scholarly journals The Role of GAD65 Autoantibodies in the development of Type-1 Diabetes

2021 ◽  
Vol 36 (3) ◽  
pp. 103-106
Author(s):  
Sri R. Prasetyo
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
Islet Cells ◽  
Gaba Release ◽  
Fine Tuning ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Key Enzyme ◽  
Type 1Diabetes

AbstractThe finding of the autoantibodies to islet cells (ICAs) in type-1 diabetes patients is important for developing the fine tuning of individualized therapy. Antibody to Glutamate decarboxylase 2 (GAD65Ab) is the most reliable sign, since it has the most stable sensitivity as diagnostic tool for detecting type-1diabetes. As a key enzyme in gamma-Aminobutyric acid (GABA) synthesis, GAD65 damage caused by GAD65 antibodies (GAD65Abs) would lead to decrease in the amount of GABA vesicles released by b-cells. Decrease of GAD65 induced by GAD65Ab may endanger the paracrine or autocrine function of GABA, that mediated by γ-aminobutyric acid type A receptors (GABAAR) would depolarized the b-cells. The depolarization then increases intracellular Calsium (Ca2+) concentration that is needed for insulin release. The effect of GABA on b-cells is also important for proliferation and anti-apoptosis of b-cells. Moreover, decrease in GABA release also impairs the inhibiting effect of GABA on T-cell proliferation and inflammatory cytokines release that may end up with escalation of GAD65 damage.Keywords: Type-1 diabetes, autoantibody, GAD65Peran Autoantibodi GAD65 dalam Perkembangan Diabetes Tipe-1AbstractPenemuan autoantibodi terhadap sel pulau atau islet cells (ICA) pada pasien diabetes tipe-1 penting untuk mengembangkan penyesuaian terapi individual. Antibodi terhadap Glutamat dekarboksilase 2 (GAD65Ab) adalah tanda yang paling dapat diandalkan, karena memiliki sensitivitas yang paling stabil sebagai alat diagnostik untuk mendeteksi diabetes tipe-1. Sebagai enzim kunci dalam sintesis asam gamma-aminobutirat (GABA), kerusakan GAD65 yang disebabkan oleh antibodi GAD65 (GAD65Abs) akan menyebabkan penurunan jumlah vesikel GABA yang dilepaskan oleh sel. Penurunan GAD65 yang diinduksi oleh GAD65Ab dapat membahayakan fungsi parakrin atau autokrin GABA, yang dimediasi oleh reseptor asam γ-aminobutirat tipe A (GABAAR) akan mendepolarisasi sel. Depolarisasi kemudian meningkatkan konsentrasi kalsium (Ca2+) intraseluler yang diperlukan untuk pelepasan insulin. Efek GABA pada sel beta juga penting untuk proliferasi dan anti-apoptosis sel beta. Selain itu, penurunan pelepasan GABA juga merusak efek penghambatan GABA pada proliferasi sel T dan pelepasan sitokin inflamasi yang mungkin berakhir dengan peningkatan kerusakan GAD65.Kata kunci: Diabetes tipe-1, autoantibodi, GAD65

scholarly journals TLR9-Deficiency in B Cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

Diabetes ◽  
2020 ◽  
pp. db200373
Author(s):  
Sha Sha ◽  
James A Pearson ◽  
Jian Peng ◽  
Youjia Hu ◽  
Juan Huang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
Mouse Model ◽  
Immune Tolerance ◽  
Diabetes Mouse

scholarly journals The Feasibility and Applicability of Stem Cell Therapy for the Cure of Type 1 Diabetes

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1589
Author(s):  
Ryota Inoue ◽  
Kuniyuki Nishiyama ◽  
Jinghe Li ◽  
Daisuke Miyashita ◽  
Masato Ono ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Islet Cells ◽  
Autologous Transplantation ◽  
Insulin Injection ◽  
Islet Cell Transplantation ◽  
The Impact

Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

scholarly journals Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes

2021 ◽  
Author(s):  
Monica Westley ◽  
Tiffany Richardson ◽  
Suhana Bedi ◽  
Baofeng Jia ◽  
Fiona S.L. Brinkman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Gut Microbiome ◽  
Pancreatic Beta Cells ◽  
Acid Decarboxylase ◽  
Host Immune System ◽  
Gamma Aminobutyric Acid ◽  
Human Gut ◽  
Autoimmune Attack

Abstract    A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.

MicroRNAs and Diabetes Mellitus Type 1

2021 ◽  
Vol 17 ◽  
Author(s):  
Farbod Bahreini ◽  
Elham Rayzan ◽  
Nima Rezaei
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Early Detection ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Islet Cells ◽  
Diabetes Mellitus Type 1 ◽  
Complementary Sequence ◽  
Multiple Organs

: Type 1 diabetes mellitus is a multifactorial, progressive, autoimmune disease with a strong genetic feature that can affect multiple organs, including kidney, eyes, and nerves. Early detection of type 1 diabetes can help critically to avoid serious damages to these organs. MicroRNAs are small RNA molecules that act in post-transcriptional gene regulation by attaching to the complementary sequence in the 3'-untranslated region of their target genes. Alterations in the expression of microRNA coding genes are extensively reported in several diseases such as type 1 diabetes. Presenting non-invasive biomarkers for early detection of type 1 diabetes by quantifying microRNAs gene expression level can be an influential step in biotechnology and medicine. This review discusses the area of microRNAs dysregulation in type 1 diabetes and affected molecular mechanisms involved in pancreatic islet cells formation and dysregulation in the expression of inflammatory elements as well as pro-inflammatory cytokines.

scholarly journals Effects of γ-Aminobutyric Acid A Receptor Activation on Counterregulatory Responses to Subsequent Exercise in Individuals With Type 1 Diabetes

Diabetes ◽  
2016 ◽  
Vol 65 (9) ◽  
pp. 2754-2759 ◽  
Author(s):  
Maka S. Hedrington ◽  
Maia Mikeladze ◽  
Donna B. Tate ◽  
Lisa M. Younk ◽  
Ian Davis ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Receptor Activation ◽  
Aminobutyric Acid

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

scholarly journals Regulated hAAT Expression from a Novel rAAV Vector and Its Application in the Prevention of Type 1 Diabetes

2019 ◽  
Vol 8 (9) ◽  
pp. 1321 ◽  
Author(s):  
Hongxia Ma ◽  
Yuanqing Lu ◽  
Keith Lowe ◽  
Lonneke van der Meijden-Erkelens ◽  
Clive Wasserfall ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transgene Expression ◽  
Viral Vectors ◽  
Fine Tuning ◽  
Vector System ◽  
Regulation System ◽  
Raav Vector

We, and others, have previously achieved high and sustained levels of transgene expression from viral vectors, such as recombinant adeno-associated virus (rAAV). However, regulatable transgene expression may be preferred in gene therapy for diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis (RA), in which the timing and dosing of the therapeutic gene product play critical roles. In the present study, we generated a positive feedback regulation system for human alpha 1 antitrypsin (hAAT) expression in the rAAV vector. We performed quantitative kinetics studies in vitro and in vivo demonstrating that this vector system can mediate high levels of inducible transgene expression. Transgene induction could be tailored to occur rapidly or gradually, depending on the dose of the inducing drug, doxycycline (Dox). Conversely, after withdrawal of Dox, the silencing of transgene expression occurred slowly over the course of several weeks. Importantly, rAAV delivery of inducible hAAT significantly prevented T1D development in non-obese diabetic (NOD) mice. These results indicate that this Dox-inducible vector system may facilitate the fine-tuning of transgene expression, particularly for hAAT treatment of human autoimmune diseases, including T1D.

GABA release in posterior hypothalamus across sleep-wake cycle

1996 ◽  
Vol 271 (6) ◽  
pp. R1707-R1712 ◽  
Author(s):  
D. Nitz ◽  
J. M. Siegel
Keyword(s):  
Receptor Agonist ◽  
High Performance ◽  
Slow Wave Sleep ◽  
Gaba Release ◽  
Posterior Hypothalamus ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Rapid Eye Movement Sleep ◽  
Unit Discharge ◽  
Selective Increase

The activity of neurons in the posterior hypothalamus (PH) is thought to contribute to the production of wakefulness and electroencephalograph desynchronization. Inactivation of neuronal activity in this area is known to induce sleep. Most PH neurons decrease unit discharge during slow-wave sleep (SWS) relative to wake and rapid eye movement sleep. In the present study, we sought to examine potential sources of inhibition or disfacilitation underlying the reduction of PH unit activity during SWS in the cat. We employed the microdialysis technique in conjunction with high-performance liquid chromatography methods for the quantification of glutamate, glycine, and gamma-aminobutyric acid (GABA) release. We found a selective increase in GABA release during SWS in the PH. Glutamate and glycine levels were unchanged across the sleep-wake cycle. microinjection of the GABAA-receptor agonist muscimol, into the same areas from which microdialysis samples were collected, increased SWS time. Our studies support the hypothesis that GABA release in the posterior hypothalamus mediates inhibition of posterior hypothalamic neurons, thereby facilitating SWS.

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