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 Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3462-3468 ◽  
Author(s):  
Meghan F. Hogan ◽  
Daniel T. Meier ◽  
Sakeneh Zraika ◽  
Andrew T. Templin ◽  
Mahnaz Mellati ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Insulin Degrading Enzyme ◽  
Β Cell ◽  
Islet Amyloid ◽  
Degrading Enzyme ◽  
Human Type

Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.

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.

Up-Regulated Pancreatic Tissue MicroRNA-375 Associates With Human Type 2 Diabetes Through β-Cell Deficit and Islet Amyloid Deposition

Pancreas ◽  
2010 ◽  
Vol 39 (6) ◽  
pp. 843-846 ◽  
Author(s):  
Hailu Zhao ◽  
Jing Guan ◽  
Heung-Man Lee ◽  
Yi Sui ◽  
Lan He ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Tissue ◽  
Amyloid Deposition ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Type

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 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 Ameliorative Effect and Mechanism of the Purified Anthraquinone-Glycoside Preparation from Rheum Palmatum L. on Type 2 Diabetes Mellitus

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1454 ◽  
Author(s):  
Fang-Rong Cheng ◽  
Hong-Xin Cui ◽  
Ji-Li Fang ◽  
Ke Yuan ◽  
Ying Guo
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Blood Glucose ◽  
Cell Apoptosis ◽  
Fasting Blood Glucose ◽  
Β Cell ◽  
Diabetes Mellitus Group ◽  
Rheum Palmatum

Rheum palmatum L. is a traditional Chinese medicine with various pharmacological properties, including anti-inflammatory, antibacterial, and detoxification effects. In this study, the mechanism of the hypoglycemic effect of purified anthraquinone-Glycoside from Rheum palmatum L. (PAGR) in streptozotocin (STZ) and high-fat diet induced type 2 diabetes mellitus (T2DM) in rats was investigated. The rats were randomly divided into normal (NC), T2DM, metformin (Met), low, middle (Mid), and high (Hig) does of PAGR groups. After six weeks of continuous administration of PAGR, the serum indices and tissue protein expression were determined, and the pathological changes in liver, kidney, and pancreas tissues were observed. The results showed that compared with the type 2 diabetes mellitus group, the fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) levels in the serum of rats in the PAGR treatment groups were significantly decreased, while superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels were noticeably increased. The expression of Fas ligand (FasL), cytochrome C (Cyt-c), and caspase-3 in pancreatic tissue was obviously decreased, and the pathological damage to the liver, kidney, and pancreas was improved. These indicate that PAGR can reduce oxidative stress in rats with diabetes mellitus by improving blood lipid metabolism and enhancing their antioxidant capacity, thereby regulating the mitochondrial apoptotic pathway to inhibitβ-cell apoptosis and improve β-cell function. Furthermore, it can regulate Fas/FasL-mediated apoptosis signaling pathway to inhibit β-cell apoptosis, thereby lowering blood glucose levels and improving T2DM.

scholarly journals Boolean network modeling of β-cell apoptosis and insulin resistance in type 2 diabetes mellitus

2019 ◽  
Vol 13 (S2) ◽  
Author(s):  
Pritha Dutta ◽  
Lichun Ma ◽  
Yusuf Ali ◽  
Peter M.A. Sloot ◽  
Jie Zheng
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cell Apoptosis ◽  
Boolean Network ◽  
Network Modeling ◽  
Β Cell

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.

The β-Cell in Human Type 2 Diabetes

2010 ◽  
pp. 501-514 ◽  
Author(s):  
Piero Marchetti ◽  
Roberto Lupi ◽  
Silvia Del Guerra ◽  
Marco Bugliani ◽  
Lorella Marselli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Β Cell ◽  
Human Type
Sign in / Sign up

Export Citation Format

Share Document