivity (a mimic of the T2D state) on human islet insulin content and functional response to glucose.ResultsIn contrast to results from islets isolated from T2D mice and human organ donors, where PGE2-mediated EP3 signaling actively contributes to beta-cell dysfunction, PGE2production and EP3 expression appeared positively associated with various measurements of functional beta-cell compensation. While GαzmRNA expression was negatively associated with islet insulin content, that of each of the Gαz-sensitive adenylate cyclase (AC) isoforms were positively associated with BMI and cyclin A1 mRNA expression, suggesting increased expression of AC1, AC5, and AC6 is a compensatory mechanism to augment beta-cell mass. Human islets over-expressing Gαzvia adenoviral transduction had reduced islet insulin content and secretion of insulin in response to stimulatory glucose as a percent of content, consistent with the effects of hyperactivation of Gαzby PGE2/EP3 signaling observed in islets exposed to the T2D physiological milieu.ConclusionsOur work sheds light on critical mechanisms in the human beta-cell compensatory response, before the progression to frank T2D.

scholarly journals Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
François Mach ◽  
Franco Dallegri ◽  
Giorgio Luciano Viviani ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Molecular Pathways ◽  
Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

scholarly journals Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3846
Author(s):  
Jun Inaishi ◽  
Yoshifumi Saisho
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Current Knowledge ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction ◽  
Pancreatic Fat

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.

scholarly journals Imaging of Human Insulin Secreting Cells with Gd-DOTA-P88, a Paramagnetic Contrast Agent Targeting the Beta Cell Biomarker FXYD2γa

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2100 ◽  
Author(s):  
Stéphane Demine ◽  
Alexander Balhuizen ◽  
Vinciane Debaille ◽  
Lieke Joosten ◽  
Maïté Fereau ◽  
...  
Keyword(s):  
Beta Cell ◽  
Contrast Agent ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Paramagnetic Contrast Agent ◽  
Biodistribution Studies ◽  
Beta Cell Line ◽  
Human Beta Cells ◽  
Human Beta Cell

Non-invasive imaging and quantification of human beta cell mass remains a major challenge. We performed pre-clinical in vivo validation of a peptide previously discovered by our group, namely, P88 that targets a beta cell specific biomarker, FXYD2γa. We conjugated P88 with DOTA and then complexed it with GdCl3 to obtain the MRI (magnetic resonance imaging) contrast agent (CA) Gd-DOTA-P88. A scrambled peptide was used as a negative control CA, namely Gd-DOTA-Scramble. The CAs were injected in immunodeficient mice implanted with EndoC-βH1 cells, a human beta cell line that expresses FXYD2γa similarly to primary human beta cells. The xenograft-bearing mice were analyzed by MRI. At the end, the mice were euthanized and the CA biodistribution was evaluated on the excised tissues by measuring the Gd concentration with inductively coupled plasma mass spectrometry (ICP-MS). The MRI and biodistribution studies indicated that Gd-DOTA-P88 accumulates in EndoC-βH1 xenografts above the level observed in the background tissue, and that its uptake is significantly higher than that observed for Gd-DOTA-Scramble. In addition, the Gd-DOTA-P88 showed good xenograft-to-muscle and xenograft-to-liver uptake ratios, two potential sites of human islets transplantation. The CA shows good potential for future use to non-invasively image implanted human beta cells.

scholarly journals The Harmine and Exendin-4 Combination Markedly Expands Human Beta Cell Mass In Vivo: Quantification and Visualization By iDISCO+ 3D Imaging

2020 ◽  
Author(s):  
Carolina Rosselot ◽  
Alexandra Alvarsson ◽  
Peng Wang ◽  
Yansui Li ◽  
Kunal Kumar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Light Sheet Microscopy ◽  
Human Beta Cell

AbstractSince all diabetes results from reductions in numbers of functional pancreatic beta cells, beta cell regenerative drugs are required for optimal and scalable future diabetes treatment. While many diabetes drugs are in clinical use, none increases human beta cell numbers. We have shown that a combination of the DYRK1A inhibitor, harmine, with the GLP1 receptor agonist, exendin-4, markedly increases human beta cell proliferation in vitro. However, technological limitations have prevented assessment of human beta cell mass in vivo. Here, we describe a novel method that combines iDISCO+ tissue clearing, insulin immunolabeling, light sheet microscopy, and volumetric quantification of human beta cells transplanted into immunodeficient mice. We demonstrate a striking seven-fold in vivo increase in human beta cell mass in response to three months of combined harmine-exendin-4 combination infusion, accompanied by lower blood glucose levels, increased plasma human insulin concentrations and enhanced beta cell proliferation. These studies unequivocally demonstrate for the first time that pharmacologic human beta cell expansion is a realistic and achievable path to diabetes therapy, and provide a rigorous, entirely novel and reproducible tool for quantifying human beta cell mass in vivo.

scholarly journals Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Valérie Plaisance ◽  
Gérard Waeber ◽  
Romano Regazzi ◽  
Amar Abderrahmani
Keyword(s):  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Oxidized Ldl ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Beta Cell Compensation ◽  
And Function

Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

scholarly journals Quantitative analysis of intra- and inter-individual variability of human beta-cell mass

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Scott K. Olehnik ◽  
Jonas L. Fowler ◽  
Gil Avramovich ◽  
Manami Hara
Keyword(s):  
Quantitative Analysis ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Individual Variability ◽  
Human Beta Cell

Quantification of the pancreatic beta-cell mass and insulin content in normal and type 2 diabetic subjects in Korea

2000 ◽  
Vol 50 ◽  
pp. 144-145
Author(s):  
Ho-Young Son ◽  
Kun-Ho Yoon ◽  
Seung-Hyun Ko ◽  
Sun-Hee Seo ◽  
Sung-Dae Moon ◽  
...  
Keyword(s):  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Insulin Content ◽  
Pancreatic Beta Cell Mass ◽  
Type 2 Diabetic

scholarly journals Systemic administration of pituitary adenylate cyclase-activating polypeptide maintains beta-cell mass and retards onset of hyperglycaemia in beta-cell-specific calmodulin-overexpressing transgenic mice

2005 ◽  
Vol 152 (5) ◽  
pp. 805-811 ◽  
Author(s):  
Shin Tsunekawa ◽  
Yoshitaka Miura ◽  
Naoki Yamamoto ◽  
Yuji Itoh ◽  
Yoh Ariyoshi ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Isolated Islets ◽  
Insulin Content ◽  
Islet Function ◽  
Primary Defect ◽  
Glucose Levels ◽  
Pituitary Adenylate Cyclase

Objective: Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to play an important role in the regulation of islet function. We investigated its effects in beta-cell-specific calmodulin-overexpressing diabetic (CaMTg) mice, in which we consider that apoptosis of beta cells is the primary defect leading to basal hyperglycaemia. Methods: CaMTg mice were treated with continuous s.c. infusions of PACAP from 2 to 4 weeks after birth, and were evaluated against littermate non-transgenic (nTg) and saline-treated CaMTg mice as to plasma glucose levels, insulin content, islet function and morphological features. Results: Remarkable and progressive hyperglycaemia was observed in CaMTg mice, and PACAP treatment blunted this elevation. Insulin secretion from isolated islets demonstrated an impaired response to glucose in CaMTg mice, and PACAP treatment did not cause any improvement. The total pancreatic insulin content in CaMTg mice decreased significantly to 19.1% of that in nTg mice. PACAP treatment of CaMTg mice increased the content to 158% of the value in saline-treated CaMTg mice. The insulin content in isolated islets from CaMTg mice also decreased to 15.9% of that in nTg mice, while PACAP treatment caused a doubling of the value. Immunohistochemical investigation revealed that the insulin-positive islet area was markedly smaller in CaMTg mice and that PACAP treatment significantly expanded the insulin-positive islet area. Conclusions: These findings indicate that PACAP treatment retards the onset of hyperglycaemia in CaMTg mice by maintaining beta-cell mass and PACAP treatment may potentially be a therapeutic measure for preventing beta-cell exhaustion during hyperglycaemia.

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