Pioglitazone improves insulin secretory capacity and prevents the loss of β-cell mass in obese diabetic db/db mice: possible protection of β cells from oxidative stress

Pregnancy imposes a substantial metabolic burden on women through weight gain and insulin resistance. Lactation reduces the risk of maternal postpartum diabetes, but the mechanisms underlying this benefit are unknown. Here, we identified long-term beneficial effects of lactation on β cell function, which last for years after the cessation of lactation. We analyzed metabolic phenotypes including β cell characteristics in lactating and non-lactating humans and mice. Lactating and non-lactating women showed comparable glucose tolerance at 2 months after delivery, but after a mean of 3.6 years, glucose tolerance in lactated women had improved compared to non-lactated women. In humans, the disposition index, a measure of insulin secretory function of β cells considering the degree of insulin sensitivity, was higher in lactated women at 3.6 years after delivery. In mice, lactation improved glucose tolerance and increased β cell mass at 3 weeks after delivery. Amelioration of glucose tolerance and insulin secretion were maintained up to 4 months after delivery in lactated mice. During lactation, prolactin induced serotonin production in β cells. Secreted serotonin stimulated β cell proliferation through serotonin receptor 2B in an autocrine and paracrine manner. In addition, intracellular serotonin acted as an antioxidant to mitigate oxidative stress and improved β cell survival. Together, our results suggest that serotonin mediates the long-term beneficial effects of lactation on female metabolic health by increasing β cell proliferation and reducing oxidative stress in β cells.

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Molecular mechanism by which pioglitazone preserves pancreatic β-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARγ agonist

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00388.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. E278-E286 ◽

Cited By ~ 43

Author(s):

Yukiko Kanda ◽

Masashi Shimoda ◽

Sumiko Hamamoto ◽

Kazuhito Tawaramoto ◽

Fumiko Kawasaki ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Cell Differentiation ◽

Cell Mass ◽

Diabetic Mice ◽

Β Cells ◽

Β Cell ◽

Oxidase Gene ◽

Pparγ Agonist ◽

Pioglitazone Treatment

Pioglitazone preserves pancreatic β-cell morphology and function in diabetic animal models. In this study, we investigated the molecular mechanisms by which pioglitazone protects β-cells in diabetic db/db mice. In addition to the morphological analysis of the islets, gene expression profiles of the pancreatic islet were analyzed using laser capture microdissection and were compared with real-time RT-PCR of db/db and nondiabetic m/m mice treated with or without pioglitazone for 2 wk or 2 days. Pioglitazone treatment (2 wk) ameliorated dysmetabolism, increased islet insulin content, restored glucose-stimulated insulin secretion, and preserved β-cell mass in db/db mice but had no significant effects in m/m mice. Pioglitazone upregulated genes that promote cell differentiation/proliferation in diabetic and nondiabetic mice. In db/db mice, pioglitazone downregulated the apoptosis-promoting caspase-activated DNase gene and upregulated anti-apoptosis-related genes. The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment. By contrast, the oxidative stress-promoting NADPH oxidase gene was downregulated, and antioxidative stress-related genes were upregulated, in db/db mice treated with pioglitazone for 2 wk, rather than 2 days. Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis. The present results strongly suggest that pioglitazone preserves β-cell mass in diabetic mice mostly by two ways; directly, by acceleration of cell differentiation/proliferation and suppression of apoptosis (acute effect); and indirectly, by deceleration of oxidative stress because of amelioration of the underlying metabolic disorder (chronic effect).

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Interorgan Crosstalk Contributing to β-Cell Dysfunction

Journal of Diabetes Research ◽

10.1155/2017/3605178 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Katsuya Tanabe ◽

Kikuko Amo-Shiinoki ◽

Masayuki Hatanaka ◽

Yukio Tanizawa

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Current Knowledge ◽

Cell Mass ◽

Β Cell ◽

Cell Dysfunction ◽

Circulating Levels ◽

Insulin Secretory Capacity ◽

Secretory Capacity

Type 2 diabetes mellitus (T2DM) results from pancreatic β-cell failure in the setting of insulin resistance. In the early stages of this disease, pancreatic β-cells meet increased insulin demand by both enhancing insulin-secretory capacity and increasing β-cell mass. As the disease progresses, β-cells fail to maintain these compensatory responses. This involves both extrinsic signals and mediators intrinsic to β-cells, which adversely affect β-cells by impairing insulin secretion, decreasing proliferative capacities, and ultimately causing apoptosis. In recent years, it has increasingly been recognized that changes in circulating levels of various factors from other organs play roles in β-cell dysfunction and cellular loss. In this review, we discuss current knowledge of interorgan communications underlying β-cell failure during the progression of T2DM.

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Oxidative Stress, β-Cell Apoptosis, and Decreased Insulin Secretory Capacity in Mouse Models of Hemochromatosis

Endocrinology ◽

10.1210/en.2004-0392 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5305-5312 ◽

Cited By ~ 138

Author(s):

Robert C. Cooksey ◽

Hani A. Jouihan ◽

Richard S. Ajioka ◽

Mark W. Hazel ◽

Deborah L. Jones ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Models ◽

Cell Apoptosis ◽

Β Cell ◽

Insulin Secretory Capacity ◽

Secretory Capacity

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Diazoxide Prevents Diabetes through Inhibiting Pancreatic β-Cells from Apoptosis via Bcl-2/Bax Rate and p38-β Mitogen-Activated Protein Kinase

Endocrinology ◽

10.1210/en.2006-0738 ◽

2007 ◽

Vol 148 (1) ◽

pp. 81-91 ◽

Cited By ~ 40

Author(s):

Qin Huang ◽

Shizhong Bu ◽

Yongwei Yu ◽

Zhiyong Guo ◽

Gautam Ghatnekar ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Apoptosis ◽

Critical Role ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Oletf Rats ◽

Insulin Secretory Capacity ◽

Secretory Capacity

Increased apoptosis of pancreatic β-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic β-cell apoptosis and its potential mechanism in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes, at the prediabetic and diabetic stages. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets, and the proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg·kg−1·d−1, administered ip) inhibited β-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet β-cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r = 0.913; P < 0.0001). Further study demonstrated that diazoxide up-regulated Bcl-2 expression and p38β MAPK, which expressed at very low levels due to the high glucose, but not c-jun N-terminal kinase and ERK. Hence, diazoxide may play a critical role in protection from apoptosis. In this study, we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting β-cell apoptosis via increasing p38β MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.

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Silencing of lncRNA PVT1 ameliorates streptozotocin-induced pancreatic β cell injury and enhances insulin secretory capacity via regulating miR-181a-5p

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0268 ◽

2020 ◽

Author(s):

Yinqin Cheng ◽

Qiaosheng Hu ◽

Jie Zhou

Keyword(s):

Oxidative Stress ◽

Insulin Secretion ◽

Cell Injury ◽

Luciferase Reporter ◽

Pancreatic Β Cell ◽

Β Cell ◽

Insulin Secretory Capacity ◽

Secretory Capacity

Diabetes mellitus (DM) is a kind of metabolic disorder characterized by long-term hyperglycemia. Accumulating evidence shows that long noncoding RNAs (lncRNAs) play significant roles in the occurrence and development of DM. This study intended to investigate the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in rat insulinoma (INS-1) cells damaged by streptozotocin (STZ) and to identify the potential mechanisms. Firstly, PVT1 expression in INS-1 cells was assessed using RT-qPCR after STZ stimulation. After PVT1-knockdown, cell apoptosis, the contents of oxidative stress-related markers and the changes of insulin secretion were detected. Results indicated that PVT1 was remarkably upregulated after STZ stimulation. PVT1-knockdown inhibited STZ-induced oxidative stress and apoptosis of INS-1 cells. Moreover, the insulin secretory capacity was notably elevated following PVT1 silencing. Subsequently, a luciferase reporter assay verified that miR-181a-5p was directly targeted by PVT1. The rescue assays revealed that miR-181a-5p inhibitor dramatically abrogated the effects of PVT1 silencing on oxidative stress, apoptosis and insulin secretion. Taken together, these findings demonstrated that PVT1-knockdown could ameliorate STZ-induced oxidative stress and apoptosis and elevate insulin secretory capacity in pancreatic β cell via regulating miR-181a-5p, suggesting a promising biomarker in DM diagnosis and treatment.

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Oxidative Stress Leads to β-Cell Dysfunction Through Loss of β-Cell Identity

Frontiers in Immunology ◽

10.3389/fimmu.2021.690379 ◽

2021 ◽

Vol 12 ◽

Author(s):

Floris Leenders ◽

Nathalie Groen ◽

Natascha de Graaf ◽

Marten A. Engelse ◽

Ton J. Rabelink ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Function ◽

Cell Mass ◽

Critical Event ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Inflammatory Conditions ◽

Β Cell Function ◽

Underlying Mechanisms

Pancreatic β-cell failure is a critical event in the onset of both main types of diabetes mellitus but underlying mechanisms are not fully understood. β-cells have low anti-oxidant capacity, making them more susceptible to oxidative stress. In type 1 diabetes (T1D), reactive oxygen species (ROS) are associated with pro-inflammatory conditions at the onset of the disease. Here, we investigated the effects of hydrogen peroxide-induced oxidative stress on human β-cells. We show that primary human β-cell function is decreased. This reduced function is associated with an ER stress response and the shuttling of FOXO1 to the nucleus. Furthermore, oxidative stress leads to loss of β-cell maturity genes MAFA and PDX1, and to a concomitant increase in progenitor marker expression of SOX9 and HES1. Overall, we propose that oxidative stress-induced β-cell failure may result from partial dedifferentiation. Targeting antioxidant mechanisms may preserve functional β-cell mass in early stages of development of T1D.

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Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

Scientific Reports ◽

10.1038/s41598-021-94725-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Brenda Strutt ◽

Sandra Szlapinski ◽

Thineesha Gnaneswaran ◽

Sarah Donegan ◽

Jessica Hill ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Transporter ◽

Cell Mass ◽

Elevated Serum ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Transporter 2 ◽

Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

International Journal of Molecular Sciences ◽

10.3390/ijms22136713 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6713

Author(s):

Romana Bohuslavova ◽

Ondrej Smolik ◽

Jessica Malfatti ◽

Zuzana Berkova ◽

Zaneta Novakova ◽

...

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Cell Mass ◽

Neonatal Diabetes ◽

Diabetes Research ◽

Pancreas Development ◽

Β Cells ◽

Β Cell ◽

Pancreatic Islet Cell ◽

Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

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