scholarly journals Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands β-Cell Mass by Increasing β-Cell Survival

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3577-3588 ◽  
Author(s):  
Jeremy A. Lavine ◽  
Philipp W. Raess ◽  
Donald S. Stapleton ◽  
Mary E. Rabaglia ◽  
Joshua I. Suhonen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Islet Cells ◽  
Cell Mass ◽  
Obese Mouse ◽  
Β Cell ◽  
Key Factor ◽  
Islet Size ◽  
Mouse Islets ◽  
Mass Expansion

An absolute or functional deficit in β-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven β-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptinob/ob mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both α- and β-cells. We bred a null Cck allele into the C57BL/6-Leptinob/ob background and investigated β-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced β-cell mass through increased β-cell death. CCK deficiency and decreased β-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect β-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase β-cell survival and expand β-cell mass to compensate for obesity-induced insulin resistance.

Tungstate promotes β-cell survival in Irs2−/− mice

2014 ◽  
Vol 306 (1) ◽  
pp. E36-E47 ◽  
Author(s):  
Joana Moitinho Oliveira ◽  
Sandra A. Rebuffat ◽  
Rosa Gasa ◽  
Deborah J. Burks ◽  
Ainhoa Garcia ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Recovery ◽  
Β Cells ◽  
Β Cell ◽  
Igf Signaling

Pancreatic β-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional β-cell mass that is associated mainly with increased β-cell apoptosis. Thus, understanding how to enhance survival of β-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in β-cells. In fact, IRS-2 is critically required for β-cell compensation in conditions of increased insulin demand and for β-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote β-cell recovery in toxin-induced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive β-cell death. To this end, we treated mice deficient in IRS2 ( Irs2−/−), which exhibit severe β-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2−/− mice in correlation with increased β-cell mass, increased β-cell replication, and a striking threefold reduction in β-cell apoptosis. Islets from treated Irs2−/− exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2−/− islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2−/− mice, consistent with reduced apoptotic rates. Our results support the finding that β-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing β-cell mass decline are potential strategies to prevent the progression to T2D.

scholarly journals Activated FoxM1 Attenuates Streptozotocin-Mediated β-Cell Death

2014 ◽  
Vol 28 (9) ◽  
pp. 1435-1447 ◽  
Author(s):  
Maria L. Golson ◽  
Matthew F. Maulis ◽  
Jennifer C. Dunn ◽  
Greg Poffenberger ◽  
Jonathan Schug ◽  
...  
Keyword(s):  
Cell Death ◽  
Transgenic Mice ◽  
Cell Injury ◽  
Immune Cell ◽  
Cell Mass ◽  
Sequencing Analysis ◽  
Β Cell ◽  
Partial Pancreatectomy ◽  
Cell Ablation ◽  
Mass Expansion

The forkhead box transcription factor FoxM1, a positive regulator of the cell cycle, is required for β-cell mass expansion postnatally, during pregnancy, and after partial pancreatectomy. Up-regulation of full-length FoxM1, however, is unable to stimulate increases in β-cell mass in unstressed mice or after partial pancreatectomy, probably due to the lack of posttranslational activation. We hypothesized that expression of an activated form of FoxM1 could aid in recovery after β-cell injury. We therefore derived transgenic mice that inducibly express an activated version of FoxM1 in β-cells (RIP-rtTA;TetO-hemagglutinin (HA)-Foxm1ΔNRD mice). This N-terminally truncated form of FoxM1 bypasses 2 posttranslational controls: exposure of the forkhead DNA binding domain and targeted proteasomal degradation. Transgenic mice were subjected to streptozotocin (STZ)-induced β-cell ablation to test whether activated FoxM1 can promote β-cell regeneration. Mice expressing HA-FoxM1ΔNRD displayed decreased ad libitum–fed blood glucose and increased β-cell mass. β-Cell proliferation was actually decreased in RIP-rtTA:TetO-HA-Foxm1NRD mice compared with that in RIP-rtTA mice 7 days after STZ treatment. Unexpectedly, β-cell death was decreased 2 days after STZ treatment. RNA sequencing analysis indicated that activated FoxM1 alters the expression of extracellular matrix and immune cell gene profiles, which may protect against STZ-mediated death. These studies highlight a previously underappreciated role for FoxM1 in promoting β-cell survival.

scholarly journals Glucokinase is required for high‐starch diet‐induced β‐cell mass expansion in mice

2021 ◽  
Author(s):  
Kazuhisa Tsuchida ◽  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Kelaier Yang ◽  
Yuki Yamauchi ◽  
...  
Keyword(s):  
Cell Mass ◽  
Β Cell ◽  
High Starch ◽  
Mass Expansion ◽  
Starch Diet

scholarly journals Assessment of β-Cell Mass and α- and β-Cell Survival and Function by Arginine Stimulation in Human Autologous Islet Recipients

Diabetes ◽  
2014 ◽  
Vol 64 (2) ◽  
pp. 565-572 ◽  
Author(s):  
R. Paul Robertson ◽  
Lindsey D. Bogachus ◽  
Elizabeth Oseid ◽  
Susan Parazzoli ◽  
Mary Elizabeth Patti ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Mass ◽  
Β Cell ◽  
And Function

scholarly journals Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

2013 ◽  
Vol 305 (1) ◽  
pp. E149-E159 ◽  
Author(s):  
Rachel E. Stamateris ◽  
Rohit B. Sharma ◽  
Douglas A. Hollern ◽  
Laura C. Alonso
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Extended Period ◽  
Time Frame ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Cyclin D2 ◽  
Mass Expansion

Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass ( 11 , 62 ). Therapies aimed at expanding β-cell mass may be useful to treat T2D ( 14 ). Although feeding rodents a high-fat diet (HFD) for an extended period (3–6 mo) increases β-cell mass by inducing β-cell proliferation ( 16 , 20 , 53 , 54 ), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.

HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27

2018 ◽  
Vol 475 (24) ◽  
pp. 3997-4010 ◽  
Author(s):  
Carrie Draney ◽  
Matthew C. Austin ◽  
Aaron H. Leifer ◽  
Courtney J. Smith ◽  
Kyle B. Kener ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Survival ◽  
Cell Mass ◽  
Cyclin B1 ◽  
Β Cell ◽  
Histone Deacetylase 1 ◽  
Cell Cycle Inhibitor ◽  
Homeobox Transcription Factor ◽  
Glucose Stimulated Insulin Secretion

The homeobox transcription factor Nkx6.1 is sufficient to increase functional β-cell mass, where functional β-cell mass refers to the combination of β-cell proliferation, glucose-stimulated insulin secretion (GSIS) and β-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional β-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase β-cell proliferation in primary rat islets and the INS-1 832/13 β-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing β-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated β-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional β-cell mass.

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

PGJ2-stimulated β-cell apoptosis is associated with prolonged UPR activation

2007 ◽  
Vol 292 (4) ◽  
pp. E1052-E1061 ◽  
Author(s):  
Kari T. Chambers ◽  
Sarah M. Weber ◽  
John A. Corbett
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cellular Response ◽  
Caspase 3 ◽  
Initiation Factor ◽  
Cytokine Signaling ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Β Cell ◽  
Cell Death Pathway

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands have been shown to possess anti-inflammatory properties that include the inhibition of transcription factor activation and the expression of inflammatory genes. Using pancreatic β-cells, we have shown that PPARγ ligands such as 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) attenuate interferon-γ-induced signal transducer and activator of transcription 1 activation and interleukin (IL)-1β-induced nuclear factor-κB activation by a pathway that correlates with endoplasmic reticulum stress and the induction of the unfolded protein response (UPR). The UPR is a conserved cellular response activated by a number of cell stressors and is believed to alleviate the stress and promote cell survival. However, prolonged activation of the UPR results in cellular death by apoptosis. In this report, we have examined the effects of PGJ2 on UPR activation and the consequences of this activation on cell survival. Consistent with induction of a cell death pathway, treatment of rat islets and RINm5F cells for 24 h with PGJ2 results in caspase-3 activation and caspase-dependent β-cell death. The actions of these ligands do not appear to be selective for β-cells, because PGJ2 stimulates macrophage apoptosis in a similar fashion. Associated with cell death is the enhanced phosphorylation of eukaryotic initiation factor 2α (eIF2α), and in cells expressing a mutant of eIF2α that cannot be phosphorylated, the stimulatory actions of PGJ2 on caspase-3 activation are augmented. These findings suggest that, whereas PGJ2-induced UPR activation is associated with an inhibition of cytokine signaling, prolonged UPR activation results in cell death, and that eIF2α phosphorylation may function in a protective manner to attenuate cell death.

scholarly journals Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

2014 ◽  
Vol 223 (1) ◽  
pp. 67-78 ◽  
Author(s):  
Noèlia Téllez ◽  
Eduard Montanya
Keyword(s):  
Cell Mass ◽  
Β Cell ◽  
Neurogenin 3 ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Blood Glucose Levels ◽  
Morphometric Analyses ◽  
Underlying Mechanisms ◽  
Mass Expansion

Induction of β-cell mass regeneration is a potentially curative treatment for diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and β-cell mass expansion in 95% pancreatectomised (Px) rats. In this study, we investigated the underlying mechanisms of gastrin-induced β-cell mass expansion after Px. After 90%-Px, rats were treated with gastrin (Px+G) or vehicle (Px+V), pancreatic remnants were harvested on days 1, 3, 5, 7, and 14 and used for gene expression, protein immunolocalisation and morphometric analyses. Gastrin- and vehicle-treated Px rats showed similar blood glucose levels throughout the study. Initially, after Px, focal areas of regeneration, showing mesenchymal cells surrounding ductal structures that expressed the cholecystokinin B receptor, were identified. These focal areas of regeneration were similar in size and cell composition in the Px+G and Px+V groups. However, in the Px+G group, the ductal structures showed lower levels of keratin 20 and β-catenin (indicative of duct dedifferentiation) and higher levels of expression of neurogenin 3 and NKX6-1 (indicative of endocrine progenitor phenotype), as compared with Px+V rats. In Px+G rats, β-cell mass and the number of scattered β-cells were significantly increased compared with Px+V rats, whereas β-cell replication and apoptosis were similar in the two groups. These results indicate that gastrin treatment-enhanced dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased β-cell neogenesis and fostered β-cell mass expansion.

scholarly journals The MAPK Kinase Kinase-1 Is Essential for Stress-Induced Pancreatic Islet Cell Death

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 3046-3053 ◽  
Author(s):  
Dariush Mokhtari ◽  
Jason W. Myers ◽  
Nils Welsh
Keyword(s):  
Cell Death ◽  
Small Interfering Rna ◽  
Islet Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Mapk Kinase ◽  
Transient Overexpression ◽  
Novel Therapeutic Strategies ◽  
Interfering Rna

The aim of the present investigation was to characterize the role of the MAPK kinase kinase-1 (MEKK-1) in stress-induced cell death of insulin producing cells. We observed that transient overexpression of the wild type MEKK-1 protein in the insulin-producing cell lines RIN-5AH and βTC-6 increased c-Jun N-terminal kinase (JNK) phosphorylation and augmented cell death induced by diethylenetriamine/nitroso-1-propylhydrazino)-1-propanamine (DETA/NO), streptozotocin (STZ), and hydrogen peroxide (H2O2). Furthermore, DETA/NO or STZ induced a rapid threonine phosphorylation of MEKK-1. Silencing of MEKK-1 gene expression in βTC-6 and human dispersed islet cells, using in vitro-generated diced small interfering RNA, resulted in protection from DETA/NO, STZ, H2O2, and tunicamycin induced cell death. Moreover, in DETA/NO-treated cells diced small interfering RNA-mediated down-regulation of MEKK-1 resulted in decreased activation of JNK but not p38 and ERK. Inhibition of JNK by treatment with SP600125 partially protected against DETA/NO- or STZ-induced cell death. In summary, our results support an essential role for MEKK-1 in JNK activation and stress-induced β-cell death. Increased understanding of the signaling pathways that augment or diminish β-cell MEKK-1 activity may aid in the generation of novel therapeutic strategies in the treatment of type 1 diabetes.

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