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Merjaneh L, Dolan LM, Suerken CK, D’Agostino R, Imperatore G, Saydah S, Roberts A, Marcovina S, Mayer-Davis EJ, Dabelea D, Lawrence JM, Pihoker C. A longitudinal assessment of diabetes autoantibodies in the SEARCH for diabetes in youth study. Pediatr Diabetes 2022; 23:1027-1037. [PMID: 36054435 PMCID: PMC9588609 DOI: 10.1111/pedi.13403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/26/2022] [Accepted: 08/14/2022] [Indexed: 11/28/2022] Open
Abstract
To assess changes in diabetes autoantibodies (DAs) over time in children and young adults with diabetes and determine whether observed changes were associated with demographic characteristics, clinical parameters and diabetes complications. Participants had DAs measured at baseline (10.3 ± 7.1 months after diabetes diagnosis) and at 12, 24 months and ≥5 years after the baseline measurement. At the ≥5-year follow-up, the presence of diabetes complications was assessed. We examined the associations between change in number of positive DAs and changes in individual DA status with the participants' characteristics and clinical parameters over time. Out of 4179 participants, 62% had longitudinal DA data and 51% had complications and longitudinal DA data. In participants with ≥1 baseline positive DA (n = 1699), 83.4% remained positive after 7.3 ± 2.3 years duration of diabetes. Decrease in number of positive DAs was associated with longer diabetes duration (p = 0.003 for 1 baseline positive DA; p < 0.001 for 2 baseline positive DAs) and younger age at diagnosis (p < 0.001 for 2 baseline positive DAs). No associations were found between change in number of positive DAs in participants with ≥1 baseline positive DA (n = 1391) and HbA1c, insulin dose, acute, or chronic complications after 7.7 ± 1.9 years duration of diabetes. DA status likely remains stable in the first 7 years after diabetes diagnosis. Younger age at diabetes diagnosis and longer duration were associated with less persistence of DAs. Measuring DAs after initial presentation may aid in diabetes classification but not likely in predicting the clinical course.
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Affiliation(s)
- Lina Merjaneh
- Department of Pediatrics, University of Washington,
Seattle, WA, USA
| | - Lawrence M. Dolan
- Department of Pediatrics, University of Cincinnati College
of Medicine, Cincinnati, OH, USA
| | - Cynthia K. Suerken
- Department of Biostatistical Sciences, Division of Public
Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Ralph D’Agostino
- Department of Biostatistical Sciences, Division of Public
Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Giuseppina Imperatore
- Division of Diabetes Translation, Centers for Disease
Control and Prevention, National Center for Chronic Disease Prevention and Health
Promotion, Atlanta, GA, USA
| | - Sharon Saydah
- Division of Diabetes Translation, Centers for Disease
Control and Prevention, National Center for Chronic Disease Prevention and Health
Promotion, Atlanta, GA, USA
| | - Alissa Roberts
- Department of Pediatrics, University of Washington,
Seattle, WA, USA
| | | | | | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public
Health, University of Colorado Denver, Aurora, CO, USA
| | - Jean M. Lawrence
- Division of Diabetes, Endocrinology, and Metabolic
Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, MD
| | - Catherine Pihoker
- Department of Pediatrics, University of Washington,
Seattle, WA, USA
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Yazidi M, Mahjoubi S, Oueslati I, Chaker F, Chihaoui M. The remission phase in adolescents and young adults with newly diagnosed type 1 diabetes mellitus: prevalence, predicting factors and glycemic control during follow-up. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 66:222-228. [PMID: 35315990 PMCID: PMC9832884 DOI: 10.20945/2359-3997000000456] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Objective There is little data about the remission phase in adolescents and young adults with newly diagnosed type 1 diabetes mellitus (T1D). The aims of this study were to determine the prevalence of remission and its predicting factors among adolescents and young adults with newly diagnosed T1D and to assess the association between remission and long-term glycemic control in this population. Methods This is a longitudinal and retrospective study including 128 type 1 diabetic patients aged between 12 and 30 years at diabetes onset. Clinical, biological and therapeutic features were collected at diagnosis and for 5 years after diagnosis. Remission was defined by an HbA1c < 6.5% with a daily insulin dose < 0.5 IU/kg/day. Results Twenty-three patients (18%) experienced a remission. The peak of remission prevalence was at 6 months after diabetes diagnosis. An insulin dose at discharge <0.8 IU/kg/day was independently associated with remission (p=0.03, adjusted OR [CI 95%] = 0.2 [0.1-0.9]). A low socioeconomic level was independently associated with non remission (p=0.02, adjusted OR [CI 95%] = 4.3 [1.3-14.3]). HbA1c was significantly lower during the first five years of follow-up in remitters. The daily insulin dose was significantly lower during the first four years of follow-up in remitters. Conclusion Occurrence of remission in adolescents and young adults with newly diagnosed T1D is associated with better glycemic control and lower insulin requirements during the first 5 years of follow-up. A lower initial dose of insulin was associated with a higher percentage of remission.
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Affiliation(s)
- Meriem Yazidi
- Department of Endocrinology, University of Tunis El Manar, Faculty of Medicine of Tunis, La Rabta Hospital, Tunis, Tunisia,
| | - Sana Mahjoubi
- Department of Endocrinology, University of Tunis El Manar, Faculty of Medicine of Tunis, La Rabta Hospital, Tunis, Tunisia
| | - Ibtissem Oueslati
- Department of Endocrinology, University of Tunis El Manar, Faculty of Medicine of Tunis, La Rabta Hospital, Tunis, Tunisia
| | - Fatma Chaker
- Department of Endocrinology, University of Tunis El Manar, Faculty of Medicine of Tunis, La Rabta Hospital, Tunis, Tunisia
| | - Melika Chihaoui
- Department of Endocrinology, University of Tunis El Manar, Faculty of Medicine of Tunis, La Rabta Hospital, Tunis, Tunisia
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Williams MD, Bacher R, Perry DJ, Grace CR, McGrail KM, Posgai AL, Muir A, Chamala S, Haller MJ, Schatz DA, Brusko TM, Atkinson MA, Wasserfall CH. Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis. Diabetes 2021; 70:932-943. [PMID: 33419759 PMCID: PMC7980194 DOI: 10.2337/db20-0937] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/01/2021] [Indexed: 12/15/2022]
Abstract
We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A), and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (median duration 4.5 years [range 0-60]). Indeed, a combined model with incorporation of disease duration, age at onset, GRS, and titers of IA-2A, ZnT8A, and GADA provided superior capacity to predict C-peptide detection (quasi-likelihood information criterion [QIC] = 334.6) compared with the capacity of disease duration, age at onset, and GRS as the sole parameters (QIC = 359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials where investigators are seeking to preserve or restore endogenous β-cell function.
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Affiliation(s)
- MacKenzie D Williams
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Rhonda Bacher
- Department of Biostatistics, College of Public Health and Health Professions, and College of Medicine, University of Florida, Gainesville, FL
| | - Daniel J Perry
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - C Ramsey Grace
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Kieran M McGrail
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Amanda L Posgai
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Andrew Muir
- Department of Pediatrics, Emory University, Atlanta, GA
| | - Srikar Chamala
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Michael J Haller
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Desmond A Schatz
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Clive H Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
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Maione F, Cappellano G, Bellan M, Raineri D, Chiocchetti A. Chicken-or-egg question: Which came first, extracellular vesicles or autoimmune diseases? J Leukoc Biol 2020; 108:601-616. [PMID: 32108378 PMCID: PMC7496139 DOI: 10.1002/jlb.3mr0120-232r] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/21/2020] [Accepted: 02/03/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular vesicles (EVs) have attracted great interest as contributors to autoimmune disease (AD) pathogenesis, owing to their immunomodulatory potential; they may also play a role in triggering tolerance disruption, by delivering auto‐antigens. EVs are released by almost all cell types, and afford paracrine or distal cell communication, functioning as biological carriers of active molecules including lipids, proteins, and nucleic acids. Depending on stimuli from the external microenvironment or on their cargo, EVs can promote or suppress immune responses. ADs are triggered by inappropriate immune‐system activation against the self, but their precise etiology is still poorly understood. Accumulating evidence indicates that lifestyle and diet have a strong impact on their clinical onset and development. However, to date the mechanisms underlying AD pathogenesis are not fully clarified, and reliable markers, which would provide early prediction and disease progression monitoring, are lacking. In this connection, EVs have recently been indicated as a promising source of AD biomarkers. Although EV isolation is currently based on differential centrifugation or density‐gradient ultracentrifugation, the resulting co‐isolation of contaminants (i.e., protein aggregates), and the pooling of all EVs in one sample, limit this approach to abundantly‐expressed EVs. Flow cytometry is one of the most promising methods for detecting EVs as biomarkers, and may have diagnostic applications. Furthermore, very recent findings describe a new method for identifying and sorting EVs by flow cytometry from freshly collected body fluids, based on specific EV surface markers.
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Affiliation(s)
- Federica Maione
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, Novara, Italy.,Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases- IRCAD, Università del Piemonte Orientale, Novara, Italy
| | - Giuseppe Cappellano
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, Novara, Italy.,Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases- IRCAD, Università del Piemonte Orientale, Novara, Italy
| | - Mattia Bellan
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, Novara, Italy.,Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Davide Raineri
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, Novara, Italy.,Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases- IRCAD, Università del Piemonte Orientale, Novara, Italy
| | - Annalisa Chiocchetti
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, Novara, Italy.,Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases- IRCAD, Università del Piemonte Orientale, Novara, Italy
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Rolandsson O, Hampe CS, Sharp SJ, Ardanaz E, Boeing H, Fagherazzi G, Mancini FR, Nilsson PM, Overvad K, Chirlaque MD, Dorronsoro M, Gunter MJ, Kaaks R, Key TJ, Khaw KT, Krogh V, Kühn T, Palli D, Panico S, Sacerdote C, Sánchez MJ, Severi G, Spijkerman AMW, Tumino R, van der Schouw YT, Riboli E, Forouhi NG, Langenberg C, Wareham NJ. Autoimmunity plays a role in the onset of diabetes after 40 years of age. Diabetologia 2020; 63:266-277. [PMID: 31713011 PMCID: PMC6946728 DOI: 10.1007/s00125-019-05016-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 08/22/2019] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. METHODS GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. RESULTS GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. CONCLUSIONS/INTERPRETATION Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
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Affiliation(s)
- Olov Rolandsson
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, 901 87, Umeå, Sweden.
| | - Christiane S Hampe
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
| | - Stephen J Sharp
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK
| | - Eva Ardanaz
- Navarre Public Health Institute, Pamplona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Publica), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Guy Fagherazzi
- CESP, Faculty of Medicine - University Paris-South, Faculty of Medicine Inserm U1018, University Paris-Saclay, Villejuif, France
| | - Francesca Romana Mancini
- CESP, Faculty of Medicine - University Paris-South, Faculty of Medicine Inserm U1018, University Paris-Saclay, Villejuif, France
| | - Peter M Nilsson
- Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Kim Overvad
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
| | - Maria-Dolores Chirlaque
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Publica), Madrid, Spain
- Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
| | - Miren Dorronsoro
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Publica), Madrid, Spain
- Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain
- Instituto BIO-Donostia, Basque Government, San Sebastian, Spain
| | - Marc J Gunter
- International Agency for Research on Cancer, Lyon, France
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Timothy J Key
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Kay-Tee Khaw
- Department of Public Health and Primary Care, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Vittorio Krogh
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Domenico Palli
- Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy
| | - Salvatore Panico
- Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Azienda Ospedaliera Universitaria (AOU) Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy
| | - Maria-José Sánchez
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Publica), Madrid, Spain
- Andalusian School of Public Health, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Universidad de Granada, Granada, Spain
| | - Gianluca Severi
- Inserm, Center for Research in Epidemiology and Population Health (CESP), Université Paris-Sud, Université Paris-Saclay, University of Versailles Saint-Quentin-en-Yvelines (UVSQ) Gustave Roussy, Villejuif, France
- Facultés de Medicine, Université Paris-Sud, Université Paris-Saclay, University of Versailles Saint-Quentin-en-Yvelines (UVSQ) Gustave Roussy, Villejuif, France
| | | | - Rosario Tumino
- Cancer Registry and Histopathology Department, 'Civic - M.P. Arezzo' Hospital, Ragusa, Italy
- Associazone Iblea per la Ricerca Epidemiologica - Organizazione Non Lucrativa di Utilità Sociale, Ragusa, Italy
| | - Yvonne T van der Schouw
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Elio Riboli
- School of Public Health, Imperial College London, London, UK
| | - Nita G Forouhi
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK
| | - Claudia Langenberg
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK
| | - Nicholas J Wareham
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK
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Alyafei F, Soliman A, Alkhalaf F, Sabt A, De Sanctis V, Elsayed N, Waseef R. Clinical and biochemical characteristics of familial type 1 diabetes mellitus (FT1DM) compared to non-familial type 1 DM (NFT1DM). ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:27-31. [PMID: 30049929 DOI: 10.23750/abm.v89is4.7358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Familial type 1 diabetes mellitus (FT1DM) comprises parent-offspring and sib-pair subgroups. The clinical and genetic characteristics of FT1DM cases with and without affected family members have been previously studied with varying results. Some investigators found similarity of presenting features whereas others reported significant differences between the two groups. OBJECTIVE To describe the clinical and biochemical characteristics of children with FT1DM in comparison with those with non-familial type 1 diabetes mellitus (NFT1DM). PATIENTS AND METHODS We performed a cross-sectional retrospective study in a cohort of children and adolescents with T1DM (n=424) aged between 6 months - 16 years attending to Hamad General Hospital Pediatric Diabetes Center, Doha (Qatar) from 2012-2016. They were divided into 2 groups. Group 1 consisted of 62 children and adolescent with FT1DM (parent-offspring or sib-pair). The other group (Group 2) consisted of 431 children and adolescents with NFT1DM. The clinical presentation and prevalence of β-cell autoimmunity (anti-glutamic acid decarboxylase (GAD) antibodies , anti-islet cell and anti-insulin antibodies), thyroid function (Free thyroxine: FT4 and thyroid-stimulating hormone: TSH), anti-thyroid peroxidase antibody (TPO) and anti-tissue transglutaminase (ATT) at their first presentation were recorded, described and analyzed. RESULTS FT1 DM was more prevalent in boys versus girls (1.4:1, respectively) whereas the prevalence of NFT1DM did not differ between genders (1:1.1, respectively). F1DM occurred relatively early in childhood (40.7% before the age of 4 years and 72% before 9 years of age) versus NFT1DM which occurred relatively later in life (80% after the age of 4 years and 40% after the age of 9 years). 35.2% of FT1DM presented with diabetic ketoacidosis (DKA) versus 32.5% of T1DM patients. Anti-islet antibodies (Ab) were detected more frequently in FT1DM versus NFT1DM. The prevalence of positive anti-insulin and anti- GAD antibodies did not differ between the two groups. Anti TPO were detected in 27.2% of NFT1DM and 35.5% of FT1DM. A primary hypothyroidism, with positive ATPO, was more prevalent in FT1DM versus NFT1DM. ATT IgA was high in 5% of NFT1DM and 19.8% of FT1DM whereas ATT IgG was high in 4.4 % of NFT1DM and 15.4% of FT1DM. CONCLUSIONS FT1DM is more prevalent in boys versus girls and occurs earlier in childhood compared to NFT1DM. Primary hypothyroidism was more prevalent in NFT1DM versus FT1DM. Anti-islet Ab and ATT antibodies were more prevalent in the FT1DM versus NFT1DM. The genetic background may explain some differences between FT1DM and NFT1DM including the age of onset, gender affection, as well as associated autoimmune disorders.
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Affiliation(s)
- Fawzia Alyafei
- Department of Pediatrics, Hamad Medical Center, Doha, Qatar.
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Jacobsen LM, Haller MJ, Schatz DA. Understanding Pre-Type 1 Diabetes: The Key to Prevention. Front Endocrinol (Lausanne) 2018; 9:70. [PMID: 29559955 PMCID: PMC5845548 DOI: 10.3389/fendo.2018.00070] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 02/16/2018] [Indexed: 01/08/2023] Open
Abstract
While the incidence of type 1 diabetes continues to rise by 3% each year, the ability to prevent this disease remains elusive. Hybrid closed loop devices, artificial pancreas systems, and continuous glucose monitoring technology have helped to ease the daily burden for many people living with type 1 diabetes. However, the artificial pancreas is not a cure; more research is needed to achieve our ultimate goal of preventing type 1 diabetes. The preceding decades have generated a wealth of information regarding the natural history of pre-type 1 diabetes. Islet autoimmunity in the form of multiple autoantibodies is known to be highly predictive of progression to disease. Staging systems have been devised to better characterize pre-type 1, direct mechanistic understanding of disease, and guide the design of prevention studies. However, there are no evidence-based recommendations for practitioners caring for autoantibody patients other than to encourage enrollment in research studies. Close monitoring of high-risk patients in natural history studies markedly reduces diabetic ketoacidosis rates at diagnosis and research participation is critical to finding a means of preventing type 1 diabetes. The discovery of an effective preventative strategy for type 1 diabetes will justify universal risk screening for all children.
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Affiliation(s)
- Laura M. Jacobsen
- Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL, United States
| | - Michael J. Haller
- Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL, United States
| | - Desmond A. Schatz
- Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL, United States
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Skevaki C, Van den Berg J, Jones N, Garssen J, Vuillermin P, Levin M, Landay A, Renz H, Calder PC, Thornton CA. Immune biomarkers in the spectrum of childhood noncommunicable diseases. J Allergy Clin Immunol 2017; 137:1302-16. [PMID: 27155027 DOI: 10.1016/j.jaci.2016.03.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/21/2016] [Accepted: 03/22/2016] [Indexed: 02/07/2023]
Abstract
A biomarker is an accurately and reproducibly quantifiable biological characteristic that provides an objective measure of health status or disease. Benefits of biomarkers include identification of therapeutic targets, monitoring of clinical interventions, and development of personalized (or precision) medicine. Challenges to the use of biomarkers include optimizing sample collection, processing and storage, validation, and often the need for sophisticated laboratory and bioinformatics approaches. Biomarkers offer better understanding of disease processes and should benefit the early detection, treatment, and management of multiple noncommunicable diseases (NCDs). This review will consider the utility of biomarkers in patients with allergic and other immune-mediated diseases in childhood. Typically, biomarkers are used currently to provide mechanistic insight or an objective measure of disease severity, with their future role in risk stratification/disease prediction speculative at best. There are many lessons to be learned from the biomarker strategies used for cancer in which biomarkers are in routine clinical use and industry-wide standardized approaches have been developed. Biomarker discovery and validation in children with disease lag behind those in adults; given the early onset and therefore potential lifelong effect of many NCDs, there should be more studies incorporating cohorts of children. Many pediatric biomarkers are at the discovery stage, with a long path to evaluation and clinical implementation. The ultimate challenge will be optimization of prevention strategies that can be implemented in children identified as being at risk of an NCD through the use of biomarkers.
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Affiliation(s)
- Chrysanthi Skevaki
- International Inflammation (in-FLAME) Network of the World Universities Network; Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, University Hospital Giessen and Marburg GmbH Baldingerstr, Marburg, Germany
| | - Jolice Van den Berg
- International Inflammation (in-FLAME) Network of the World Universities Network; Department of Immunology/Microbiology Rush University Medical Center Chicago, Chicago, Ill
| | - Nicholas Jones
- International Inflammation (in-FLAME) Network of the World Universities Network; Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales
| | - Johan Garssen
- International Inflammation (in-FLAME) Network of the World Universities Network; Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Beta Faculty, Utrecht University, Utrecht, The Netherlands
| | - Peter Vuillermin
- International Inflammation (in-FLAME) Network of the World Universities Network; Child Health Research Unit, Barwon Health, School of Medicine, Deakin University, Geelong, Australia
| | - Michael Levin
- International Inflammation (in-FLAME) Network of the World Universities Network; Division of Asthma and Allergy, University of Cape Town, and the Department of Pediatrics and Child Health, Red Cross Children's Hospital, Cape Town, South Africa
| | - Alan Landay
- International Inflammation (in-FLAME) Network of the World Universities Network; Department of Immunology/Microbiology Rush University Medical Center Chicago, Chicago, Ill
| | - Harald Renz
- International Inflammation (in-FLAME) Network of the World Universities Network; Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, University Hospital Giessen and Marburg GmbH Baldingerstr, Marburg, Germany
| | - Philip C Calder
- International Inflammation (in-FLAME) Network of the World Universities Network; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, Southampton University Hospital NHS Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - Catherine A Thornton
- International Inflammation (in-FLAME) Network of the World Universities Network; Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales.
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9
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Bansal N, Hampe CS, Rodriguez L, Smith EO, Kushner J, Balasubramanyam A, Redondo MJ. DPD epitope-specific glutamic acid decarboxylase (GAD)65 autoantibodies in children with Type 1 diabetes. Diabet Med 2017; 34:641-646. [PMID: 26802570 PMCID: PMC4958605 DOI: 10.1111/dme.13077] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2016] [Indexed: 12/18/2022]
Abstract
AIM To study whether DPD epitope-specific glutamate decarboxylase autoantibodies are found more frequently in children with milder forms of Type 1 diabetes. METHODS We prospectively evaluated 75 children with new-onset autoimmune Type 1 diabetes, in whom we collected demographic, anthropometric and clinical data and measured islet autoantibodies. Glutamate decarboxylase 65 autoantibody-positive samples were analysed for epitope specificities using recombinant Fab against the DPD-defined epitope of glutamate decarboxylase 65. RESULTS After adjustment for age, positive DPD epitope recognition was significantly associated with higher C-peptide levels at onset (P = 0.02, r2 =0.21, n = 35), and high DPD recognition in the highest quartile tended to be associated with HbA1c ≤ 53 mmol/mol (7%) at the last follow-up [mean (sd) follow-up 1.3 (0.4) years; P = 0.07; for the model, P = 0.044, n = 30)]. Age- and sex-adjusted BMI percentile was significantly correlated with recognition of the DPD-defined epitope (P < 0.03, r2 =0.14, n = 34), but this correlation was driven by the older age group (age ≥ 10 years; P = 0.016, r2 =0.27, n = 21) and was not significant in younger children (P = 0.93, n = 13). There were no independent associations with sex, race/ethnicity, diabetic ketoacidosis, HbA1c , HLA DR3-DQ2/DR4-DQ8 or autoantibody number. CONCLUSIONS Our findings suggest that recognition of the DPD-defined glutamate decarboxylase 65 autoantibody epitope at Type 1 diabetes onset is directly associated with β-cell function, BMI and age, which supports the hypothesis that immunological factors contribute to the clinical heterogeneity of Type 1 diabetes. Larger studies relating epitope-specific glutamate decarboxylase 65 autoantibody to clinical phenotype in children with Type 1 diabetes are warranted.
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Affiliation(s)
- N. Bansal
- Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
| | - C. S. Hampe
- Department of Medicine, University of Washington, Seattle, WA
| | - L. Rodriguez
- Department of Pediatrics, Section of Pediatric Endocrinology, Children’s Hospital of San Antonio, Baylor College of Medicine, San Antonio, TX
| | - E. O’Brian Smith
- Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - J. Kushner
- Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
| | - A. Balasubramanyam
- Translational Metabolism Unit, Diabetes Research Center, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA
| | - M. J. Redondo
- Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
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10
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Laugsand LE, Janszky I, Vatten LJ, Dalen H, Midthjell K, Grill V, Carlsson S. Autoimmune diabetes in adults and risk of myocardial infarction: the HUNT study in Norway. J Intern Med 2016; 280:518-531. [PMID: 27445256 DOI: 10.1111/joim.12530] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND The long-term consequences of autoimmune diabetes in adults (AIDA) are largely unexplored. OBJECTIVE To investigate the risk of myocardial infarction (MI) in AIDA compared to type 2 diabetes, taking into consideration the effects of socio-economic and lifestyle factors, the metabolic syndrome and glycaemic control. METHODS A total of 62 995 participants including 207 individuals with AIDA (onset ≥35 years and anti-GAD positive) and 2322 individuals with type 2 diabetes (onset ≥35 years and anti-GAD negative), from the population-based Norwegian HUNT study, were followed for a first MI during the period 1995-2008. We identified 2614 MIs by hospital records or the National Cause of Death Registry. Cox proportional hazard models were used to estimate the risk of MI by diabetes subgroups after adjustment for age and socio-economic and lifestyle factors. RESULTS AIDA amongst women was associated with a nearly fourfold increased risk of MI [hazard ratio (HR) 3.63, 95% confidence interval (CI) 2.21-5.96) compared to nondiabetic participants, whereas no excess risk was found in men with AIDA (HR 1.30, 95% CI 0.70-2.52). By contrast, type 2 diabetes was associated with an increased MI risk in both men (HR 1.92, 95% CI 1.62-2.26) and women (HR 2.39, 95% CI 1.98-2.89). The metabolic profile was more favourable in patients with AIDA than in those with type 2 diabetes, but glycaemic control was worse. Multivariable models and sensitivity analyses suggest that these results were robust. CONCLUSIONS Women with AIDA were more likely to develop MI, compared to men with AIDA and both men and women with type 2 diabetes. Further investigations are warranted to confirm this gender difference.
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Affiliation(s)
- L E Laugsand
- Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. .,Department of Cardiology, St. Olavs Hospital, Trondheim, Norway.
| | - I Janszky
- Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
| | - L J Vatten
- Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - H Dalen
- Department of Internal Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.,Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - K Midthjell
- HUNT Research Centre, Department of Community Medicine and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway
| | - V Grill
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - S Carlsson
- Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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11
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Stoupa A, Dorchy H. HLA-DQ genotypes - but not immune markers - differ by ethnicity in patients with childhood onset type 1 diabetes residing in Belgium. Pediatr Diabetes 2016; 17:342-50. [PMID: 26134450 DOI: 10.1111/pedi.12293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/31/2015] [Accepted: 06/01/2015] [Indexed: 12/28/2022] Open
Abstract
AIM The aim of this study was to compare genetic (HLA-DQ) and immune markers in a large population of type 1 diabetic (T1D) children and adolescents residing in the same environment, but of different ethnic origin: European Caucasians (EC), Moghrabin Caucasians (MC), Black Africans (BA) and of Mixed Origin (MO). METHODS Retrospective study, including 452 patients with T1D aged 0.1-17.5 yr at diagnosis recruited at the Diabetology Clinic of the University Children's Hospital Queen Fabiola from May 1995 to March 2013. HLA-DQ genotyping, diabetes-associated autoantibodies, organ-specific autoantibodies, and other markers of autoimmunity were studied. RESULTS The proportion of the different ethnic groups was: 55% EC, 35% MC, 6% BA, and 4% MO. Between these four groups, there were no significant differences concerning age, hemoglobin A1c (HbA1c), presence of diabetic ketoacidosis, random C-peptide level at diagnosis and 2 yr later. The two most frequent haplotypes were DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 with a significant higher prevalence in MC and EC (p = 0.002 and 0.03, respectively). The high-risk heterozygous genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more frequent in EC than in MC, whereas the homozygous genotype DQA1*0501-DQB1*0201/DQA1*0501-DQB1*0201 was more prevalent in MC (p = 0.019). These susceptible genotypes were more frequent in youngest patients (p = 0.003). Diabetes-associated autoantibodies, organ-specific autoantibodies, and other immune markers did not statistically differ between ethnic groups. CONCLUSIONS These observations in a large population of T1D children and adolescents of different ethnic groups residing in Belgium show significant differences in HLA-DQ status, but not in diabetes-associated autoantibodies, organ-specific autoantibodies, or other immune markers.
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Affiliation(s)
- Athanasia Stoupa
- Diabetology Clinic, University Children's Hospital Queen Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Harry Dorchy
- Diabetology Clinic, University Children's Hospital Queen Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
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12
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Barker A, Lauria A, Schloot N, Hosszufalusi N, Ludvigsson J, Mathieu C, Mauricio D, Nordwall M, Van der Schueren B, Mandrup-Poulsen T, Scherbaum WA, Weets I, Gorus FK, Wareham N, Leslie RD, Pozzilli P. Age-dependent decline of β-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study. Diabetes Obes Metab 2014; 16:262-7. [PMID: 24118704 DOI: 10.1111/dom.12216] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 09/14/2013] [Accepted: 09/14/2013] [Indexed: 01/12/2023]
Abstract
AIMS C-peptide secretion is currently the only available clinical biomarker to measure residual β-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. METHODS We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on β-cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. RESULTS Fasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (p < 0.0001). CONCLUSIONS This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of β-cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.
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Affiliation(s)
- A Barker
- Department MRC Epidemiology Unit, Cambridge Institute of Public Health, Cambridge, UK
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13
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Olsson L, Grill V, Midthjell K, Ahlbom A, Andersson T, Carlsson S. Mortality in adult-onset autoimmune diabetes is associated with poor glycemic control: results from the HUNT Study. Diabetes Care 2013; 36:3971-8. [PMID: 24130367 PMCID: PMC3836133 DOI: 10.2337/dc13-0564] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Knowledge on mortality in autoimmune diabetes with adult onset is limited. We compared mortality in adult-onset autoimmune diabetes and type 2 diabetes, taking into account metabolic risk factors, HbA1c, lifestyle, and socioeconomic factors. RESEARCH DESIGN AND METHODS Participants of the population-based HUNT2 Study (second survey of the Norwegian HelseUndersøkelsen i Nord-Trøndelag Study; n = 64,264) were followed up prospectively for mortality in the Cause of Death Registry (1995-2009). Diabetes with onset ≥35 years was classified as autoimmune diabetes in adults if anti-GAD was positive (n = 208) and as type 2 diabetes if anti-GAD was negative (n = 2,425). Hazard ratios (HRs) of mortality from all-causes, cardiovascular disease (CVD), and ischemic heart disease (IHD) were calculated using the Cox proportional hazards model. RESULTS Prevalence of the metabolic syndrome was lower in autoimmune diabetes than in type 2 diabetes (55 vs. 77%, P < 0.001). Still, autoimmune diabetes was associated with an increased risks of mortality from all-causes (HR 1.55 [95% CI 1.25-1.92]), CVD (1.87 [1.40-2.48]), and IHD (2.39 [1.57-3.64]), equally high as in type 2 diabetes in analyses where individuals without diabetes were used as the reference group. The increased risk was not explained by overweight, lifestyle, socioeconomic position, or presence of the metabolic syndrome. Excess mortality was primarily observed in individuals with elevated HbA1c. CONCLUSIONS Mortality in autoimmune diabetes was as high as in type 2 diabetes, despite a more favorable baseline metabolic risk profile. Excess risk was associated with poor glycemic control. The results from this study, the largest so far on mortality in autoimmune diabetes in adults, underscore the importance of optimal treatment modalities to improve survival in adult-onset autoimmune diabetes.
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14
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Rasouli B, Grill V, Midthjell K, Ahlbom A, Andersson T, Carlsson S. Smoking is associated with reduced risk of autoimmune diabetes in adults contrasting with increased risk in overweight men with type 2 diabetes: a 22-year follow-up of the HUNT study. Diabetes Care 2013; 36:604-10. [PMID: 23172971 PMCID: PMC3579345 DOI: 10.2337/dc12-0913] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate the association between smoking habits and risk of autoimmune diabetes in adults and of type 2 diabetes. RESEARCH DESIGN AND METHODS We used data from the three surveys of the Nord-Trøndelag Health Study, spanning 1984-2008 and including a cohort of 90,819 Norwegian men (48%) and women (52%) aged ≥20 years. Incident cases of diabetes were identified by questionnaire and classified as type 2 diabetes (n = 1,860) and autoimmune diabetes (n = 140) based on antibodies to glutamic decarboxylase (GADA) and age at onset of diabetes. Hazard ratios (HRs) adjusted for confounders were estimated by Cox proportional hazards regression models. RESULTS The risk of autoimmune diabetes was reduced by 48% (HR 0.52 [95% CI 0.30-0.89]) in current smokers and 58% in heavy smokers (0.42 [0.18-0.98]). The reduced risk was positively associated with number of pack-years. Heavy smoking was associated with lower levels of GADA (P = 0.001) and higher levels of C-peptide (964 vs. 886 pmol/L; P = 0.03). In contrast, smoking was associated with an increased risk of type 2 diabetes, restricted to overweight men (1.33 [1.10-1.61]). Attributable proportion due to an interaction between overweight and heavy smoking was estimated to 0.40 (95% CI 0.23-0.57). CONCLUSIONS In this epidemiological study, smoking is associated with a reduced risk of autoimmune diabetes, possibly linked to an inhibitory effect on the autoimmune process. An increased risk of type 2 diabetes was restricted to overweight men.
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Affiliation(s)
- Bahareh Rasouli
- Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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15
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Besser REJ, Shields BM, Casas R, Hattersley AT, Ludvigsson J. Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C-peptide in pediatric diabetes. Diabetes Care 2013; 36:195-201. [PMID: 23111058 PMCID: PMC3554273 DOI: 10.2337/dc12-0836] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Mixed-meal tolerance test (MMTT) area under the curve C-peptide (AUC CP) is the gold-standard measure of endogenous insulin secretion in type 1 diabetes but is intensive and invasive to perform. The 90-min MMTT-stimulated CP ≥0.2 nmol/L (90CP) is related to improved clinical outcomes, and CP ≥0.1 nmol/L is the equivalent fasting measure (FCP). We assessed whether 90CP or FCP are alternatives to a full MMTT. RESEARCH DESIGN AND METHODS CP was measured during 1,334 MMTTs in 421 type 1 diabetes patients aged <18 years at 3, 9, 18, 48, and 72 months duration. We assessed: 1) correlation between mean AUC CP and 90CP or FCP; 2) sensitivity and specificity of 90CP ≥0.2 nmol/L and FCP ≥ 0.1 nmol/L to detect peak CP ≥0.2 nmol/L and the equivalent AUC CP; and 3) how the time taken to reach the CP peak varied with age of diagnosis and diabetes duration. RESULTS AUC CP was highly correlated to 90CP (r(s) = 0.96; P < 0.0001) and strongly correlated to FCP (r(s) = 0.84; P < 0.0001). AUC CP ≥23 nmol/L/150 min was the equivalent cutoff for peak CP ≥0.2 nmol/L (98% sensitivity/97% specificity). A 90CP ≥0.2 nmol/L correctly classified 96% patients using AUC or peak CP, whereas FCP ≥0.1 nmol/L classified 83 and 85% patients, respectively. There was only a small difference seen between peak and 90CP (median 0.02 nmol/L). The CP peak occurred earlier in patients with longer diabetes duration (6.1 min each 1-year increase in duration) and younger age (2.5 min each 1-year increase). CONCLUSIONS 90CP is a highly sensitive and specific measure of AUC and peak CP in children and adolescents with type 1 diabetes and offers a practical alternative to a full MMTT.
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Affiliation(s)
- Rachel E J Besser
- Peninsula National Institute of Health Research Clinical Research Facility, Peninsula Medical School, University of Exeter, Exeter, United Kingdom.
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16
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Dabelea D, Mayer-Davis EJ, Andrews JS, Dolan LM, Pihoker C, Hamman RF, Greenbaum C, Marcovina S, Fujimoto W, Linder B, Imperatore G, D'Agostino R. Clinical evolution of beta cell function in youth with diabetes: the SEARCH for Diabetes in Youth study. Diabetologia 2012; 55:3359-68. [PMID: 22990715 PMCID: PMC4492685 DOI: 10.1007/s00125-012-2719-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 08/17/2012] [Indexed: 01/12/2023]
Abstract
AIMS/HYPOTHESIS Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study. METHODS Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models. RESULTS Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA(1c) and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month). CONCLUSIONS/INTERPRETATION SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.
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Affiliation(s)
- D Dabelea
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, 13001 East 17th Ave, Aurora, CO 80045, USA.
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17
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Gan MJ, Albanese-O'Neill A, Haller MJ. Type 1 diabetes: current concepts in epidemiology, pathophysiology, clinical care, and research. Curr Probl Pediatr Adolesc Health Care 2012; 42:269-91. [PMID: 23046732 DOI: 10.1016/j.cppeds.2012.07.002] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease mediated by a combination of genetic and environmental triggers resulting in lymphocytic infiltration of pancreatic islets, destruction of beta cells, and lifelong dependency on exogenous insulin. Although T1D is prevalent (1 in 300) and its incidence is steadily increasing worldwide (3% per year), the exact gene-environment interactions precipitating the disease remain unknown. Living with T1D is challenging for patients, families, and caregivers. Because of the relative paucity of pediatric endocrinologists, general pediatricians and other subspecialists may occasionally be faced with the task of managing diabetes-related complaints. Herein, we provide a comprehensive review of the natural history, pathophysiology, and contemporary management of T1D. In addition, recent advances in T1D research are discussed.
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Affiliation(s)
- Mary Joyce Gan
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
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18
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Sørgjerd EP, Skorpen F, Kvaløy K, Midthjell K, Grill V. Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway. Diabetologia 2012; 55:1310-8. [PMID: 22297581 DOI: 10.1007/s00125-012-2463-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Accepted: 12/22/2011] [Indexed: 11/29/2022]
Abstract
AIMS The aetiology of latent autoimmune diabetes in adults (LADA), assessed by autoimmune markers, is insufficiently clarified. We cross-sectionally investigated the prevalence and prospectively the prediabetic and postdiabetic presence of antibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 and zinc transporter 8 in LADA and in type 1 diabetes. METHODS We included 208 'classic' type 1, 161 LADA and 302 type 2 diabetic cases from the second (HUNT2: 1995–1997) and third (HUNT3: 2006–2008) Nord-Trøndelag health surveys. Prospective data were available for 59 type 1, 44 LADA and 302 type 2 diabetic cases followed from HUNT2 to HUNT3. From HUNT3, 24 type 1 diabetic and 31 LADA incident cases were available. RESULTS Cross-sectionally, 90% of LADA cases were positive for only one antibody (10% multiple-antibodypositive). Prospectively, 59% of GADA-positive LADA patients in HUNT2 were no longer positive in HUNT3. LADA patients who became negative possessed less frequently risk HLA haplotypes and were phenotypically more akin to those with type 2 diabetes than to those who stayed positive. Still, those losing positivity differed from those with type 2 diabetes by lower C-peptide levels (p = 0.009). Of incident LADA cases in HUNT3, 64% were already antibody-positive in HUNT2, i.e. before diabetes diagnosis. These incident LADA cases were phenotypically more akin to type 1 diabetes than were those who did not display positivity in HUNT2. CONCLUSION/INTERPRETATION The pattern of antibodies, the postdiabetic loss or persistence as well as the prediabetic absence or presence of antibodies influence LADA phenotypes. Time-dependent presence or absence of antibodies adds new modalities to the heterogeneity of LADA.
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Affiliation(s)
- E P Sørgjerd
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, NTNU, HUNT Research Centre, Forskningsveien 2, 7600 Levanger, Norway.
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Serfaty FM, Dantas JR, Almeida MH, Duarte JDG, Kupfer R, Campos F, Zajdenverg L, Milech A, Rodacki M, Oliveira JEPD. [GADA persistence and detectable C peptide in patients with long standing diabetes mellitus type 1]. ARQUIVOS BRASILEIROS DE ENDOCRINOLOGIA E METABOLOGIA 2010; 54:449-54. [PMID: 20694405 DOI: 10.1590/s0004-27302010000500004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Accepted: 04/05/2010] [Indexed: 11/21/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate if GADA+ and detectable CP had any influence in other autoimmune diseases, glycemic control, and risks of retinopathy in diabetes mellitus type 1 (T1DM) lasting longer than 3 years of duration. SUBJECTS AND METHODS Fifty T1DM subjects were interviewed, performed fundoscopic examination, and measured CP before and after glucagon, HbA1C, and GADA. RESULTS GADA+ (n = 17) had a higher frequency of other autoimmune diseases when compared to GADA (p = 0.02). Detectable CP was also associated with a higher prevalence of these diseases (p = 0.03), although, retinopathy was not influenced by either one. Detectable CP had no influence in the glycemic control (mean HbA1C) (p = 0.28). However, insulin daily doses were lower in this group (0.62 vs. 0.91 U/kg/day; p = 0.004). CONCLUSION Although not recommend as a marker of other autoimmune diseases, GADA+ seems to be not only a pancreatic autoimmunity signal. Detectable CP may also have some promising influence in detecting these diseases. Neither influenced the presence of retinopathy, but insulin daily requirements were smaller when CP was present.
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Affiliation(s)
- Fabiano Marcel Serfaty
- Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione, Rio de Janeiro, RJ, Brasil.
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Beta-cell autoantibodies and their function in Taiwanese children with type 1 diabetes mellitus. J Formos Med Assoc 2010; 108:856-61. [PMID: 19933029 DOI: 10.1016/s0929-6646(09)60417-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND/PURPOSE To understand the importance of autoimmunity in the development of type 1 diabetes in Taiwanese children, we evaluated the presence of beta-cell autoantibodies and their correlation with residual beta-cell function. METHODS From 1989 to 2006, 157 Taiwanese children with newly diagnosed type 1 diabetes were enrolled in this study. We determined the presence of beta-cell autoantibodies, such as glutamic acid decarboxylase autoantibodies (GADAs), insulinoma antigen 2 autoantibodies (IA-2As), and insulin autoantibodies (IAAs). A 6-minute glucagon test was also performed at diagnosis. RESULTS At diagnosis, 73% of children tested positive for GADAs, 76% for IA-2As and 21% for IAAs. Ninety-two percent of them had at least one of the beta-cell autoantibodies detected. Positivity for IAAs was more frequent in patients younger than 5 years than in those older than 5 years (45% vs. 13%). Using multiple regression analysis, the presence of GADAs or IAAs, or age of onset of these patients was an independent factor for residual beta-cell function. Younger patients and those with GADAs had less residual beta-cell function at disease onset, whereas those with IAAs had more insulin reserve. CONCLUSION Autoimmunity plays an important role in the pathogenesis of type 1 diabetes in Taiwanese children, and the presence of IAAs tends to be more common in younger children.
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Chatenoud L. The use of CD3-specific antibodies in autoimmune diabetes: a step toward the induction of immune tolerance in the clinic. Handb Exp Pharmacol 2008:221-36. [PMID: 18071948 DOI: 10.1007/978-3-540-73259-4_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
CD3-specific monoclonal antibodies were the first rodent monoclonals introduced in clinical practice in the mid 1980s as approved immunosuppressants to prevent and treat organ allograft rejection. Since then compelling evidence has been accumulated to suggest that in addition to their immunosuppressive properties, CD3-specific antibodies can also afford inducing immune tolerance especially in the context of ongoing immune responses. Thus, they are highly effective at restoring self-tolerance in overt autoimmunity, a capacity first demonstrated in the experimental setting, which was recently transferred to the clinic with success.
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Keymeulen B. New therapies aimed at the preservation or restoration of beta cell function in type 1 diabetes. Acta Clin Belg 2006; 61:275-85. [PMID: 17240745 DOI: 10.1179/acb.2006.047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Type 1 diabetes is caused by an immune-mediated destruction of the insulin-secreting beta cells in the pancreas. The disease can become clinically apparent at any age. At diagnosis, there is invariably some residual beta cell function and more so in adults than in children. Recent studies--including one conducted mainly in Belgium--have provided proof of principle that short-term anti-T-cell antibody treatment is able to preserve residual beta cell function for at least 18 months. The resultant stabilizing effect on metabolic control is expected to delay or limit chronic complications in these patients. With a similar goal in mind, nonuremic C-peptide negative patients are offered beta cell transplantation. The outcome of these implants looks promising but their final applicability hinges on finding ways to induce immune tolerance to the donor beta cells. A widespread application, however, will only occur if the shortage of viable human donor cells can be overcome. Both xenotransplantation and stem cell therapy provide possible strategies to solve this problem and represent areas of intense investigation. The ultimate goal is prevention of clinical disease. Studies by the Belgian Diabetes Registry and others in first degree family members of type 1 diabetic patients have refined the identification of individuals at very high risk of hyperglycaemia so that new immunological treatments can be tested in the prediabetic phase.
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Affiliation(s)
- B Keymeulen
- Academisch Ziekenhuis and Diabetes Research Centre -Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium.
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Ohtsu S, Takubo N, Kazahari M, Nomoto K, Yokota F, Kikuchi N, Koike A, Matsuura N. Slowly progressing form of type 1 diabetes mellitus in children: genetic analysis compared with other forms of diabetes mellitus in Japanese children. Pediatr Diabetes 2005; 6:221-9. [PMID: 16390391 DOI: 10.1111/j.1399-543x.2005.00133.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
AIMS Slowly progressing insulin-dependent diabetes mellitus (SPIDDM, hereafter referred to as IDDMS in this article) is a unique subtype of type 1 diabetes in Japanese children. To clarify the genetic background of IDDMS, we analyzed HLA-DRB1, -DQB1 and -DQA1 alleles, phenotypes, and genotypes and compared them with acute-onset type 1 diabetes, non-insulin-dependent diabetes mellitus (NIDDM), and control subjects. METHODS HLA-DRB1, -DQA1, and -DQB1 types were defined by DNA analysis using polymerase chain reaction (PCR), and typing for human leukocyte antigen (HLA) was performed by the sequencing-based typing (SBT) method using Match Maker and MT Navigator in combination. HLA-A24 was determined by the PCR-sequence-specific oligo-nucleotide probe (PCR-SSOP) method. The 234 patients with type 1 diabetes were divided into three groups: 32 cases of IDDMS, 137 cases of acute-onset form aged more than 5 yr (IDDMA), and 65 cases of acute-onset form less than 5 yr of age at onset (IDDME). In addition, we studied 55 children with type 2 diabetes (NIDDM) and 97 normal controls. RESULTS The patients with IDDMS were older at diagnosis and had a greater body mass index (BMI) than those with IDDM (A + E). The prevalence of islet autoantbodies was not significantly different from IDDMA. The allele frequencies of DRB1*0405, DQA1*0302, and DQB1*0401 were significantly increased; however, DRB1*0901, DQA1*03, DQB1*0303, and HLA-A24 were low and not significantly different from control subjects. CONCLUSIONS HLA phenotypes and genotypes in patients with IDDMS were different from those in NIDDM and control subjects and were closer to those of IDDMA. Together with a low prevalence of HLA-A24, the genetic features are similar to those of SPIDDM and latent autoimmune diabetes in adults (LADA) in adults. In our series, the clinical features such as lack of obesity and lack of responsiveness to oral hypoglycemic agents were most different from those of adults' onset.
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Affiliation(s)
- Shigeyuki Ohtsu
- Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan
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Abstract
Despite extensive and ongoing investigations of the immune mechanisms of autoimmune diabetes in humans and animal models, there is much less information about the natural history of insulin secretion before and after the clinical presentation of type 1 diabetes and the factors that may affect its course. Studies of insulin production previously published and from the Diabetes Prevention Trial (DPT)-1 suggest that there is progressive impairment in insulin secretory responses but the reserve in response to physiological stimuli may be significant at the time of diagnosis, although maximal responses are more significantly impaired. Other factors, including insulin resistance, may play a role in the timing of clinical presentation along this continuum. The factors that predict the occurrence and rapidity of decline in beta-cell function are still largely unknown, but most studies have identified islet cell autoantibodies as predictors of future decline and age as a determinant of residual insulin production at diagnosis. Historical as well as recent clinical experience has emphasized the importance of residual insulin production for glycemic control and prevention of end-organ complications. Understanding the modifiers and predictors of beta-cell function would allow targeting immunological approaches to those individuals most likely to benefit from therapy.
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Affiliation(s)
- Nicole A Sherry
- Naomie Berrie Diabetes Center and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Ave., New York, New York 10032, USA
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Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352:2598-608. [PMID: 15972866 DOI: 10.1056/nejmoa043980] [Citation(s) in RCA: 822] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Type 1 diabetes mellitus is a T-cell-mediated autoimmune disease that leads to a major loss of insulin-secreting beta cells. The further decline of beta-cell function after clinical onset might be prevented by treatment with CD3 monoclonal antibodies, as suggested by the results of a phase 1 study. To provide proof of this therapeutic principle at the metabolic level, we initiated a phase 2 placebo-controlled trial with a humanized antibody, an aglycosylated human IgG1 antibody directed against CD3 (ChAglyCD3). METHODS In a multicenter study, 80 patients with new-onset type 1 diabetes were randomly assigned to receive placebo or ChAglyCD3 for six consecutive days. Patients were followed for 18 months, during which their daily insulin needs and residual beta-cell function were assessed according to glucose-clamp-induced C-peptide release before and after the administration of glucagon. RESULTS At 6, 12, and 18 months, residual beta-cell function was better maintained with ChAglyCD3 than with placebo. The insulin dose increased in the placebo group but not in the ChAglyCD3 group. This effect of ChAglyCD3 was most pronounced among patients with initial residual beta-cell function at or above the 50th percentile of the 80 patients. In this subgroup, the mean insulin dose at 18 months was 0.22 IU per kilogram of body weight per day with ChAglyCD3, as compared with 0.61 IU per kilogram with placebo (P<0.001). In this subgroup, 12 of 16 patients who received ChAglyCD3 (75 percent) received minimal doses of insulin (< or =0.25 IU per kilogram per day) as compared with none of the 21 patients who received placebo. Administration of ChAglyCD3 was associated with a moderate "flu-like" syndrome and transient symptoms of Epstein-Barr viral mononucleosis. CONCLUSIONS Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.
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Affiliation(s)
- Bart Keymeulen
- Academic Hospital and Diabetes Research Center, Brussels Free University-VUB, Brussels.
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Yang L, Zhou ZG, Huang G, Ouyang LL, Li X, Yan X. Six-year follow-up of pancreatic β cell function in adults with latent autoimmune diabetes. World J Gastroenterol 2005; 11:2900-5. [PMID: 15902725 PMCID: PMC4305656 DOI: 10.3748/wjg.v11.i19.2900] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the characteristics of the progression of islet β cell function in Chinese latent autoimmune diabetes in adult (LADA) patients with glutamic acid decarboxylase antibody (GAD-Ab) positivity, and to explore the prognostic factors for β cell function.
METHODS: Forty-five LADA patients with GAD-Ab positivity screened from phenotypic type 2 diabetic (T2DM) patients and 45 T2DM patients without GAD-Ab matched as controls were followed-up every 6 mo. Sixteen patients in LADA1 and T2DM1 groups respectively have been followed-up for 6 years, while 29 patients in LADA2 and T2DM2 groups respectively for only 1.5 years. GAD-Ab was determined by radioligand assay, and C-peptides (CP) by radioimmune assay.
RESULTS: The percentage of patients whose fasting CP (FCP) decreased more than 50% compared with the baseline reached to 25.0% at 1.5th year in LADA1 group, and FCP level decreased (395.8±71.5 vs 572.8±72.3 pmol/L, P<0.05) at 2.5th year and continuously went down to the end of follow-up. No significant changes of the above parameters were found in T2DM1 group. The average decreased percentages of FCP per year in LADA and T2DM patients were 15.8% (4.0-91.0%) and 5.2% (-3.5 to 35.5%, P = 0.000) respectively. The index of GAD-Ab was negatively correlated with the FCP in LADA patients (rs = -0.483, P = 0.000). The decreased percentage of FCP per year in LADA patients were correlated with GAD-Ab index, body mass index (BMI) and age at onset (rs = 0.408, -0.301 and -0.523 respectively, P<0.05). Moreover, GAD-Ab was the only risk factor for predicting β cell failure in LADA patients (B = 1.455, EXP (B) = 4.283, P = 0.023).
CONCLUSION: The decreasing rate of islet β cell function in LADA, being highly heterogeneous, is three times that of T2DM patients. The titer of GAD-Ab is an important predictor for the progression of islet β cell function, and age at onset and BMI could also act as the predictors.
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Affiliation(s)
- Lin Yang
- Institute of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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Bruno G, Cerutti F, Merletti F, Cavallo-Perin P, Gandolfo E, Rivetti M, Runzo C, Pinach S, Pagano G. Residual beta-cell function and male/female ratio are higher in incident young adults than in children: the registry of type 1 diabetes of the province of Turin, Italy, 1984-2000. Diabetes Care 2005; 28:312-7. [PMID: 15677785 DOI: 10.2337/diacare.28.2.312] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The hypothesis of age-dependent variations in epidemiologic and clinical features at onset of type 1 diabetes has been assessed in the registry of the province of Turin, Italy. RESEARCH DESIGN AND METHODS The study base is the population 0-29 years of age of the province of Turin, in the period from 1984 to 2000. Islet cell antibody (ICA), GAD antibody (GADA), antibodies to protein tyrosine phosphatase (IA2), and C-peptide were measured in subgroups of the cohort. RESULTS One thousand fifty-six incident cases have been identified (completeness of ascertainment 98.1%). Rates per 100,000 person-years were similar in males and females in the age-group 0-14 years (10.7, 95% CI 9.5-12.0 vs. 9.8, 8.6-11.1). In the age-group 15-29 years, males had higher risk than females (7.7, 6.9-8.6 vs. 5.3, 4.6-6.1; rate ratio, 1.46, 95% CI 1.23-1.74; P = 0.00002). Fasting plasma C-peptide values (n = 575) were twofold lower in the age-group 0-14 years than in the age-group 15-29 years (0.10 vs. 0.23 nmol/l; P < 0.0001). Frequencies of ICA and IA2 positivities (n = 183) decreased with increasing age, whereas frequency of GADA positivity increased. Idiopathic cases were 12.6% and had higher mean values of fasting (0.28 vs. 0.14 nmol/l; P = 0.043) and stimulated C-peptide (0.59 vs. 0.34 nmol/l; P = 0.05). In logistic regression analyses, subjects with fasting C-peptide values in the upper quartile had higher likelihood of being older (odds ratio 1.20 for year, 95% CI 1.11-1.28), ICA negative (0.26, 0.10-0.70), and female (1.29, 0.48-3.42). CONCLUSIONS This study shows 1) sex differences in incidence rates in young adults; 2) better preserved beta-cell function in young adults, in idiopathic cases (12%), and in ICA-negative cases; and 3) lower frequencies of ICA and IA2 positivities and higher frequency of GADA positivity in young adults than in children.
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Affiliation(s)
- Graziella Bruno
- Department of Internal Medicine, University of Turin, corso Dogliotti 14, I-10126 Turin, Italy.
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Ortqvist E, Björk E, Wallensteen M, Ludvigsson J, Aman J, Johansson C, Forsander G, Lindgren F, Berglund L, Bengtsson M, Berne C, Persson B, Karlsson FA. Temporary preservation of beta-cell function by diazoxide treatment in childhood type 1 diabetes. Diabetes Care 2004; 27:2191-7. [PMID: 15333483 DOI: 10.2337/diacare.27.9.2191] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We examined the effect of diazoxide, an ATP-sensitive K(+) channel opener and inhibitor of insulin secretion, on beta-cell function and remission in children at clinical onset of type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 56 subjects (21 girls and 35 boys, age 7-17 years) were randomized to 3 months of active treatment (diazoxide 5-7.5 mg/kg in divided doses) or placebo in addition to multiple daily insulin injections and were followed for 2 years. RESULTS Diazoxide decreased circulating C-peptide concentrations by approximately 50%. After cessation of the treatment, basal and meal-stimulated C-peptide concentrations increased to a maximum at 6 months, followed by a decline. Meal-stimulated C-peptide concentration was significantly higher at 12 months (0.43 +/- 0.22 vs. 0.31 +/- 0.26 nmol/l, P = 0.018) and tended to fall less from clinical onset to 24 months in the diazoxide- vs. placebo-treated patients (-0.05 +/- 0.24 vs. -0.18 +/- 0.26 nmol/l, P = 0.064). At 24 months, the meal-stimulated C-peptide concentrations were 0.24 +/- 0.20 and 0.20 +/- 0.17 nmol/l, respectively. Side effects of diazoxide were prevalent. CONCLUSIONS This study demonstrates that partial inhibition of insulin secretion for 3 months at onset of childhood type 1 diabetes suspends the period of remission and temporarily preserves residual insulin production. Further evaluation of the full potential of beta-cell rest will require compounds with less side effects as well as protocols optimized for sustained secretory arrest.
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Affiliation(s)
- Eva Ortqvist
- Department of Woman and Child Health, Astrid Lindgrens Children's Hospital, Karolinska Institutet, Stockholm, Sweden.
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Monge L, Bruno G, Pinach S, Grassi G, Maghenzani G, Dani F, Pagano G. A clinically orientated approach increases the efficiency of screening for latent autoimmune diabetes in adults (LADA) in a large clinic-based cohort of patients with diabetes onset over 50 years. Diabet Med 2004; 21:456-9. [PMID: 15089790 DOI: 10.1111/j.1464-5491.2004.01177.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIMS To assess if a clinically orientated approach improves screening for latent autoimmune diabetes in adults (LADA) in patients developing diabetes over age 50. METHODS From a clinic-based cohort of 3327 patients with Type 2 DM diagnosed over age 50 we recruited those with at least one feature suggestive of insulin deficiency: (i) fasting blood glucose > or = 15 mmol/l and/or HbA(1c) > or = 10% in spite of adequate compliance to diet and treatment; (ii) decreasing body weight > or = 10% in the previous 3 months in spite of constant diet; (iii) BMI < 25 mg/kg(2). A control group of 240 patients not presenting any of the previous criteria was randomly selected from the out-patient clinic. RESULTS We identified 220 (6.6%) patients, of whom 70 were positive for glutamic acid decarboxylase antibodies (GADA) and/or islet cell antibodies (ICA), giving a prevalence of LADA of 31.8% (95% CI 25.7-38.4). In contrast, no patient randomly selected from the remaining cohort had marker positivities. With respect to patients negative for both ICA and GADA, those who were positive had lower C-peptide values (0.53 +/- 0.51 vs. 0.88 +/- 0.42 nmol/l, P < 0.001); the lowest levels were found in patients in whom both antibodies were positive. In linear regression analysis, variables independently associated with fasting C-peptide were GADA (beta = -0.25, P < 0.001), ICA (beta = -0.15, P = 0.04), BMI (beta = 0.03, P < 0.001) and duration of diabetes (beta = -0.02, P < 0.001). CONCLUSION This study shows that: (i) a clinically orientated approach increases the efficiency of a screening programme for LADA, so that one in three screened patients are classified correctly; (ii) ICA and GADA positivity were negatively associated with residual beta-cell function, independent of BMI and duration of the disease; (iii) positivity for both ICA and GADA identifies patients with the lowest residual beta-cell function.
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Affiliation(s)
- L Monge
- Diabetes Unit, Azienda Ospedaliera S. Giovanni Battista, Corsa Bramante 88-90, 10126 Turin, Italy.
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Schölin A, Björklund L, Borg H, Arnqvist H, Björk E, Blohmé G, Bolinder J, Eriksson JW, Gudbjörnsdottir S, Nyström L, Ostman J, Karlsson AF, Sundkvist G. Islet antibodies and remaining beta-cell function 8 years after diagnosis of diabetes in young adults: a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden. J Intern Med 2004; 255:384-91. [PMID: 14871463 DOI: 10.1046/j.1365-2796.2003.01273.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVES To establish the prevalence of remaining beta-cell function 8 years after diagnosis of diabetes in young adults and relate the findings to islet antibodies at diagnosis and 8 years later. DESIGN Population-based cohort study. SETTING Nationwide from all Departments of Medicine and Endocrinology in Sweden. SUBJECTS A total of 312 young (15-34 years old) adults diagnosed with diabetes during 1987-88. MAIN OUTCOME MEASURE Plasma connecting peptide (C-peptide) 8 years after diagnosis. Preserved beta-cell function was defined as measurable C-peptide levels. Three islet antibodies - cytoplasmic islet cell antibodies (ICA), glutamic acid decarboxylase antibodies and tyrosine phosphatase antibodies - were measured. RESULTS Amongst 269 islet antibody positives (ab+) at diagnosis, preserved beta-cell function was found in 16% (42/269) 8 years later and these patients had a higher body mass index (median 22.7 and 20.5 kg m-2, respectively; P = 0.0003), an increased frequency of one islet antibody (50 and 24%, respectively; P = 0.001), and a lower prevalence of ICA (55 and 6%, respectively; P = 0.007) at diagnosis compared with ab+ without remaining beta-cell function. Amongst the 241 patients without detectable beta-cell function at follow-up, 14 lacked islet antibodies, both at diagnosis and at follow-up. CONCLUSIONS Sixteen per cent of patients with autoimmune type 1 diabetes had remaining beta-cell function 8 years after diagnosis whereas 5.8% with beta-cell failure lacked islet autoimmunity, both at diagnosis and at follow-up.
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Affiliation(s)
- A Schölin
- Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden.
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Herold KC. Treatment of type 1 diabetes mellitus to preserve insulin secretion. Endocrinol Metab Clin North Am 2004; 33:93-111, ix. [PMID: 15053897 DOI: 10.1016/j.ecl.2004.01.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Kevan C Herold
- Division of Endocrinology, Department of Medicine, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
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Steele C, Hagopian WA, Gitelman S, Masharani U, Cavaghan M, Rother KI, Donaldson D, Harlan DM, Bluestone J, Herold KC. Insulin secretion in type 1 diabetes. Diabetes 2004; 53:426-33. [PMID: 14747294 DOI: 10.2337/diabetes.53.2.426] [Citation(s) in RCA: 127] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Type 1 diabetes, a chronic autoimmune disease, causes destruction of insulin-producing beta-cells over a period of years. Although many markers of the autoimmune process have been described, none can convincingly predict the rate of disease progression. Moreover, there is relatively little information about changes in insulin secretion in individuals with type 1 diabetes over time. Previous studies document C-peptide at a limited number of time points, often after a nonphysiologic stimulus, and under non-steady-state conditions. Such methods do not provide qualitative information and may not reflect physiologic responses. We have studied qualitative and quantitative insulin secretion to a 4-h mixed meal in 41 patients with newly diagnosed type 1 diabetes and followed the course of this response for 24 months in 20 patients. Newly diagnosed diabetic patients had an average total insulin secretion in response to a mixed meal that was 52% of that in nondiabetic control subjects, considerably higher than has been described previously. In diabetic patients there was a decline of beta-cell function at an average rate of 756 +/- 132 pmol/month to a final value of 28 +/- 8.4% of initial levels after 2 years. There was a significant correlation between the total insulin secretory response and control of glucose, measured by HbA(1c) (P = 0.003). Two persistent patterns of insulin response were seen depending on the peak insulin response following the oral meal. Patients with an early insulin response (i.e., within the first 45 min after ingestion) to a mixed meal, which was also seen in 37 of 38 nondiabetic control subjects, had a significantly accelerated loss of insulin secretion, as compared with those in whom the insulin response occurred after this time (P < 0.05), and significantly greater insulin secretory responses at 18 and 24 months (P < 0.02). These results, which are the first qualitative studies of insulin secretion in type 1 diabetes, indicate that the physiologic metabolic response is greater at diagnosis than has previously been appreciated, and that the qualitative insulin secretory response is an important determinant of the rate of metabolic decompensation from autoimmune destruction.
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Affiliation(s)
- Chynna Steele
- Department of Medicine, Division of Endocrinology, and the Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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Gorus FK, Weets I, Couck P, Pipeleers DG. Epidemiology of type 1 and type 2 diabetes. The added value of diabetes registries for conducting clinical studies: the Belgian paradigm. Acta Clin Belg 2004; 59:1-13. [PMID: 15065690 DOI: 10.1179/acb.2004.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Diabetes registries have documented that the lifetime risk of diabetes amounts to at least 10% in the western world. Moreover the prevalence of type 2 diabetes is increasing worldwide especially in developing countries. Furthermore there is a secular trend toward earlier clinical manifestation of both type 1 and type 2 diabetes. In the absence of a permanent cure for primary diabetes the present estimated number of at least 150 million diabetic patients worldwide is expected to double within the next 20 years. Consequently a sharp increase in the global burden of chronic diabetes complications is to be feared in the coming decades. Therefore it is absolutely mandatory to intensify research efforts aiming at identifying the etiological factors involved and designing effective strategies for prediction and prevention of the disease and its devastating complications. Diabetes registries constitute instruments of choice to conduct such studies because they are able to collect standardised clinical, demographic and biological information from sufficiently large representative groups of patients and risk groups such as first degree relatives. Since 1989, the Belgian Diabetes Registry is studying all types of diabetes presenting before age 40 in Belgium and provides a paradigm of how diabetes registries may also contribute to the advancement of knowledge on disease heterogeneity, etiology, prediction and prevention.
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Affiliation(s)
- F K Gorus
- Diabetes Research Center, Faculteit Geneeskunde en Academisch Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan 101-103, 1090 Brussel.
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Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes 2004; 53:250-64. [PMID: 14693724 DOI: 10.2337/diabetes.53.1.250] [Citation(s) in RCA: 369] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The underlying cause of type 1 diabetes, loss of beta-cell function, has become the therapeutic target for a number of interventions in patients with type 1 diabetes. Even though insulin therapies continue to improve, it remains difficult to achieve normal glycemic control in type 1 diabetes, especially long term. The associated risks of hypoglycemia and end-organ diabetic complications remain. Retention of beta-cell function in patients with type 1 diabetes is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. To facilitate the development of therapies aimed at altering the type 1 diabetes disease process, an American Diabetes Association workshop was convened to identify appropriate efficacy outcome measures in type 1 diabetes clinical trials. The following consensus emerged: While measurements of immune responses to islet cells are important in elucidating pathogenesis, none of these measures have directly correlated with the decline in endogenous insulin secretion. HbA(1c) is a highly valuable clinical measure of glycemic control, but it is an insensitive measure of beta-cell function, particularly with the currently accepted standard of near-normal glycemic control. Rates of severe hypoglycemia and diabetic complications ultimately will be improved by therapies that are effective at preserving beta-cell function but as primary outcomes require inordinately large and protracted trials. Endogenous insulin secretion is assessed best by measurement of C-peptide, which is cosecreted with insulin in a one-to-one molar ratio but unlike insulin experiences little first pass clearance by the liver. Measurement of C-peptide under standardized conditions provides a sensitive, well accepted, and clinically validated assessment of beta-cell function. C-peptide measurement is the most suitable primary outcome for clinical trials of therapies aimed at preserving or improving endogenous insulin secretion in type 1 diabetes patients. Available data demonstrate that even relatively modest treatment effects on C-peptide will result in clinically meaningful benefits. The development of therapies for addressing this important unmet clinical need will be facilitated by trials that are carefully designed with beta-cell function as determined by C-peptide measurement as the primary efficacy outcome.
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Affiliation(s)
- Jerry P Palmer
- Department of Medicine, University of Washington,and DVA Puget Sound Health Care System, Seattle, Washington 98108, USA.
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Bernene J, Zgonis T, Jolly GP. Diabetes mellitus and pharmacological therapy. Clin Podiatr Med Surg 2003; 20:635-53. [PMID: 14636030 DOI: 10.1016/s0891-8422(03)00066-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Diabetes mellitus can be a devastating lifelong disease if not treated appropriately. The physician and the patient should be aware of both extremes involved with DM: hyperglycemia and hypoglycemia. Patient education and preventive care are perhaps more important in this disease than many others. A multidisciplinary approach involving the patient, physician, and diabetic educator is best to assure a better quality of life. Enormous advances in the treatment of diabetes have occurred over the past decade and even greater ones can be expected in the future. New drugs, insulin delivery devices, and noninvasive glucose monitoring machines have the potential to normalize blood sugar levels and return diabetics to a near normal lifespan without complications.
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Affiliation(s)
- James Bernene
- Department of Medicine, New Britain General Hospital, New Britain, CT 06052, USA
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Hanifi-Moghaddam P, Schloot NC, Kappler S, Seissler J, Kolb H. An association of autoantibody status and serum cytokine levels in type 1 diabetes. Diabetes 2003; 52:1137-42. [PMID: 12716743 DOI: 10.2337/diabetes.52.5.1137] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
At onset of type 1 diabetes, the islet autoantibody status of patients has been reported to predict progression of the disease. We therefore tested the hypothesis that the systemic immunoregulatory balance, as defined by levels of circulating cytokines and chemokines, is associated with islet autoantibody status. In 50 patients with recent-onset type 1 diabetes, antibodies to GAD and insulinoma-associated antigen 2 (IA-2) were analyzed by radioimmunoassay; cytoplasmic islet cell antibodies were determined by indirect immunofluorescence. Cytokine and chemokine concentrations were measured by rigidly evaluated double antibody enzyme-linked immunosorbent assay. Of four classically defined Th1/Th2 cytokines (gamma-interferon, interleukin [IL]-5, IL-10, IL-13), none showed an association with multiple autoantibody positivity. Of six mediators mainly produced by innate immunity cells, three were associated with multiple autoantibody status (IL-18 increased, MIF and MCP-1 decreased) and three were unaffected (IL-12, MIP-1beta, IP-10). GAD and/or IA-2 antibody titers negatively correlated with systemic concentrations of MIF, MIP-1beta, and IL-12. Combining the data of several cytokine and chemokine levels made it possible to predict islet antibody positivity in individual patients with 85% sensitivity and 94% specificity. These data suggest a close association of islet antibody status with systemic immunoregulation in type 1 diabetes.
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Affiliation(s)
- Pejman Hanifi-Moghaddam
- German Diabetes Research Institute, Heinrich-Heine University of Düsseldorf, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany
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Bhowmick SK, Estrada B, Rettig KR. Insulin-dependent diabetes mellitus in 2 male African American children after Kawasaki disease. Pediatrics 2002; 110:e27. [PMID: 12165626 DOI: 10.1542/peds.110.2.e27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Two children with insulin-dependent diabetes mellitus (IDDM) presented with diabetic ketoacidosis within 4 months of being diagnosed with Kawasaki disease (KD). Both patients were African American males younger than 4 years of age. Immune markers associated with the autoimmune cause of diabetes were not detectable in these patients at the time of diagnosis with IDDM. In 1 patient, the immune markers were repeated 6 months after diagnosis but remained negative. Both patients currently require approximately 1 unit of insulin/kg/d. Occurrence of IDDM after KD is rare; we could find no such reports in the English literature. The cause of diabetes in these 2 patients remains elusive, as does the cause of KD.
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Affiliation(s)
- Samar K Bhowmick
- Section of Pediatric Endocrinology and Metabolism, University of South Alabama, Mobile, Alabama 36617-7722, USA.
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Christie MR, Mølvig J, Hawkes CJ, Carstensen B, Mandrup-Poulsen T. IA-2 antibody-negative status predicts remission and recovery of C-peptide levels in type 1 diabetic patients treated with cyclosporin. Diabetes Care 2002; 25:1192-7. [PMID: 12087018 DOI: 10.2337/diacare.25.7.1192] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The use of cyclosporin in recent-onset type 1 diabetes has demonstrated the potential for immune intervention in the treatment and prevention of the disease. However, a proportion of patients failed to respond to cyclosporin treatment. Indicators of resistance to immune intervention would be valuable for the most effective use of such therapies in disease prevention. The aim of this study was to determine whether presence of IA-2 antibodies is such a marker. RESEARCH DESIGN AND METHODS IA-2 antibodies were determined by radioligand binding assay in sera from patients recruited into the Canadian-European cyclosporin trial. Insulin dose requirements and glucagon-stimulated C-peptide secretion were analyzed in patients grouped according to IA-2 antibody status at entry. RESULTS Cyclosporin treatment had no significant effect on frequency of IA-2 antibodies during the 1 year of treatment. Cyclosporin caused significant reduction in insulin requirements and significant increases in C-peptide secretion mainly in patients negative for IA-2 antibodies. Analysis of GAD antibodies in combination with antibodies to IA-2 indicated that the group most resistant to cyclosporin were IA-2 antibody positive, GAD antibody negative. CONCLUSIONS The results demonstrate that IA-2 antibody analysis is valuable in identifying individuals for whom immunosuppressive treatment would be most effective.
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Affiliation(s)
- Michael R Christie
- Department of Medicine, Guy's, King's and St. Thomas' School of Medicine, London, UK.
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Borg H, Gottsäter A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 2002; 51:1754-62. [PMID: 12031962 DOI: 10.2337/diabetes.51.6.1754] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
To clarify the relationships between islet antibodies (islet cell antibody [ICA], GAD antibody [GADA], and IA-2 antibody [IA-2A]) versus the progression of beta-cell dysfunction, we have followed a group of diabetic patients from their diagnosis at 21-73 years of age. Patients with ICA had high levels of GADA and/or IA-2A at diagnosis and a more severe beta-cell dysfunction 5 years after diagnosis than those with only GADA in low concentrations. The aim of the current 12-year follow-up study was to examine the further progression of beta-cell dysfunction in relation to islet antibodies at and after diagnosis. Among 107 patients, complete beta-cell failure 12 years after diagnosis was restricted to those with islet antibodies at diagnosis (16 of 21 [77%] with multiple antibodies and 4 of 5 [80%] with only GADA). In contrast, among antibody-negative patients, fasting P-C-peptide levels were unchanged. Most GADA-positive patients (22 of 27 [81%]) remained GADA positive after 12 years. Associated with decreasing fasting P-C-peptide levels (0.85 nmol/l [0.84] at diagnosis vs. 0.51 nmol/l [0.21] 12 years after diagnosis, P < 0.05), ICA developed after diagnosis in 6 of 105 originally antibody negative mostly overweight patients. In conclusion, multiple islet antibodies or GADA alone at diagnosis of diabetes predict future complete beta-cell failure. After diagnosis, GADA persisted in most patients, whereas ICA development in patients who were antibody negative at diagnosis indicated decreasing beta-cell function.
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Affiliation(s)
- Henrik Borg
- Department of Endocrinology, Lund University, Malmö University Hospital, Malmö, Sweden.
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Abstract
The diagnosis of type 1 diabetes versus other forms of diabetes such as type 2 diabetes is paramount to guiding proper therapy. Several islet autoantibodies have been identified that serve to diagnose immune-mediated, type 1a diabetes in clinically ambiguous cases. These autoantibodies also serve to predict type 1 diabetes in nondiabetic individuals. The most useful islet autoantibodies include islet cell cytoplasmic autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies, and insulinoma-associated-2 autoantibodies. Once type 1 diabetes can be safely and reliably prevented, large-scale islet autoantibody screening programs of the general pediatric population may be warranted. It is controversial whether islet autoantibodies influence the course of type 1 diabetes following diagnosis.
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Affiliation(s)
- William E Winter
- Department of Pathology, Laboratory Medicine & Immunology, University of Florida, Gainesville, Florida 32610-0275, USA.
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Van der Auwera BJ, Schuit FC, Weets I, Ivens A, Van Autreve JE, Gorus FK. Relative and absolute HLA-DQA1-DQB1 linked risk for developing type I diabetes before 40 years of age in the Belgian population: implications for future prevention studies. Hum Immunol 2002; 63:40-50. [PMID: 11916169 DOI: 10.1016/s0198-8859(01)00362-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
HLA-DQ genotyping remains the cornerstone of genetic risk stratification in type I diabetes prediction and prevention studies. We developed a genetic screening strategy for predisposition to type I diabetes in the Belgian population based upon HLA-DQA1-DQB1 typing and taking into account the age at clinical onset. A group of 1866 autoantibody-positive type I patients below age 40 years recruited by the Belgian Diabetes Registry and a group of 750 control subjects were DQA1-DQB1 genotyped. In the total study population 16 different DQA1-DQB1 haplotypes were revealed, allowing the stratification of 81 genotypes in ten different genotype groups. Apart from the highest risk DQA1*-DQB1* genotype 0301-0302/0501-0201 (odds ratio 21; absolute risk 6%), three other genotype groups conferred a highly significant disease risk (p < 10(-6)). Altogether, these susceptibility genotypes were carried by 9% of the control subjects versus 60% of the patients diagnosed before age 40 years and up to 70% of those under age 5 years. All other genotypes were protective, neutral, infrequent or associated with a moderate protection or susceptibility. A strong, although not absolute protection was conferred by DQB1*0602-positive haplotypes (odds ratio = 0.03). This study in a large cohort of autoantibody-positive patients shows that a DQA1-DQB1-based genotyping strategy allows the identification of a subgroup representing less than 10% of the Belgian population but harbouring the majority of future type I patients arising in childhood or early adulthood. Future prediction and prevention studies should take into account the age dependency of this HLA-DQ associated risk.
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Gorus FK, Pipeleers DG. Prospects for predicting and stopping the development of type 1 of diabetes. Best Pract Res Clin Endocrinol Metab 2001; 15:371-89. [PMID: 11554777 DOI: 10.1053/beem.2001.0152] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The prevention of diabetes and its devastating complications is the prime goal of diabetes care. In immune-mediated type 1 diabetes, beta cell destruction can be predicted with increasing confidence both before and after diagnosis, thus allowing the development of preventative strategies. Multicentre clinical trials with the natural products insulin and nicotinamide have been launched, but the results will only be available in a few years time. Meanwhile, observational studies in large representative risk groups can help to refine the selection of subjects with a more homogenous risk for beta cell destruction, thereby reducing the need for large sample sizes. The comparison between biological markers and disease progression will help to define surrogate disease end-points that can be monitored before the hard clinical end-points of hyperglycaemia or remission. These advances will facilitate the start of new pilot trials to identify relatively safe candidate interventions adapted to disease stage.
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Affiliation(s)
- F K Gorus
- Diabetes Research Centre, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, B-1090, Belgium
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Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 2001; 24:1460-7. [PMID: 11473087 DOI: 10.2337/diacare.24.8.1460] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Type 1 diabetes is caused by the immune-mediated destruction of islet insulin-secreting beta-cells. This chronic destructive process is associated with both cellular and humoral immune changes in the peripheral blood that can be detected months or even years before the onset of clinical diabetes. Throughout this prediabetic period, metabolic changes, including altered glucose tolerance and reduced insulin secretion, deteriorate at variable rates and eventually result in clinical diabetes. A fraction of individuals with humoral immunological changes have clinical diabetes that initially is not insulin-requiring. The onset of diabetes in these patients is usually in adult life, and because their diabetes is at least initially not insulin-requiring, they appear clinically to be affected by type 2 diabetes. Such patients probably have the same disease process as patients with type 1 diabetes in that they have similar HLA genetic susceptibility as well as autoantibodies to islet antigens, low insulin secretion, and a higher rate of progression to insulin dependency. These patients are defined as being affected by an autoimmune type of diabetes not requiring insulin at diagnosis, which is also named latent autoimmune diabetes of the adult (LADA). Special attention should be paid to diagnose such patients because therapy may influence the speed of progression toward insulin dependency, and in this respect, efforts should be made to protect residual C-peptide secretion. LADA can serve as a model for designing new strategies for prevention of type 1 diabetes but also as a target group for prevention in its own right.
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Affiliation(s)
- P Pozzilli
- Università Campus Biomedico and the. Università La Sapienza, Rome, Italy.
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