scholarly journals Loss of XBP1 Leads to Early-Onset Retinal Neurodegeneration in a Mouse Model of Type I Diabetes

2019 ◽  
Vol 8 (6) ◽  
pp. 906 ◽  
Author(s):  
Todd McLaughlin ◽  
Manhal Siddiqi ◽  
Joshua J. Wang ◽  
Sarah X. Zhang
Keyword(s):  
Mouse Model ◽  
Er Stress ◽  
Early Onset ◽  
Type I Diabetes ◽  
Neuronal Survival ◽  
Type I ◽  
Protein Homeostasis ◽  
Retinal Neurons ◽  
And Function

Retinal neuronal injury and degeneration is one of the primary manifestations of diabetic retinopathy, a leading cause of vision loss in working age adults. In pathological conditions, including diabetes and some physiological conditions such as aging, protein homeostasis can become disrupted, leading to endoplasmic reticulum (ER) stress. Severe or unmitigated ER stress can lead to cell death, which in retinal neurons results in irreversible loss of visual function. X-box binding protein 1 (XBP1) is a major transcription factor responsible for the adaptive unfolded protein response (UPR) to maintain protein homeostasis in cells undergoing ER stress. The purpose of this study is to determine the role of XBP1-mediated UPR in retinal neuronal survival and function in a mouse model of type 1 diabetes. Using a conditional retina-specific XBP1 knockout mouse line, we demonstrate that depletion of XBP1 in retinal neurons results in early onset retinal function decline, loss of retinal ganglion cells and photoreceptors, disrupted photoreceptor ribbon synapses, and Müller cell activation after induction of diabetes. Our findings suggest an important role of XBP1-mediated adaptive UPR in retinal neuronal survival and function in diabetes.

scholarly journals ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2066
Author(s):  
Bianca A. Meyer ◽  
Shirin Doroudgar
Keyword(s):  
Er Stress ◽  
Protein Secretion ◽  
Secretory Pathway ◽  
Cell Types ◽  
Protein Homeostasis ◽  
Cell Type ◽  
Select Group ◽  
And Function ◽  
Review Current

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled “The Role of Proteostasis Derailment in Cardiac Diseases.”

The Role of Interferon-α in the Development of Type I Diabetes

1996 ◽  
pp. 154-166
Author(s):  
Xiaojian Huang ◽  
Bruce Hultgren ◽  
Sharon Pitts-Meek ◽  
Jim Hully ◽  
Jim Maclachlan ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Interferon Α ◽  
Type I

scholarly journals The Role of Type I Diabetes in Intervertebral Disc Degeneration

Spine ◽  
2019 ◽  
Vol 44 (17) ◽  
pp. 1177-1185 ◽  
Author(s):  
Fabrizio Russo ◽  
Luca Ambrosio ◽  
Kevin Ngo ◽  
Gianluca Vadalà ◽  
Vincenzo Denaro ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Type I Diabetes ◽  
Type I

Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans

1997 ◽  
Vol 272 (3) ◽  
pp. E371-E378 ◽  
Author(s):  
G. F. Lewis ◽  
M. Vranic ◽  
A. Giacca
Keyword(s):  
Type I Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Insulin Delivery ◽  
Suppressive Effect ◽  
Type I ◽  
Constant Rate ◽  
Hepatic Glucose ◽  
Infusion Method

The present study examines the role of glucagon in modulating the hepatic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng x kg(-1) x min(-1)) during equimolar portal and peripheral insulin delivery in seven healthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by approximately 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/- 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was suppressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinemic periods than when glucagon was infused during the basal period only; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). Tolbutamide had no effect on HGP when infused into three C-peptide-negative individuals with type I diabetes during a low-dose insulin and glucagon infusion. These data suggest that glucagon levels are an important determinant of the balance between insulin's direct and indirect effects on HGP, with glucagon likely potentiating the direct hepatic effect of insulin.

scholarly journals Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model

2010 ◽  
Vol 9 (1) ◽  
pp. 55 ◽  
Author(s):  
Peter E Westerweel ◽  
Cindy TJ van Velthoven ◽  
Tri Q Nguyen ◽  
Krista den Ouden ◽  
Dominique PV de Kleijn ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Type I Diabetes ◽  
Type I ◽  
Muscle Progenitor Cells ◽  
Diabetes Mouse

scholarly journals Cancer Biology and Prevention in Diabetes

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1380 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Julie E. Goodwin
Keyword(s):  
Type Ii Diabetes ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Type I Diabetes ◽  
Type I ◽  
Type Ii ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Risk Of Cancer

The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

The possible role of Coxsackie A and echo viruses in the pathogenesis of type I diabetes mellitus studied by IgM analysis

1992 ◽  
Vol 24 (1) ◽  
pp. 13-22 ◽  
Author(s):  
G. Frisk ◽  
E. Nilsson ◽  
T. Tuvemo ◽  
G. Friman ◽  
H. Diderholm
Keyword(s):  
Diabetes Mellitus ◽  
Type I Diabetes ◽  
Type I Diabetes Mellitus ◽  
Type I

scholarly journals Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway

2018 ◽  
Vol 47 (2) ◽  
pp. 579-589 ◽  
Author(s):  
Wei Li ◽  
Yaojun Lu ◽  
Ruijuan Han ◽  
Qiang Yue ◽  
Xiurong Song ◽  
...  
Keyword(s):  
Mouse Model ◽  
Progenitor Cells ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Cardiac Progenitor Cells ◽  
Cardiomyocyte Differentiation ◽  
Rt Pcr ◽  
And Function

Background/Aims: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. Methods: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. Results: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. Conclusions: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

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