المؤلفون: Katrin Moira Heim, Martin E. Kreis, Stefan Angermair, Fabian Halleck, Arne Sattler, Katja Kotsch, Helena Stockmann, Dmytro Khadzhynov, Sascha Treskatsch

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Cellular immunity, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), T cell, Programmed Cell Death 1 Receptor, Severity of Illness Index, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Intensive care, medicine, Humans, Aged, Aged, 80 and over, SARS-CoV-2, business.industry, Age Factors, COVID-19, General Medicine, T helper cell, Middle Aged, Th1 Cells, medicine.disease, Comorbidity, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Commentary, Interleukin-2, Female, Disease Susceptibility, business, Ex vivo

الوصف: Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e03688bab38d81eca8efbaf0e659dfaTest
https://doi.org/10.1172/jci140965Test

المؤلفون: Peng Li, Leqing Zhu, Liehua Deng, Zhizhong Li, Hua Zhang, Yueqi Song, Xichun Xia, Jianlei Hao, Xiao Wang, Chengbin Guo, Zhinan Yin, Guangchao Cao, Yixia Tian, Wei Zhou, Yunfei Gao, Jingxiang Zhong, Guodong Sun

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Keratinocytes, Male, 0301 basic medicine, Chemokine, Glutamine, Cellular differentiation, medicine.disease_cause, Autoimmunity, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Glutaminase, T-Lymphocyte Subsets, Psoriasis, medicine, Animals, Humans, RNA, Messenger, Histone H3 acetylation, Aged, Mice, Knockout, Glutaminolysis, biology, Chemistry, Interleukin-17, Cell Differentiation, General Medicine, Middle Aged, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, MALT1, 030104 developmental biology, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Case-Control Studies, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Th17 Cells, Female, IL17A, Metabolic Networks and Pathways, Research Article

الوصف: Psoriasis is a severe disease associated with the disturbance of metabolism and inflammation, but the molecular mechanisms underlying these aspects of psoriasis pathology are poorly understood. Here, we report that glutaminase 1–mediated (GLS1-mediated) glutaminolysis was aberrantly activated in patients with psoriasis and in psoriasis-like mouse models, which promoted Th17 and γδ T17 (IL-17A–producing γδ T) cell differentiation through enhancement of histone H3 acetylation of the Il17a promoter, thereby contributing to the immune imbalance and development of psoriasis. We further demonstrate that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease was constitutively active in psoriatic CD4(+) and γδ T cells, thereby supporting GLS1 expression by stabilizing c-Jun, which directly binds to the GLS1 promoter region. Blocking the activity of either GLS1 or MALT1 protease resolved Th17 and γδ T17 cell differentiation and epidermal hyperplasia in the psoriasis-like mouse models. Finally, IL-17A enhanced GLS1 expression via the MALT1/cJun pathway in keratinocytes, resulting in hyperproliferation of and chemokine production by keratinocytes. Our findings identify the role of the MALT1/cJun/GLS1/glutaminolysis/H3 acetylation/T17 axis in psoriasis pathogenesis and reveal potential therapeutic targets for this disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1f6d904955d64d82e287033ac565778Test
https://doi.org/10.1172/jci129269Test

المؤلفون: Lai Yee Cheong, Ruby L. C. Hoo, Xiaoyu Xiao, Yang Liu, Yang Xiao, Zhiguang Zhou, Boya Liao, Aimin Xu, Xiaoping Wu, Lingling Shu

المصدر: JCI Insight, Vol 6, Iss 7 (2021)
JCI Insight

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Adoptive cell transfer, T-Lymphocytes, Autoimmunity, medicine.disease_cause, Fatty Acid-Binding Proteins, Diabetes Mellitus, Experimental, 03 medical and health sciences, Islets of Langerhans, 0302 clinical medicine, Immune system, Endocrinology, Mice, Inbred NOD, Medicine, Animals, Humans, Benzothiazoles, NOD mice, Autoantibodies, Bone Marrow Transplantation, Innate immunity, Type 1 diabetes, geography, geography.geographical_feature_category, Innate immune system, business.industry, Macrophages, Diabetes, Autoantibody, General Medicine, Carbocyanines, Middle Aged, medicine.disease, Islet, Mice, Mutant Strains, 030104 developmental biology, Diabetes Mellitus, Type 1, 030220 oncology & carcinogenesis, Immunology, Female, business, Research Article

الوصف: Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level was significantly elevated in patients with type 1 diabetes and their first-degree relatives and positively correlated with the titers of several islet autoantibodies. In nonobese diabetic (NOD) mice, increased FABP4 expression in islet macrophages started from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice was markedly reduced by pharmacological inhibition or genetic ablation of FABP4 or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activated innate immune responses in islets by enhancing the infiltration and polarization of macrophages to proinflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells toward Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for β cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b49e44f810f16457012d14ea324cf550Test
https://doaj.org/article/4cae76f959a34aa7a137d440a57963ccTest

المؤلفون: John D. Port, Tiffany Cortes, Gregory N. Ruegsegger, Ana L. Creo, Andrea R.S. Huebner, Yogish C. Kudva, Aida N. Lteif, Katherine A. Klaus, Surendra Dasari, K. Sreekumaran Nair, Hang Joon Jo, Ronald C. Petersen, Jan Mendelt Tillema

المصدر: JCI Insight, Vol 6, Iss 5 (2021)
JCI Insight

مصطلحات موضوعية: Adult, Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Pilot Projects, Phosphocreatine, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Memory, Diabetes mellitus, Internal medicine, Fractional anisotropy, medicine, Insulin, Humans, Dementia, Cognitive Dysfunction, Sensory cortex, Translational Science, Biomedical, Type 1 diabetes, business.industry, Diabetes, Cognition, Somatosensory Cortex, General Medicine, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Medicine, Female, Clinical Medicine, business

الوصف: BACKGROUND Type 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function. METHODS We therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions. RESULTS Insulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition. CONCLUSION Transient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation. TRIAL REGISTRATION ClinicalTrials.gov NCT03392441. FUNDING Clinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df35e605fd35bca18e9e9717df343f45Test
https://doaj.org/article/89e91ea96c224a14803019bb961e2cc3Test

المؤلفون: Gissette Reyes-Soffer, Henry N. Ginsberg

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Apolipoprotein E, medicine.medical_specialty, endocrine system diseases, Coronary Artery Disease, Disease, Diabetes Mellitus, Experimental, Oligodeoxyribonucleotides, Antisense, Coronary artery disease, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Prospective Studies, Vascular Calcification, Triglycerides, Mice, Knockout, Apolipoprotein C-III, Type 1 diabetes, Lipoprotein lipase, business.industry, General Medicine, Middle Aged, Atherosclerosis, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Endocrinology, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Commentary, Female, Apolipoprotein C3, business, Research Article, Foam Cells

الوصف: Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency, rather than hyperglycemia, elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we examined the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic expression of Apoc3 in diabetic mice, resulting in lower levels of TRLs, without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibition of APOC3 might reduce CVD risk in patients with T1DM.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0749743924d73a885f0d02c9ccc83a9bTest
https://doi.org/10.1172/jci131333Test

المؤلفون: Mark Harris, Ranjeny Thomas, Martin J. Hessner, Rhonda Geoffrey, Anne-Sophie Bergot, Breanna Lam, Kerry Buchanan, Elisavet Serti, Rosita Moya, Alessandra Mandelli, Irene Gotuzzo, Manuela Battaglia, Joanna D. Davies, Aditi Narsale, Benedetta Pessina, Gian Maria Giamporcaro, TingTing Lu

المصدر: JCI Insight, Vol 6, Iss 2 (2021)
JCI Insight

مصطلحات موضوعية: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Oncology, Autoimmune diseases, medicine.medical_treatment, Cell, Autoimmunity, medicine.disease_cause, 0302 clinical medicine, T-Lymphocyte Subsets, IL-2 receptor, Child, education.field_of_study, Diabetes, General Medicine, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Disease Progression, Medicine, Female, Immunotherapy, Research Article, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Population, Immunology, T cells, Alefacept, Interleukin-7 Receptor alpha Subunit, Young Adult, 03 medical and health sciences, Diabetes mellitus, Internal medicine, medicine, Humans, education, Proportional Hazards Models, Type 1 diabetes, business.industry, Interleukin-2 Receptor alpha Subunit, Infant, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Multivariate Analysis, business

الوصف: Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain β cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, β cell survival, and response to antiinflammatory immunotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b18ca9272dda4aa45bece327b8ae55f8Test
https://doaj.org/article/20ba8c4ce6b4454ea7c69dca229e3557Test

المؤلفون: Maria Fernandez Rubin De Celis, Diane Mathis, Archana Vijayakumar, Pedro M. Moraes-Vieira, Dionicio Siegel, Alan Saghatelian, Ismail Syed, James F. Mohan, Barbara B. Kahn, Andrew T. Nelson

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, endocrine system, medicine.medical_specialty, endocrine system diseases, Cell Survival, T-Lymphocytes, T cell, Palmitic Acid, Nod, Diabetes Mellitus, Experimental, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Mice, Inbred NOD, Insulin-Secreting Cells, Internal medicine, medicine, Animals, Humans, Insulin, B cell, Aged, NOD mice, Cell growth, Chemistry, Esters, General Medicine, Glucose Tolerance Test, Middle Aged, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Immune System, 030220 oncology & carcinogenesis, Commentary, Female, Insulitis, Stearic Acids, CD8

الوصف: Palmitic acid esters of hydroxy stearic acids (PAHSAs) are endogenous antidiabetic and antiinflammatory lipids. Here, we show that PAHSAs protect against type 1 diabetes (T1D) and promote β cell survival and function. Daily oral PAHSA administration to nonobese diabetic (NOD) mice delayed the onset of T1D and markedly reduced the incidence of T1D, whether PAHSAs were started before or after insulitis was established. PAHSAs reduced T and B cell infiltration and CD4+ and CD8+ T cell activation, while increasing Treg activation in pancreata of NOD mice. PAHSAs promoted β cell proliferation in both NOD mice and MIN6 cells and increased the number of β cells in NOD mice. PAHSAs attenuated cytokine-induced apoptotic and necrotic β cell death and increased β cell viability. The mechanism appears to involve a reduction of ER stress and MAPK signaling, since PAHSAs lowered ER stress in NOD mice, suppressed thapsigargin-induced PARP cleavage in human islets, and attenuated ERK1/2 and JNK1/2 activation in MIN6 cells. This appeared to be mediated in part by glucagon-like peptide 1 receptor (GLP-1R) and not the G protein-coupled receptor GPR40. PAHSAs also prevented impairment of glucose-stimulated insulin secretion and improved glucose tolerance in NOD mice. Thus, PAHSAs delayed the onset of T1D and reduced its incidence by attenuating immune responses and exerting direct protective effects on β cell survival and function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::499e34da0668ce296976fc5094ee51f3Test
https://doi.org/10.1172/jci122445Test

المؤلفون: Shufeng Li, Annette Bakker, Kavita Y. Sarin, Mika M. Tabata, Pamela Knight

المصدر: JCI Insight, Vol 5, Iss 16 (2020)
JCI Insight

مصطلحات موضوعية: 0301 basic medicine, Adult, Pathology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Neurofibromatosis 1, Adolescent, Malignant peripheral nerve sheath tumor, Comorbidity, Dermatology, Spinal neurofibromas, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Prevalence, Neurofibroma, Humans, Genetic variation, Registries, Neurofibromatosis, neoplasms, Aged, Neurofibromin 1, business.industry, Genetic heterogeneity, Genetic disorder, General Medicine, Phenotypic trait, Middle Aged, medicine.disease, nervous system diseases, 030104 developmental biology, Phenotype, Dysplasia, 030220 oncology & carcinogenesis, Mutation, Medicine, business, Neurological disorders, Research Article, Genetic diseases, Neuroscience

الوصف: Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children’s Tumor Foundation’s NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.
A large clinical phenotypic co-association and cluster analyses is reported for 2051 adult patients with Neurofibromatosis Type 1.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6b2985be0c1f54c8a1ca7f5cb518d27dTest
https://doaj.org/article/097c0850c842415abb2e9486dc716821Test

المؤلفون: Stephen J. Enos, Mollie K. Huber, Joana Almaça, Jorge Santini, Ricardo L. Pastori, Mirza Muhammad Fahd Qadir, Alberto Pugliese, Christian M. Cohrs, Helmut Hiller, Stephan Speier, Maria Beery, Julia K. Panzer, Juan Domínguez-Bendala, Mark A. Atkinson, Alejandro Caicedo, Edward A. Phelps, Sirlene Cechin, John R. Weitz, Irina Kusmartseva, Denise M. Drotar

المصدر: JCI insight 5:134525 (2020)
JCI Insight

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Cell physiology, endocrine system, Pathology, medicine.medical_specialty, Adolescent, endocrine system diseases, Cell, Enteroendocrine cell, medicine.disease_cause, Autoimmunity, Tissue Culture Techniques, Pathogenesis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Insulin-Secreting Cells, Diabetes mellitus, medicine, Humans, Child, Pancreas, Autoimmune Diseases, Beta Cells, Diabetes, Endocrinology, Type 1 diabetes, business.industry, General Medicine, medicine.disease, Tissue Donors, Diabetes Mellitus, Type 1, 030104 developmental biology, medicine.anatomical_structure, Technical Advance, Child, Preschool, 030220 oncology & carcinogenesis, Female, business

الوصف: In type 1 diabetes (T1D), autoimmune destruction of pancreatic beta cells leads to insulin deficiency and loss of glycemic control. However, knowledge about human pancreas pathophysiology in T1D remains incomplete. To address this limitation, we established a pancreas tissue slice platform of donor organs with and without diabetes, facilitating the first live cell studies of human pancreas in T1D pathogenesis to our knowledge. We show that pancreas tissue slices from organ donors allow thorough assessment of processes critical for disease development, including insulin secretion, beta cell physiology, endocrine cell morphology, and immune infiltration within the same donor organ. Using this approach, we compared detailed pathophysiological profiles for 4 pancreata from donors with T1D with 19 nondiabetic control donors. We demonstrate that cell loss, beta cell dysfunction, alterations of beta cell physiology, and islet infiltration contributed differently to individual cases of T1D, allowing insight into pathophysiology and heterogeneity of T1D pathogenesis. Thus, our study demonstrates that organ donor pancreas tissue slices represent a promising and potentially novel approach in the search for successful prevention and reversal strategies of T1D.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f63476339e1164c9eeceb0ad18778170Test
https://doi.org/10.1172/jci.insight.134525Test

المؤلفون: Carla J. Greenbaum, Alyssa Ylescupidez, Carmella Evans-Molina, Viral N. Shah, Kellee M. Miller, Wei Hao, Kristen J. Nadeau, Jennifer L. Sherr, Henry T. Bahnson, Tamara S. Hannon, Michael R. Rickels, Mark A. Clements, Richard E. Pratley

المصدر: J Clin Invest

مصطلحات موضوعية: 0301 basic medicine, Adult, Blood Glucose, Male, medicine.medical_specialty, Arginine, Adolescent, Hypoglycemia, Glucagon, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Insulin-Secreting Cells, medicine, Humans, Glycemic, Proinsulin, Aged, Type 1 diabetes, C-Peptide, business.industry, C-peptide, General Medicine, Middle Aged, medicine.disease, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 1, chemistry, Glucagon-Secreting Cells, 030220 oncology & carcinogenesis, Hyperglycemia, Female, Clinical Medicine, business

الوصف: BACKGROUND: Residual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known. METHODS: We studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (0.200–0.400; n = 15), or high (>0.400; n = 17). We compared the groups’ glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp. RESULTS: Low and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group. CONCLUSION: These results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control. FUNDING: Funding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::67de680e736dd9c6feea057f91663ed1Test
https://europepmc.org/articles/PMC7108933Test/