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

2010 ◽  
Vol 298 (2) ◽  
pp. E278-E286 ◽  
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).

scholarly journals Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion

2007 ◽  
Vol 38 (2) ◽  
pp. 193-206 ◽  
Author(s):  
Amanda M Ackermann ◽  
Maureen Gannon
Keyword(s):  
Cell Differentiation ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Development ◽  
Proliferation And Apoptosis ◽  
Patients With Diabetes ◽  
Mass Development ◽  
Differentiation And Proliferation

Pancreatic β-cells are responsible for producing all of the insulin required by an organism to maintain glucose homeostasis. Defects in development, maintenance, or expansion of β-cell mass can result in impaired glucose metabolism and diabetes. Thus, identifying the molecular regulators of these processes may provide new therapeutic targets for diabetes. Additionally, understanding the processes of β-cell differentiation and proliferation may allow for in vitro cultivation of β-cells in sufficient amounts to be transplanted into patients with diabetes. This review addresses many of the transcription factors and signaling pathways that play a role in early pancreatic development and endocrine cell (specifically β-cell) differentiation, conditions that influence β-cell mass development and molecular regulators of β-cell proliferation and apoptosis that are responsible for maintaining and expanding β-cell mass.

scholarly journals Lactation improves pancreatic β cell mass and function through serotonin production

2020 ◽  
Vol 12 (541) ◽  
pp. eaay0455
Author(s):  
Joon Ho Moon ◽  
Hyeongseok Kim ◽  
Hyunki Kim ◽  
Jungsun Park ◽  
Wonsuk Choi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Glucose Tolerance ◽  
Serotonin Receptor ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Beneficial Effects

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.

Insulin signalling in islets

2008 ◽  
Vol 36 (3) ◽  
pp. 290-293 ◽  
Author(s):  
Shanta J. Persaud ◽  
Dany Muller ◽  
Peter M. Jones
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Insulin Signalling ◽  
Cell Mass ◽  
Human Islets ◽  
Human Islet ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Β Cells ◽  
Β Cell

Studies in transgenic animals, rodent insulin-secreting cell lines and rodent islets suggest that insulin acts in an autocrine manner to regulate β-cell mass and gene expression. Very little is known about the in vitro roles played by insulin in human islets, and the regulatory role of insulin in protecting against β-cell apoptosis. We have identified mRNAs encoding IRs (insulin receptors) and downstream signalling elements in dissociated human islet β-cells by single-cell RT (reverse transcription)–PCR, and perifusion studies have indicated that insulin does not have an autocrine role to regulate insulin secretion from human islets, but activation of the closely related IGF-1 (insulin-like growth factor 1) receptors is linked to inhibition of insulin secretion. Knockdown of IR mRNA by siRNAs (small interfering RNAs) decreased IR protein expression without affecting IGF-1 receptor levels, and blocked glucose stimulation of preproinsulin gene expression. Similar results were obtained when human islet IRS (IR substrate)-2 was knocked down, whereas depletion of IRS-1 caused an increase in preproinsulin mRNA levels. Studies using the mouse MIN6 β-cell line indicated that glucose protected β-cells from undergoing apoptosis and that this was a consequence, at least in part, of insulin release in response to elevated glucose. IGF-1 also exerted anti-apoptotic effects. These data indicate that insulin can exert autocrine effects in human islets through receptors on β-cells. It protects β-cells against apoptosis and increases preproinsulin mRNA synthesis, but does not affect insulin secretion.

scholarly journals Single-Cell RNAseq Reveals That Pancreatic β-Cells From Very Old Male Mice Have a Young Gene Signature

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3431-3438 ◽  
Author(s):  
Yurong Xin ◽  
Haruka Okamoto ◽  
Jinrang Kim ◽  
Min Ni ◽  
Christina Adler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Function ◽  
Functional Decline ◽  
Cell Mass ◽  
Gene Signature ◽  
Β Cells ◽  
Β Cell ◽  
Very Old ◽  
Old Mice

Aging improves pancreatic β-cell function in mice. This is a surprising finding because aging is typically associated with functional decline. We performed single-cell RNA sequencing of β-cells from 3- and 26-month-old mice to explore how changes in gene expression contribute to improved function with age. The old mice were healthy and had reduced blood glucose levels and increased β-cell mass, which correlated to their body weight. β-Cells from young and old mice had similar transcriptome profiles. In fact, only 193 genes (0.89% of all detected genes) were significantly regulated (≥2-fold; false discovery rate < 0.01; normalized counts > 5). Of these, 183 were down-regulated and mainly associated with pathways regulating gene expression, cell cycle, cell death, and survival as well as cellular movement, function, and maintenance. Collectively our data show that β-cells from very old mice have transcriptome profiles similar to those of young mice. These data support previous findings that aging is not associated with reduced β-cell mass or functional β-cell decline in mice.

scholarly journals Puerarin protects pancreatic β-cell survival via PI3K/Akt signaling pathway

2014 ◽  
Vol 53 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Zhipeng Li ◽  
Zhaoshui Shangguan ◽  
Yijie Liu ◽  
Jihua Wang ◽  
Xuejun Li ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Mass ◽  
Akt Signaling ◽  
Pancreatic Β Cell ◽  
Diabetic Mice ◽  
Akt Signaling Pathway ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
And Function

Pancreatic β-cell loss because of apoptosis is the major cause of type 1 diabetes (T1D) and late stage T2D. Puerarin possesses anti-diabetic properties; whether it acts directly on pancreatic β-cell is not clear. This study was designed to investigate the effects of puerarin on pancreatic β-cell survival and function. Diabetes was induced in male C57BL/6 mice by a single peritoneal injection of streptozotocin (STZ). Pancreatic β-cell survival and function were assessed in diabetic mice by measuring β-cell apoptosis, β-cell mass, pancreatic insulin content, and glucose tolerance, and in cultured islets and clonial MIN6 β-cells by measuring β-cell viability and apoptosis and glucose-stimulated insulin secretion. We found that pre-treatment with puerarin decreased the incidence of STZ-induced diabetes. Puerarin increased pancreatic β-cell mass via β-cell apoptosis inhibition in diabetic mice, and increased serum insulin, whereas it decreased blood glucose levels and improved glucose tolerance. In cultured islets and MIN6 cells, puerarin protected β-cell from cobalt chloride (CoCl2)-induced apoptosis and restored the impaired capacity of glucose-stimulated insulin secretion. Puerarin protection of β-cell survival involved the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. In conclusion, puerarin protects pancreatic β-cell function and survival via direct effects on β-cells, and its protection of β-cell survival is mediated by the PI3K/Akt pathway. As a safe natural plant extraction, puerarin might serve as a preventive and/or therapeutic approach for diabetes.

scholarly journals Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2237
Author(s):  
Yuko Okano ◽  
Atsuro Takeshita ◽  
Taro Yasuma ◽  
Masaaki Toda ◽  
Kota Nishihama ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Tolerance ◽  
Mouse Model ◽  
Pancreatic Islet ◽  
Glucose Intolerance ◽  
Cell Mass ◽  
Diabetic Mice ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Mouse

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

scholarly journals Regulation of islet function and gene expression by prolactin during pregnancy

2019 ◽  
Author(s):  
Vipul Shrivastava ◽  
Megan Lee ◽  
Marle Pretorius ◽  
Guneet Makkar ◽  
Carol Huang
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Serum Insulin ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Insulin Level ◽  
Β Cells ◽  
Β Cell

AbstractPancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr+/−) mice are glucose intolerant, had a lower number of β cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its β-cell specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, allowing conditional deletion of Prlr from β cells in adult mice. In this study, we found that β-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mouse with global Prlr reduction, β-cell-specific Prlr loss led to a lower β-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus β-cell-specific Prlr reduction, we found some important differences in genes that regulate apoptosis and insulin secretion. This suggests that Prlr has both cell-autonomous and non-cell-autonomous effect on β cells, beyond its regulation of pro-proliferative genes.

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

Metabolism ◽  
2004 ◽  
Vol 53 (4) ◽  
pp. 488-494 ◽  
Author(s):  
Hitoshi Ishida ◽  
Makoto Takizawa ◽  
Sachihiko Ozawa ◽  
Yoko Nakamichi ◽  
Shinya Yamaguchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Secretory Capacity ◽  
Secretory Capacity

scholarly journals Combination of GLP-1 Receptor Activation and Glucagon Blockage Promotes Pancreatic β-Cell Regeneration In Situ in Type 1 Diabetic Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Liangbiao Gu ◽  
Dandan Wang ◽  
Xiaona Cui ◽  
Tianjiao Wei ◽  
Kun Yang ◽  
...  
Keyword(s):  
Clinical Application ◽  
Cell Mass ◽  
Receptor Activation ◽  
Great Promise ◽  
Cell Regeneration ◽  
Pancreatic Β Cell ◽  
Diabetic Mice ◽  
Β Cells ◽  
Β Cell

Pancreatic β-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse β-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote recovery of functional β-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded β-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β cells. The pancreatic β-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β cells/α cells. Our study evaluated the effect of liraglutide, GCGR mAb monotherapy, or combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.

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

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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