Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Aston-Mourney, Kathryn; Proietto, Joseph; Morahan, Grant; Andrikopoulos, Sofianos

doi:10.1007/s00125-008-0930-2

Cited by 65 publications

(50 citation statements)

References 55 publications

(52 reference statements)

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“…The results in this work support the concept (Aston-Mourney et al 2008) that increased and sustained insulin levels that promote NADPH oxidase activity and ROS production may be detrimental to pancreatic β cell survival. Hence, induction of increased insulin secretion in patients with obesity and insulin resistance that are already hyperinsulinemic may actually accelerate the deterioration of pancreatic β cells, a consideration supported by the results presented in this report.…”

Section: :3supporting

confidence: 85%

“…In general, insulin acts as a growth factor that plays an antiapoptotic role and protects cells from death through activation of the PI3-kinase and ERK signaling pathways (Muller et al 2006, Jensen & De Meyts 2009, and insulin therapy can protect β cells from deterioration (Del Parigi 2008). It has been shown, however, that hypersecretion of insulin (insulin resistance) may precede β cell dysfunction and may be an important factor in the progression to β cell failure (Fernandez et al 2001, Aston-Mourney et al 2008, Lu et al 2010. Furthermore, in conditions of energy stress, hyperactivation of the mTORC1 complex, mediated by growth factors including insulin, may induce apoptosis (Gwinn et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic β cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic β cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic β cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100 nM) for 24 h selectively increased the production of ROS in pancreatic β cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time-and dose-dependent decrease in cellular reducing power of pancreatic β cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos. The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H 2 O 2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic β cells.

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Section: :3supporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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“…In addition, an excessive insulin signaling may provoke insulin resistance in the liver and muscle (Ueno et al, 2005) as well as -cell exhaustion (Aston-Mourney et al, 2008) and therefore, contributing to the development of type II diabetes (Figure 2). …”

Section: Physiological and Pathophysiological Consequences Of Er Up-mentioning

confidence: 99%

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

Nadal

Alonso-Magdalena

Soriano

et al. 2009

Molecular and Cellular Endocrinology

253

180

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. The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Molecular and Cellular Endocrinology, Elsevier, 2009, 304 (1-2) Please cite this article as: Nadal, A., Alonso-Magdalena, P., Soriano, S., Quesada, I., Ropero, A.B., The pancreatic ␤-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. THE PANCREATIC -CELL AS A TARGET OF ESTROGENS AND XENOESTROGENS: IMPLICATIONS FOR BLOOD GLUCOSE HOMEOSTASIS AND DIABETESAngel Rosen & Spiegelman, 2006;Fritsche et al., 2008). During the fasting state, insulin remains at low levels because plasma glucose concentration is low. In this situation, the levels of the counter-regulatory hormones, glucagon, adrenaline and corticosteroids are increased to promote hepatic glucose production. In contrast, insulin, the only hormone in the body able to decrease blood glucose levels, is increased during the fed state. Insulin decreases blood glucose by promoting adipocyte and muscle glucose uptake, as well as by preventing the liver from producing glucose by suppressing glycogenolysis and gluconeogenesis (Fritsche et al., 2008). neurotransmitters, hormones and nutrients, among which glucose is the most important.Normally, in response to short glucose stimulation, insulin biosynthesis is regulated by the increased translation of the preproinsulin transcript. After a prolonged glucose exposure, however, it is regulated via the insulin gene transcription (Orland et al., 1985;Permutt & Rotwein, 1983;Poitout et al., 2006). Both transcriptional and translational regulation of insulin biosynthesis is essential to maintain the intracellular stores of insulin on a long term basis.The secretory response of -cells depends on their electrical activity. This consists of oscillations of the membrane potential that range from electrically silent periods to depolarised plateaus on which Ca 2+ -action potentials originate (Rorsman et al., 2000).The classical stimulus-secretion coupling that drives insulin release involves the closure of K ATP channels by increasing the intracellular ATP/ADP ratio (Ashcroft et al., 1984) and diadenosine polyphosphates concentration (DPs) (Ripoll et al., 1996) oscillatory pattern is originated (Nadal et al., 1999;Santos et al., 1991;Valdeolmillos et al., 1989), which triggers a pulsatile insulin secretion (Barbosa et al., 1998;Gilon et al., 1993;Dyachok et al., 2008). Estrogens, estrogen receptors and blood glucose homeostasisT...

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“…In addition, while the effects of GLP1 on pancreatic hormone secretion are glucose dependent, which virtually eliminates the risk of hypoglycaemia, the actions of insulin and SUs are not dependent on elevated glucose levels, and thus therapies with these agents lead to much higher rates of hypoglycaemia. Furthermore, while non-glucose-dependent insulin secretagogues, such as SUs, may place excessive stress on pancreatic b-cells and potentially promote b-cell apoptosis (Maedler et al 2005, Takahashi et al 2007, Aston-Mourney et al 2008, incretins activate signalling pathways that provide protection against apoptosis (Trumper et al 2002, Hui et al 2003, Wang et al 2004. Preclinical studies in rodents have provided hope that enhancing GLP1R signalling may be able to halt the progressive decline in b-cell mass and perhaps even promote the growth of new b-cells in vivo (Xu et al 1999, Stoffers et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

Lamont

Andrikopoulos

2014

Journal of Endocrinology

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Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet b-cells and an increase in b-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase b-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic b-cells, but may be useful for preserving any remaining b-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

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Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Abstract: In many countries, first-or second-line pharma-

Cited by 65 publications

References 55 publications

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

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