TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

Mori, Hitoe; Takahashi, Hirokazu; Mine, Keiichiro; Higashimoto, Ken; Inoue, Kanako; Kojima, Motoyasu; Kuroki, Shigetaka; Eguchi, Takahisa; Ono, Yasuhiro; Inuzuka, Sadataka; Soejima, Hidenobu; Nagafuchi, Seiho; Anzai, Keizo

doi:10.3390/genes12030400

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…IFNα, a type 1 interferon, induces HLA class I expression, ER stress markers, and inflammation in human β cells, and acts in coordination with IL-1β to elicit β-cell death [180]. Polymorphisms in TYK2, a type I interferon receptor signaling molecule, confer risk for the development of diabetes [181]. Mice carrying a mutant Tyk2 fail to respond to type I interferon appropriately, leading to a failed β-cell antiviral response and sensitization to virus-induced diabetes [182].…”

Section: Ifnγ and Ifnα Signaling In β-Cell Deathmentioning

confidence: 99%

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

et al. 2021

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β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.

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Section: Ifnγ and Ifnα Signaling In β-Cell Deathmentioning

confidence: 99%

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

et al. 2021

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“…The TYK2 gene located in 19p13.2 is associated with the cytoplasmic domain of type I and type II cytokine receptors, and is a component of both the type I and type III interferon signaling pathways [ 60 , 61 ]. The TYK2 gene has a critical importance in the etiology of autoimmune and inflammatory diseases, specifically type 1 and type 2 diabetes, due to its association with the pancreatic β-cell-specific suppression of cytokine response including IFN [ 61 , 62 , 63 , 64 , 65 ].…”

Section: Resultsmentioning

confidence: 99%

Whole-Exome Sequencing in Family Trios Reveals De Novo Mutations Associated with Type 1 Diabetes Mellitus

Mousa

Albarguthi

Albreiki

et al. 2023

Biology

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Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by insulin deficiency and loss of pancreatic islet β-cells. The objective of this study is to identify de novo mutations in 13 trios from singleton families that contribute to the genetic basis of T1DM through the application of whole-exome sequencing (WES). Of the 13 families sampled for this project, 12 had de novo variants, with Family 7 having the highest number (nine) of variants linked to T1DM/autoimmune pathways, whilst Family 4 did not have any variants past the filtering steps. There were 10 variants of 7 genes reportedly associated with T1DM (MST1; TDG; TYRO3; IFIHI; GLIS3; VEGFA; TYK2). There were 20 variants of 13 genes that were linked to endocrine, metabolic, or autoimmune diseases. Our findings demonstrate that trio-based WES is a powerful approach for identifying new candidate genes for the pathogenesis of T1D. Genotyping and functional annotation of the discovered de novo variants in a large cohort is recommended to ascertain their association with disease pathogenesis.

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“…Mediating interferon response in connection to resistance to various infections Mediating Th1-and Th17-type immune reactions [50,58,59] UBASH3A Downregulating the NF-kB signalling pathway upon T cell receptor stimulation, thus reducing the IL2 expression [46,60] A genetic link between T1D and T2D is of special interest as the associated loci for them were thought to be almost completely separated despite the partially shared phenotype. Newer studies, however, found several shared risk genes or genetic polymorphisms [59,[61][62][63][64]. Some of the genes located in shared risk loci interact to mutually regulate important islet functions that are disturbed by disease-associated variants, leading to β-cell dysfunction [61].…”

Section: Regulating the Effects Of Cytokines Inside β-Cells For Proap...mentioning

confidence: 99%

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

Zajec

Podkrajšek

Tesovnik

et al. 2022

Genes

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Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease.

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TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

Cited by 9 publications

References 44 publications

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Whole-Exome Sequencing in Family Trios Reveals De Novo Mutations Associated with Type 1 Diabetes Mellitus

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

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