scholarly journals Increased  -Cell Apoptosis Prevents Adaptive Increase in  -Cell Mass in Mouse Model of Type 2 Diabetes: Evidence for Role of Islet Amyloid Formation Rather Than Direct Action of Amyloid

Diabetes ◽  
2003 ◽  
Vol 52 (9) ◽  
pp. 2304-2314 ◽  
Author(s):  
A. E. Butler ◽  
J. Janson ◽  
W. C. Soeller ◽  
P. C. Butler
Keyword(s):  
Type 2 Diabetes ◽  
Mouse Model ◽  
Cell Apoptosis ◽  
Direct Action ◽  
Cell Mass ◽  
Amyloid Formation ◽  
Islet Amyloid

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.

PS18 - 90. Role of tPA in islet amyloid formation and beta cell (dys)function in type 2 diabetes mellitus (DM2)

2011 ◽  
Vol 9 (3) ◽  
pp. 153-153
Author(s):  
Anghelus Ostroveanu ◽  
Mariette Sprong ◽  
Jet Jacobs ◽  
Martijn Gebbink ◽  
Jo W.M. Höppener
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Beta Cell ◽  
Amyloid Formation ◽  
Islet Amyloid

Dual role of interleukin-1β in islet amyloid formation and its β-cell toxicity: Implications for type 2 diabetes and islet transplantation

2017 ◽  
Vol 19 (5) ◽  
pp. 682-694 ◽  
Author(s):  
Yoo Jin Park ◽  
Garth L. Warnock ◽  
Ziliang Ao ◽  
Nooshin Safikhan ◽  
Mark Meloche ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Islet Transplantation ◽  
Dual Role ◽  
Interleukin 1Β ◽  
Amyloid Formation ◽  
Cell Toxicity ◽  
Β Cell ◽  
Islet Amyloid

scholarly journals Development of a Nongenetic Mouse Model of Type 2 Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Elizabeth R. Gilbert ◽  
Zhuo Fu ◽  
Dongmin Liu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Serum Insulin ◽  
Cell Mass ◽  
Low Fat ◽  
Β Cell ◽  
Islet Mass ◽  
Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

scholarly journals THE ROLE OF SURVIVIN AND RAF-1 KINASE AGAINST ENHANCEMENT OF PANCREATIC BETA-CELL APOPTOSIS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

2018 ◽  
Vol 11 (11) ◽  
pp. 344
Author(s):  
Eva Decroli ◽  
Asman Manaf ◽  
Syafril Syahbuddin ◽  
Sarwono Waspadji ◽  
Dwisari Dillasamola
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Beta Cell ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Beta Cell Apoptosis

Objective: This study aimed to reveal differences in levels of survivin and Raf-1 kinase in prediabetes, controlled Type 2 diabetes mellitus (T2DM), uncontrolled T2DM, and their relationship with hemoglobin A1c (HbA1c) levels and serum triglyceride levels.Methods: This study was an observational study with a cross-sectional design. The study involved 60 people with T2DM who visited the endocrine and metabolic clinic and 30 prediabetes patients. The variables were survivin levels and Raf-1 kinase enzymes that examined using enzyme-linked immunosorbent assay techniques. HbA1c values are measured by high-performance liquid chromatography and triglyceride levels measured by enzymatic method.Results: Average levels of Raf-1 kinase were significantly higher in the prediabetes group, controlled T2DM, and uncontrolled T2DM (11.6±1.4 pg mL, 9.9±1.1 pg/mL, and 9.1±1.5 pg/mL). Survivin was significantly higher in the prediabetes group, controlled T2DM, and uncontrolled T2DM (5.4±0.4 pg mL, 5.0±0.2 pg/mL, and 4.7±0.1 pg/mL). There was no correlation between HbA1c with Raf-1 kinase levels (R=−0.215, p=0.250), but there was a correlation between HbA1c with serum survivin levels (R=−0.6, *p<0.05). There was a correlation between the levels of triglycerides with survivin but not with Raf-1 kinase (R=−0.267, *p=0.039).Conclusion: Survivin and Raf-1 kinase levels are lower in uncontrolled T2DM. This explained the role of survivin and Raf-1 kinase against enhancement of pancreatic beta-cell apoptosis in patients with T2DM.

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

scholarly journals A Novel Mouse Model for Type 2 Diabetes and Non-alcoholic Fatty Liver Disease: Spontaneous Amelioration of Diabetes by Augmented Beta Cell Mass

2009 ◽  
Vol 56 (2) ◽  
pp. 227-234 ◽  
Author(s):  
Aya OZE-FUKAI ◽  
Tomomi FUJISAWA ◽  
Ken SUGIMOTO ◽  
Koji NOJIMA ◽  
Nobuyasu SHINDO ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Liver Disease ◽  
Mouse Model ◽  
Beta Cell ◽  
Fatty Liver Disease ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease
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