scholarly journals CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis

2016 ◽  
Vol 30 (4) ◽  
pp. 446-454 ◽  
Author(s):  
T. Gurlo ◽  
J. F. Rivera ◽  
A. E. Butler ◽  
M. Cory ◽  
J. Hoang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Protein Misfolding ◽  
Nuclear Translocation ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Islet Amyloid

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP−/− mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

scholarly journals β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition

2011 ◽  
Vol 178 (6) ◽  
pp. 2632-2640 ◽  
Author(s):  
Catherine A. Jurgens ◽  
Mirna N. Toukatly ◽  
Corinne L. Fligner ◽  
Jayalakshmi Udayasankar ◽  
Shoba L. Subramanian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Type

scholarly journals Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis

2008 ◽  
Vol 29 (3) ◽  
pp. 303-316 ◽  
Author(s):  
Leena Haataja ◽  
Tatyana Gurlo ◽  
Chang J. Huang ◽  
Peter C. Butler
Keyword(s):  
Type 2 Diabetes ◽  
Neurodegenerative Diseases ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloidogenic Proteins ◽  
Toxic Oligomer

Abstract Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of β-cell mass with increased β-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic β-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. In this review we discuss emerging evidence to suggest that formation of intracellular IAPP oligomers may contribute to β-cell loss in T2DM. The accumulated evidence permits the amyloid hypothesis originally developed for neurodegenerative diseases to be reformulated as the toxic oligomer hypothesis. However, as in neurodegenerative diseases, it remains unclear exactly why amyloidogenic proteins form oligomers in vivo, what their exact structure is, and to what extent these oligomers play a primary or secondary role in the cytotoxicity in what are now often called unfolded protein diseases.

scholarly journals A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
Author(s):  
Xiao-Ting Huang ◽  
Shao-Jie Yue ◽  
Chen Li ◽  
Yan-Hong Huang ◽  
Qing-Mei Cheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Stimulation Of ◽  
Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

Managing the β-cell with GLP-1 in type 2 diabetes

2008 ◽  
Vol 8 (2_suppl) ◽  
pp. S19-S25 ◽  
Author(s):  
Baptist Gallwitz
Keyword(s):  
Type 2 Diabetes ◽  
Phase Ii ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Neonatal Rat ◽  
Β Cell ◽  
Β Cell Function

The clinical course of type 2 diabetes mellitus is characterised by a progressive decline in β -cell mass. The changing β-cell mass reflects a shifting balance between β-cell neogenesis, islet neogenesis and β-cell apoptosis. In persons with diabetes, administration of exogenous glucagon-like peptide-1 (GLP-1) improves glucose sensitivity and insulin synthesis and may help increase β cell mass. As the effects of GLP-1 on the β cell are becoming better understood at both the molecular and cellular levels, it has become possible to develop therapies with the potential to harness and sustain the positive effects of endogenous GLP-1 in patients with type 2 diabetes. Data from in vitro, preclinical and phase II studies show promising results with GLP-1 analogues in improving β-cell function in patients with type 2 diabetes. For example, in vitro models have shown the GLP-1 analogue liraglutide inhibits β-cell apoptosis in isolated neonatal rat islets. In vitro, animal models demonstrate increasing β-cell mass with liraglutide administration. Results from a recently completed phase II clinical trial with liraglutide in patients with type 2 diabetes demonstrate that daily treatment markedly improves β -cell function as shown by an increased first-phase insulin response and secretory capacity and a decreased proinsulin:insulin ratio. Now, phase III trials continue to bear out the potential for liraglutide for treatment of patients with type 2 diabetes.Br J Diabetes Vasc Dis 2008;8 (Suppl 2): S19-S25

Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 348-352 ◽  
Author(s):  
Miriam Cnop
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction

The prevalence of Type 2 diabetes is increasing dramatically as a result of the obesity epidemic, and poses a major health and socio-economic burden. Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin secretion. This insulin deficiency results from pancreatic β-cell dysfunction and death. Western diets rich in saturated fats cause obesity and insulin resistance, and increase levels of circulating NEFAs [non-esterified (‘free’) fatty acids]. In addition, they contribute to β-cell failure in genetically predisposed individuals. NEFAs cause β-cell apoptosis and may thus contribute to progressive β-cell loss in Type 2 diabetes. The molecular pathways and regulators involved in NEFA-mediated β-cell dysfunction and apoptosis are beginning to be understood. We have identified ER (endoplasmic reticulum) stress as one of the molecular mechanisms implicated in NEFA-induced β-cell apoptosis. ER stress was also proposed as a mechanism linking high-fat-diet-induced obesity with insulin resistance. This cellular stress response may thus be a common molecular pathway for the two main causes of Type 2 diabetes, namely insulin resistance and β-cell loss. A better understanding of the molecular mechanisms contributing to pancreatic β-cell loss will pave the way for the development of novel and targeted approaches to prevent Type 2 diabetes.

scholarly journals A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1593
Author(s):  
Phyu-Phyu Khin ◽  
Jong-Han Lee ◽  
Hee-Sook Jun
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Dedifferentiation Process

Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

scholarly journals DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

2012 ◽  
Vol 49 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Shinobu Shimizu ◽  
Tetsuya Hosooka ◽  
Tomokazu Matsuda ◽  
Shun-ichiro Asahara ◽  
Maki Koyanagi-Kimura ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Serum Concentration ◽  
Er Stress ◽  
Cell Mass ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4

The development of type 2 diabetes is accompanied by a progressive decline in β-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on β cells was studied in diabetic mice. Diabetic pancreatic β cell-specific C/EBPB transgenic (TG) mice exhibit decreased β-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on β cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased β-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in β cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in β cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic β cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.

Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide

2007 ◽  
Vol 293 (6) ◽  
pp. E1656-E1662 ◽  
Author(s):  
Chang-jiang Huang ◽  
Leena Haataja ◽  
Tatyana Gurlo ◽  
Alexandra E. Butler ◽  
Xiuju Wu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Cell Mass ◽  
Islet Amyloid Polypeptide ◽  
Protein Overexpression ◽  
Β Cell ◽  
Islet Amyloid

The islet in type 2 diabetes is characterized by an ∼60% β-cell deficit, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) but not rodent IAPP (rIAPP) forms toxic oligomers and amyloid fibrils in an aqueous environment. We previously reported that overexpression of hIAPP in transgenic rats triggered endoplasmic reticulum (ER) stress-induced apoptosis in β-cells. In the present study, we sought to establish whether the cytotoxic effects of hIAPP depend on its propensity to oligomerize, rather than as a consequence of protein overexpression. To accomplish this, we established a novel homozygous mouse model overexpressing rIAPP at a comparable expression rate and, on the same background, as a homozygous transgenic hIAPP mouse model previously reported to develop diabetes associated with β-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in β-cell mass due to increased β-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased β-cell mass. Both rIAPP and hIAPP transgenic mice have increased expression of BiP, but only hIAPP transgenic mice have elevated ER stress markers (X-box-binding protein-1, nuclear localized CCAAT/enhancer binding-protein homologous protein, active caspase-12, and accumulation of ubiquitinated proteins). These findings indicate that the β-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.

scholarly journals Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

2021 ◽  
Author(s):  
Hung Tae Kim ◽  
Arnaldo H. de Souza ◽  
Heidi Umhoefer ◽  
JeeYoung Han ◽  
Lucille Anzia ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Mass ◽  
Human Islets ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cell

AbstractLoss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of both type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. Now, we demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.One Sentence SummaryCholecystokinin ameliorates pancreatic β-cell death under models of stress and after transplant of human islets.

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