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Ravikumar V, Ahmed A, Anjankar A. A Review on Latent Autoimmune Diabetes in Adults. Cureus 2023; 15:e47915. [PMID: 38034250 PMCID: PMC10683931 DOI: 10.7759/cureus.47915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 10/29/2023] [Indexed: 12/02/2023] Open
Abstract
Latent autoimmune diabetes (LADA) is an unique form of diabetes that has characteristics of both type 1 and type 2 diabetes. Type 1.5 diabetes also known as LADA is occasionally confused for type 2 diabetes because there is delay in presenting features and early insulin independence. LADA, on the other hand, is an autoimmune disorder that differs from type 2 diabetes in that autoantibodies against pancreatic beta cells are what characterise it. Insulin production eventually diminishes due to the autoimmune destruction of pancreatic beta cells as a result of the pathophysiology of LADA. Autoantibodies to glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2), and insulin are frequently detected in LADA patients. These autoantibodies have important implications for therapy strategies and are essential in differentiating LADA from type 2 diabetes. LADA clinical management is very challenging. The aim of this article is to view the characteristics, disease presentation, diagnostic challenges, progression and treatment modalities of LADA.
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Affiliation(s)
- Vijay Ravikumar
- Medical Education, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Ariba Ahmed
- Medical Education, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Ashish Anjankar
- Biochemistry, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
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Wang W, Huang F, Han C. Efficacy of Regimens in the Treatment of Latent Autoimmune Diabetes in Adults: A Network Meta-analysis. Diabetes Ther 2023; 14:1723-1752. [PMID: 37584857 PMCID: PMC10499777 DOI: 10.1007/s13300-023-01459-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/03/2023] [Indexed: 08/17/2023] Open
Abstract
INTRODUCTION Latent autoimmune diabetes in adults (LADA) is a highly heterogeneous autoimmune condition with clinical and genetic characteristics that fall between those of type 1 diabetes mellitus and type 2 diabetes mellitus; therefore, there are no uniform criteria for the selection of therapeutic agents. We conducted a network meta-analysis to evaluate the efficacy of various therapeutic agents for LADA by comparing their effects on various indicators used to reflect LADA. METHODS We searched the PubMed, Cochrane Library, Embase and Web of Science databases from their inception to March 2023 and collected data from 14 randomized controlled trials on glucose-lowering drugs for LADA, including 23 studies and 15 treatment regimens. The effectiveness of drugs was ranked and evaluated by combining surface under the cumulative ranking (SUCRA) plots and forest plots. Factors that may influence study heterogeneity were also searched and analyzed by combining subgroup analysis, publication bias, funnel plots and sensitivity analysis. RESULTS The results of the network meta-analysis showed that insulin had the most significant effect on the control of change from baseline in glycosylated hemoglobin, type A1 (ΔHbA1c). Insulin combined with dipeptidyl peptidase-4 (DPP-4) inhibitors performed the best in reducing fasting blood glucose and body mass index. Treatment regimens involving thiazolidinediones were the most advantageous in HbA1c, fasting C-peptide and postprandial C-peptide control. Longer dosing may be more beneficial in maintaining islet β-cell function in the LADA population. CONCLUSION LADA is an immune condition with high heterogeneity, and treatment should be administered according to the C-peptide level of the LADA population. For this population with LADA with a certain level of β-cell function, combinations of insulin with DPP-4 inhibitors or thiazolidinediones probably can be more effective treatment options to maintain islet function and normal blood glucose. TRIAL REGISTRATION PROSPERO CRD42023410795.
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Affiliation(s)
- Wanqing Wang
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu Province, China
| | - Fei Huang
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu Province, China
| | - Chunchao Han
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, No. 4655, University Road, University Science and Technology Park, Changqing District, Jinan, 250355, Shandong Province, China.
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Barton-Maxwell V. A Case Report of LADA in the Primary Care Setting. J Nurse Pract 2023. [DOI: 10.1016/j.nurpra.2023.104539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
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Patil SP. Atypical Diabetes and Management Considerations. Prim Care 2022; 49:225-237. [DOI: 10.1016/j.pop.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Yau B, Hocking S, Andrikopoulos S, Kebede MA. Targeting the insulin granule for modulation of insulin exocytosis. Biochem Pharmacol 2021; 194:114821. [PMID: 34748819 DOI: 10.1016/j.bcp.2021.114821] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 02/08/2023]
Abstract
The pancreatic β-cells control insulin secretion in the body to regulate glucose homeostasis, and β-cell stress and dysfunction is characteristic of Type 2 Diabetes. Pharmacological targeting of the β-cell to increase insulin secretion is typically utilised, however, extended use of common drugs such as sulfonylureas are known to result in secondary failure. Moreover, there is evidence they may induce β-cell failure in the long term. Within β-cells, insulin secretory granules (ISG) serve as compartments to store, process and traffic insulin for exocytosis. There is now growing evidence that ISG exist in multiple populations, distinct in their protein composition, motility, age, and capacity for secretion. In this review, we discuss the implications of a heterogenous ISG population in β-cells and highlight the need for more understanding into how unique ISG populations may be targeted in anti-diabetic therapies.
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Affiliation(s)
- Belinda Yau
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia.
| | - Samantha Hocking
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia; Central Clinical School, Faculty of Medicine and Health and Department of Endocrinology Royal Prince Alfred Hospital, NSW, Australia
| | | | - Melkam A Kebede
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
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Yang L, Liang H, Liu X, Wang X, Cheng Y, Zhao Y, Liu L, Huang G, Wang X, Zhou Z. Islet Function and Insulin Sensitivity in Latent Autoimmune Diabetes in Adults Taking Sitagliptin: A Randomized Trial. J Clin Endocrinol Metab 2021; 106:e1529-e1541. [PMID: 33475138 PMCID: PMC7993585 DOI: 10.1210/clinem/dgab026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Indexed: 12/17/2022]
Abstract
CONTEXT The long-term effects of dipeptidyl peptidase-4 inhibitors on β-cell function and insulin sensitivity in latent autoimmune diabetes in adults (LADA) are unclear. OBJECTIVE To investigate the effects of sitagliptin on β-cell function and insulin sensitivity in LADA patients receiving insulin. DESIGN AND SETTING A randomized controlled trial at the Second Xiangya Hospital. METHODS Fifty-one patients with LADA were randomized to sitagliptin + insulin (SITA) group or insulin alone (CONT) group for 24 months. MAIN OUTCOME MEASURES Fasting C-peptide (FCP), 2-hour postprandial C-peptide (2hCP) during mixed-meal tolerance test, △CP (2hCP - FCP), and updated homeostatic model assessment of β-cell function (HOMA2-B) were determined every 6 months. In 12 subjects, hyperglycemic clamp and hyperinsulinemic euglycemic clamp (HEC) tests were further conducted at 12-month intervals. RESULTS During the 24-month follow-up, there were no significant changes in β-cell function in the SITA group, whereas the levels of 2hCP and △CP in the CONT group were reduced at 24 months. Meanwhile, the changes in HOMA2-B from baseline were larger in the SITA group than in the CONT group. At 24 months, first-phase insulin secretion was improved in the SITA group by hyperglycemia clamp, which was higher than in the CONT group (P < .001), while glucose metabolized (M), insulin sensitivity index, and M over logarithmical insulin ratio in HEC were increased in the SITA group (all P < .01 vs baseline), which were higher than in the CONT group. CONCLUSION Compared with insulin intervention alone, sitagliptin plus insulin treatment appeared to maintain β-cell function and improve insulin sensitivity in LADA to some extent.
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Affiliation(s)
- Lin Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Huiying Liang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Affiliated Dongguan People’s Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, China
| | - Xinyuan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xia Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ying Cheng
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yunjuan Zhao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Lingjiao Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiangbing Wang
- Division of Endocrinology, Metabolism and Nutrition, Rutgers University-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Correspondence: Zhiguang Zhou, MD, PhD, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha 410011, Hunan, China.
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Buzzetti R, Tuomi T, Mauricio D, Pietropaolo M, Zhou Z, Pozzilli P, Leslie RD. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Diabetes 2020; 69:2037-2047. [PMID: 32847960 PMCID: PMC7809717 DOI: 10.2337/dbi20-0017] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving form of autoimmune diabetes, described as latent autoimmune diabetes of adults (LADA), accounts for 2-12% of all patients with adult-onset diabetes, though they show considerable variability according to their demographics and mode of ascertainment. While therapeutic strategies aim for metabolic control and preservation of residual insulin secretory capacity, endotype heterogeneity within LADA implies a personalized approach to treatment. Faced with a paucity of large-scale clinical trials in LADA, an expert panel reviewed data and delineated one therapeutic approach. Building on the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus for T2D and heterogeneity within autoimmune diabetes, we propose "deviations" for LADA from those guidelines. Within LADA, C-peptide values, proxy for β-cell function, drive therapeutic decisions. Three broad categories of random C-peptide levels were introduced by the panel: 1) C-peptide levels <0.3 nmol/L: a multiple-insulin regimen recommended as for T1D; 2) C-peptide values ≥0.3 and ≤0.7 nmol/L: defined by the panel as a "gray area" in which a modified ADA/EASD algorithm for T2D is recommended; consider insulin in combination with other therapies to modulate β-cell failure and limit diabetic complications; 3) C-peptide values >0.7 nmol/L: suggests a modified ADA/EASD algorithm as for T2D but allowing for the potentially progressive nature of LADA by monitoring C-peptide to adjust treatment. The panel concluded by advising general screening for LADA in newly diagnosed non-insulin-requiring diabetes and, importantly, that large randomized clinical trials are warranted.
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Affiliation(s)
- Raffaella Buzzetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Tiinamaija Tuomi
- Division of Endocrinology, Abdominal Center, Helsinki University Hospital, Institute for Molecular Medicine Finland FIMM and Research Program for Clinical and Molecular Metabolism, University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland
- Lund University Diabetes Center, University of Lund, Malmo, Sweden
| | - Didac Mauricio
- Department of Endocrinology & Nutrition, CIBERDEM, Hospital de la Santa Creu i Sant Pau & Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Autonomous University of Barcelona, Barcelona, Spain
| | - Massimo Pietropaolo
- Division of Endocrinology, Diabetes and Metabolism, Diabetes Research Center, Baylor College of Medicine, Houston, TX
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Paolo Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University, Rome, Italy
- Blizard Institute, Barts and The London School of Medicine and Dentistry, University of London, London, U.K
| | - Richard David Leslie
- Blizard Institute, Barts and The London School of Medicine and Dentistry, University of London, London, U.K.
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Koufakis T, Katsiki N, Zebekakis P, Dimitriadis G, Kotsa K. Therapeutic approaches for latent autoimmune diabetes in adults: One size does not fit all. J Diabetes 2020; 12:110-118. [PMID: 31449359 DOI: 10.1111/1753-0407.12982] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/02/2019] [Accepted: 08/22/2019] [Indexed: 12/20/2022] Open
Abstract
Recent advances in the understanding of latent autoimmune diabetes in adults (LADA) pathophysiology make it increasingly evident that people with LADA comprise a heterogenous group of patients. This makes the establishment of a standard treatment algorithm challenging. On top of its glucose-lowering action, insulin may exert anti-inflammatory effects, rendering it an attractive therapeutic choice for a type of diabetes in which autoinflammation and beta cell insufficiency play major pathogenetic roles. However, there is growing evidence that other antidiabetic drugs, such as metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and thiazolidinediones, might have a role in optimizing glycemic control and preserving beta cell function in individuals with LADA, either alone or in combination with insulin. Although most of these drugs have been routinely used in the daily clinical setting for years, large prospective randomized trials are needed to assess whether they are capable of delaying progression to insulin dependence as well as their effects on diabetic complications. The aim of the present review is to discuss the current state and future perspectives of LADA therapy, emphasizing the need for individualized and patient-centered therapeutic approaches.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Niki Katsiki
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - George Dimitriadis
- Research Institute and Diabetes Center, Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Attikon" University Hospital, Athens, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
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Nishimura A, Matsumura K, Kikuno S, Nagasawa K, Okubo M, Mori Y, Kobayashi T. Slowly Progressive Type 1 Diabetes Mellitus: Current Knowledge And Future Perspectives. Diabetes Metab Syndr Obes 2019; 12:2461-2477. [PMID: 31819572 PMCID: PMC6886592 DOI: 10.2147/dmso.s191007] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/18/2019] [Indexed: 12/21/2022] Open
Abstract
Slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM), sometimes referred to as latent autoimmune diabetes in adults (LADA), is a heterogeneous disease that is often confused with type 1 and type 2 diabetes. As a result, there were few diagnostic criteria for this disorder until 2012, when the Japan Diabetes Society established criteria that could be used in clinical practice. A primary question is whether pathologic markers for type 1 or type 2 diabetes are present in the pancreas of patients with SPIDDM, because the phenotype of SPIDDM is similar to both type 1 and type 2 diabetes. Recent studies clarified pathologic findings in the pancreas of patients with SPIDDM, which included T-cell-mediated insulitis, a marker of type 1 diabetes; pseudoatrophic islets (islets specifically devoid of beta cells), another hallmark of type 1 diabetes; and a lack of amylin (ie, islet amyloid polypeptide) deposition to the islet cells, a pathologic marker of type 2 diabetes. In terms of preventing the loss of beta-cell function in patients with SPIDDM, several studies have shown that some drugs, including dipeptidyl peptidase-4 inhibitors, are effective. There is an increased need for early diagnosis of SPIDDM to preserve beta-cell function. This review presents updated findings on the pathogenesis and immunologic findings of the affected pancreas, diagnostic markers, risk factors for progression of beta-cell dysfunction, epidemiology, clinical features, diagnostic strategies, prevention strategies, and clinical options for patients with SPIDDM.
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Affiliation(s)
- Akihiro Nishimura
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Kimio Matsumura
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Shota Kikuno
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Kaoru Nagasawa
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Minoru Okubo
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Yasumichi Mori
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Tetsuro Kobayashi
- Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan
- Correspondence: Tetsuro Kobayashi Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-Ku, Tokyo, JapanTel +81-3-3588-1111Fax +81-3-3582-7068 Email
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Tang X, Yan X, Zhou H, Yang X, Niu X, Liu J, Ji Q, Ji L, Li X, Zhou Z. Prevalence and identification of type 1 diabetes in Chinese adults with newly diagnosed diabetes. Diabetes Metab Syndr Obes 2019; 12:1527-1541. [PMID: 31695456 PMCID: PMC6718056 DOI: 10.2147/dmso.s202193] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 06/18/2019] [Indexed: 01/19/2023] Open
Abstract
AIM This study aimed to estimate the prevalence of latent autoimmune diabetes of adults (LADA) and classic type 1 diabetes mellitus (T1DM) in newly diagnosed adult diabetes in China. METHOD This cross-sectional study involved 17,349 newly diagnosed diabetes in adults aged ≥30 years from 46 hospitals within 31 months. Demographic characteristics, clinical features, and medical history were collected by trained researchers. T1DM as a whole was comprised of classic T1DM and LADA. Classic T1DM was identified based on the clinical phenotype of insulin-dependency, and LADA was differentiated from patients with initially an undefined diabetes type with standardized glutamic acid decarboxylase autoantibody testing at the core laboratory. The age and sex distributions from a large national survey of diabetes in China conducted in 2010 were used to standardize the prevalence of classic T1DM and LADA. RESULTS Among 17,349 adult patients, the prevalence of T1DM was 5.49% (95% CI: 4.90-6.08%) (5.14% [95% CI: 4.36-5.92%] in males and 6.16% [95% CI: 5.30-7.02%] in females), with 65% of these having LADA. The prevalence of classic T1DM decreased with increasing age (p<0.05), while that of LADA was stable (p>0.05). The prevalence of T1DM in overweight or obese patients was 3.42% (95% CI: 3.20-3.64%) and 2.42% (95% CI: 1.83-3.01%), respectively, and LADA accounted for 76.5% and 79.2% in these two groups. CONCLUSION We draw the conclusion that T1DM, especially LADA, was prevalent in newly diagnosed adult-onset diabetes in China, which highlights the importance of routine islet autoantibodies testing in clinical practice.
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Affiliation(s)
- Xiaohan Tang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, People’s Republic of China
- National Clinical Research Center for Metabolic Diseases, Changsha, People’s Republic of China
| | - Xiang Yan
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, People’s Republic of China
- National Clinical Research Center for Metabolic Diseases, Changsha, People’s Republic of China
| | - Houde Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- National Clinical Research Center for Metabolic Diseases, Changsha, People’s Republic of China
- Hunan Key Laboratory for Metabolic Bone Diseases, Changsha, People’s Republic of China
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, People’s Republic of China
| | - Xiaohong Niu
- Department of Endocrinology, Heji Hospital Affiliated to Changzhi Medical College, Changzhi, People’s Republic of China
| | - Jing Liu
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, People’s Republic of China
| | - Qiuhe Ji
- Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi'an, People’s Republic of China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Xia Li
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, People’s Republic of China
- National Clinical Research Center for Metabolic Diseases, Changsha, People’s Republic of China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, People’s Republic of China
- National Clinical Research Center for Metabolic Diseases, Changsha, People’s Republic of China
- Correspondence: Zhiguang Zhou Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Furong District, Changsha, Hunan410011, People’s Republic of ChinaTel +86 7 318 529 2154Email
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Pieralice S, Pozzilli P. Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management. Diabetes Metab J 2018; 42:451-464. [PMID: 30565440 PMCID: PMC6300440 DOI: 10.4093/dmj.2018.0190] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 11/14/2018] [Indexed: 12/16/2022] Open
Abstract
Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.
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Affiliation(s)
- Silvia Pieralice
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
| | - Paolo Pozzilli
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
- Centre of Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
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Pozzilli P, Pieralice S. Latent Autoimmune Diabetes in Adults: Current Status and New Horizons. Endocrinol Metab (Seoul) 2018; 33:147-159. [PMID: 29947172 PMCID: PMC6021307 DOI: 10.3803/enm.2018.33.2.147] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 05/23/2018] [Accepted: 05/28/2018] [Indexed: 12/16/2022] Open
Abstract
Autoimmune diabetes is a heterogeneous disease which can arise at any age. Subjects with adult-onset autoimmune diabetes who do not necessitate insulin-therapy for at least 6 months after diagnosis are demarcated as having latent autoimmune diabetes in adults (LADA). This condition is more heterogeneous than young-onset autoimmune diabetes and shares clinical and metabolic characteristics with both type 2 and type 1 diabetes. Patients with LADA are considered by having highly variable β-cell destruction, different degrees of insulin resistance and heterogeneous titre and pattern of islet autoantibody, suggesting different pathophysiological pathways partially explaining the heterogeneous phenotypes of LADA. To date the heterogeneity of LADA does not allow to establish a priori treatment algorithm and no specific guidelines for LADA therapy are available. These subjects are mostly treated as affected by type 2 diabetes, a factor that might lead to the progression to insulin-dependency quickly. A personalised medicine approach is necessary to attain optimal metabolic control and preserve β-cell function to decrease the risk of long-term diabetes complications. Recent data concerning the use of oral antidiabetic agents as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists indicate up-and-coming results in term of protect C-peptide levels and improving glycaemic control. This review summarises current knowledge on LADA, emphasising controversies regarding its pathophysiology and clinical features. Moreover, we discuss data available about novel therapeutic approaches that can be considered for prevention of β-cell loss in LADA.
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Affiliation(s)
- Paolo Pozzilli
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
- Centre of Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary, University of London, London, UK.
| | - Silvia Pieralice
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
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Wod M, Yderstræde KB, Halekoh U, Beck-Nielsen H, Højlund K. Metabolic risk profiles in diabetes stratified according to age at onset, islet autoimmunity and fasting C-peptide. Diabetes Res Clin Pract 2017; 134:62-71. [PMID: 28987750 DOI: 10.1016/j.diabres.2017.09.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/22/2017] [Accepted: 09/27/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Islet autoimmunity, age at onset and time to insulin treatment are often used to define subgroups of diabetes. However, the latter criterion is not clinical useful. Here, we examined whether an unbiased stratification of diabetes according to age at onset, fasting C-peptide and GAD autoantibodies (GADab) defines groups with differences in glycaemic control and markers of cardiometabolic risk. DESIGN AND METHODS A cohort of 4374 adults with relatively newly diagnosed diabetes referred to a Danish hospital during 1997-2012 was stratified according to age at onset above or below 30 years, fasting C-peptide above or below 300 pmol/l (CPEPhigh or CPEPlow), and presence or absence of GADab (GADpos or GADneg). HbA1c, BMI, blood pressure (BP), lipid profile, alanine aminotransferase (ALT) and creatinine were evaluated. RESULTS GADab were present in 13% of the cohort. Age at onset was not associated with major differences between groups. Patients with insulin deficient diabetes (CPEPlow; n = 503) had higher HbA1c but otherwise lower cardiometabolic risk (lower BMI, BP, LDL, triacylglycerol, and ALT, and higher HDL) than both patients with latent autoimmune diabetes of adults (LADA defined as GADposCPEPhigh; n = 327) and patients with type 2 diabetes (GADnegCPEPhigh; n = 3544). Patients with LADA defined an intermediate group with higher HbA1c but otherwise lower cardiometabolic risk than patients with type 2 diabetes. CONCLUSIONS Our results demonstrate that fasting C-peptide and GADab status, but not age at onset, define groups of patients with diabetes with clinically relevant differences in glycaemic control and cardiometabolic risk.
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Affiliation(s)
- Mette Wod
- Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark
| | - Knud B Yderstræde
- Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark
| | - Ulrich Halekoh
- Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, DK-5000 Odense, Denmark
| | - Henning Beck-Nielsen
- Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark
| | - Kurt Højlund
- Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark; Section of Molecular Diabetes and Metabolism, Institute of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
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Buzzetti R, Zampetti S, Maddaloni E. Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol 2017; 13:674-686. [PMID: 28885622 DOI: 10.1038/nrendo.2017.99] [Citation(s) in RCA: 165] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus.
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Affiliation(s)
- Raffaella Buzzetti
- Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy
| | - Simona Zampetti
- Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy
| | - Ernesto Maddaloni
- Department of Medicine, Unit of Endocrinology and Diabetes, University Campus Bio-Medico, Via Álvaro del Portillo 21, 00128, Rome, Italy
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Awata T, Shimada A, Maruyama T, Oikawa Y, Yasukawa N, Kurihara S, Miyashita Y, Hatano M, Ikegami Y, Matsuda M, Niwa M, Kazama Y, Tanaka S, Kobayashi T. Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S). Diabetes Ther 2017; 8:1123-1134. [PMID: 28929327 PMCID: PMC5630555 DOI: 10.1007/s13300-017-0299-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the β-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA). METHODS In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used. RESULTS On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased. CONCLUSION The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the β-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors. CLINICAL TRIAL REGISTRATION Japanese Clinical Trials Registry UMIN000003693.
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Affiliation(s)
- Takuya Awata
- Department of Diabetes, Endocrinology and Metabolism, International University of Health and Welfare Hospital, Iguchi, Nasushiobara-shi, Tochigi, Japan.
| | - Akira Shimada
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Taro Maruyama
- Department of Internal Medicine, Saitama Social Insurance Hospital, Saitama, Japan
| | - Yoichi Oikawa
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Nobuyuki Yasukawa
- Department of Diabetes, Endocrinology and Metabolism, International University of Health and Welfare Hospital, Iguchi, Nasushiobara-shi, Tochigi, Japan
| | - Susumu Kurihara
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yumi Miyashita
- Division of RI Laboratory, Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Masako Hatano
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yuichi Ikegami
- Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Masafumi Matsuda
- Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | | | | | | | - Tetsuro Kobayashi
- Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan
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Kumar A, de Leiva A. Latent autoimmune diabetes in adults (LADA) in Asian and European populations. Diabetes Metab Res Rev 2017; 33. [PMID: 28198081 DOI: 10.1002/dmrr.2890] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 01/18/2017] [Accepted: 02/02/2017] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus is a chronic disorder caused by relative or absolute insulin deficiency and characterized by chronic hyperglycaemia. It is expected that by year 2025, 80% of all type 2 diabetic patients will be living in developing or low- and middle-income countries. Among Asians, there has been an overall increase in abdominal obesity; however, the risk of diabetes in these populations starts at much lower body mass index as compared to Caucasians. A significant proportion of diabetic patients with adult-onset, initially nonrequiring insulin treatment, have diabetes-associated autoantibodies in their sera. A new subclass of diabetes with the designation of latent autoimmune diabetes of adult-onset (LADA) has been proposed for this category of subjects. Studies have demonstrated that patients with autoimmune diabetes, characterized by the presence of glutamic decarboxylase autoantibodies display a different clinical phenotype from classical type 2 diabetes without glutamic decarboxylase autoantibodies. This subset of phenotypic type 2 diabetes subjects with islet autoantibodies tend to have sulphonylurea failure and need insulin treatment earlier in the disease process. Diagnosing LADA at an initial stage will be important so that insulin can be initiated earlier, facilitating improved glycemic control sooner as well as the preservation of residual beta-cell function in adult-onset autoimmune diabetes. Because of differences in dietary habits, environmental factors, and phenotypic characteristics between European and Asian populations, there may be heterogeneity in the prevalence and other characteristics of LADA in these two populations.
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Affiliation(s)
- Alok Kumar
- Department of Diabetes, Endocrinology and Nutrition, Hospital de Sant Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Alberto de Leiva
- Department of Diabetes, Endocrinology and Nutrition, Hospital de Sant Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- EDUAB-IIB-HSP (CIBER-BBN, ISCIII), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- Fundación DIABEM, Barcelona, Spain
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O’Neal KS, Johnson JL, Panak RL. Recognizing and Appropriately Treating Latent Autoimmune Diabetes in Adults. Diabetes Spectr 2016; 29:249-252. [PMID: 27899877 PMCID: PMC5111528 DOI: 10.2337/ds15-0047] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
| | - Jeremy L. Johnson
- Southwestern Oklahoma State University College of Pharmacy, Tulsa, OK
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Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev 2016; 32:289-96. [PMID: 26385269 DOI: 10.1002/dmrr.2717] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 07/31/2015] [Accepted: 08/07/2015] [Indexed: 11/11/2022]
Abstract
BACKGROUND To assess the efficacy and tolerability of saxagliptin and C-peptide secretion in patients with diagnosed type 2 diabetes classified as glutamic acid decarboxylase antibody (GADA)-positive or GADA-negative. METHODS Post hoc analysis of data pooled from five randomized, placebo-controlled, 24-week phase 3 studies (n = 2709) was conducted. We evaluated mean change from baseline at week 24 in HbA1c , fasting plasma glucose, postprandial plasma glucose, fasting and postprandial C-peptide, and HOMA2-%β and the proportion of patients achieving HbA1c < 7% (53 mmol/mol) at week 24. RESULTS Saxagliptin produced greater adjusted mean reductions from baseline in HbA1c versus placebo for GADA-negative [difference vs placebo (95% CI), -0.62% (-0.71% to -0.54%); -6.8 mmol/mol (-7.8, -5.9)] and GADA-positive patients [-0.64% (-1.01% to -0.27%); -7.0 mmol/mol (-11.0, -3.0)]. Consistently, saxagliptin produced a greater reduction from baseline in fasting plasma glucose and postprandial plasma glucose versus placebo in GADA-positive versus GADA-negative patients, and more patients achieved HbA1c < 7% (53 mmol/mol) with saxagliptin versus placebo in both GADA-negative and GADA-positive patients. Saxagliptin increased β-cell function as assessed by HOMA2-%β and postprandial C-peptide area under the curve from baseline in patients in both GADA-positive and GADA-negative patients. Adverse events and hypoglycaemic events were similar across treatment groups and GADA categories. CONCLUSION Saxagliptin was effective in lowering blood glucose levels and generally well tolerated in GADA-positive patients. Interestingly, saxagliptin appears to improve β-cell function in these patients, although a longer treatment duration may be needed to confirm this finding.
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Affiliation(s)
- R Buzzetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - P Pozzilli
- Department of Endocrinology and Diabetes, Università Campus Bio-Medico, Rome, Italy
- Centre for Immunology, St. Bartholomew's Hospital and the London School of Medicine, Queen Mary, University of London, London, UK
| | | | - N Iqbal
- Bristol-Myers Squibb, Princeton, NJ, USA
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Laugesen E, Østergaard JA, Leslie RDG. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabet Med 2015; 32:843-52. [PMID: 25601320 PMCID: PMC4676295 DOI: 10.1111/dme.12700] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2015] [Indexed: 12/13/2022]
Abstract
Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.
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Affiliation(s)
- E Laugesen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- The Danish Diabetes Academy, Odense, Denmark
| | - J A Østergaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- The Danish Diabetes Academy, Odense, Denmark
| | - R D G Leslie
- Centre for Diabetes, The Blizard Institute, London, UK
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Tanaka S, Okubo M, Nagasawa K, Takizawa S, Ichijo M, Ichijo S, Kaneshige M, Aida K, Shimura H, Mori Y, Kobayashi T. Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM). Diabetol Int 2015; 7:42-52. [PMID: 30603242 DOI: 10.1007/s13340-015-0211-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 04/28/2015] [Indexed: 11/28/2022]
Abstract
Aims Whether the titer of glutamic acid decarboxylase antibodies (GADAs), especially a low titer, is a marker of progression of beta cell dysfunction in patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) is unclear. Materials and methods Patients were subdivided as follows: patients with high GADA titers [≥10 U/ml (≥180 WHO U/ml): high GADA] (group 1, n = 37); those with low GADA titers [<10 U/ml (<180 WHO U/ml): low GADA] (group 2, n = 33); those without GADA and with islet cell antibodies (ICA) (group 3, n = 8); those without both GADA and ICA and with insulinoma-associated antigen 2 antibodies (IA-2A) (group 4, n = 6). We also allocated 198 type 2 diabetic patients without any GADA, ICA or IA-2A as group 5. Serum C-peptide responses to annual oral glucose tolerance tests (OGTTs) were followed up for a mean of 107 months from entry. Results The proportion of patients progressing to an insulin-dependent state in groups 1, 2, 3 and 4 was significantly higher than in group 5. C-peptide responses in OGTTs of patients in groups 1 and 2 were decreased at a significantly higher rate than in group 5. Multivariate Cox proportional hazard analysis revealed that factors including high GADA, low GADA, onset age <45 years, duration of diabetes <24 months, body mass index (BMI) <22.0 kg/m2, low degree of preserved beta cell function and ICA were independent risk factors for progression to an insulin-dependent state. Conclusions SPIDDM patients with low GADA titers have a significantly higher risk of progression to an insulin-dependent state than type 2 diabetic patients, suggesting that the presence of GADA, irrespective of the titer, is a hallmark of beta cell failure. Other risk factors for further progression to an insulin-dependent state in SPIDDM patients were ICA, onset age, duration of diabetes, BMI and residual beta cell function.
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Affiliation(s)
- Shoichiro Tanaka
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan
| | - Minoru Okubo
- 2Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2, Minato, Tokyo, 105-8470 Japan.,3Okinaka Memorial Institute for Medical Research, 2-2-2, Minato, Tokyo, 105-8470 Japan
| | - Kaoru Nagasawa
- 2Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2, Minato, Tokyo, 105-8470 Japan.,3Okinaka Memorial Institute for Medical Research, 2-2-2, Minato, Tokyo, 105-8470 Japan
| | - Soichi Takizawa
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan
| | - Masashi Ichijo
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan
| | - Sayaka Ichijo
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan
| | - Masahiro Kaneshige
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan
| | - Kaoru Aida
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan
| | - Hiroki Shimura
- 4Department of Laboratory Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima-shi, Fukushima 960-1295 Japan
| | - Yasumichi Mori
- 2Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2, Minato, Tokyo, 105-8470 Japan.,3Okinaka Memorial Institute for Medical Research, 2-2-2, Minato, Tokyo, 105-8470 Japan
| | - Tetsuro Kobayashi
- 1Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan.,3Okinaka Memorial Institute for Medical Research, 2-2-2, Minato, Tokyo, 105-8470 Japan
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Abstract
So much has changed in the field of diabetes diagnosis and management in the United States. Unhealthy lifestyle choices have hastened an epidemic of childhood obesity, causing a paradigm shift in how childhood diabetes is conceptualized. Once thought a consequence of obesity, sedentary lifestyle, and genetics, diabetes with onset in adults has been found to have a variant with autoimmunity. As the lines among adult-onset, child-onset, and type 1 and type 2 diabetes mellitus become more blurred, best practices in management and prevention become more complicated. This article highlights key points regarding 2 variants, juvenile-onset type 2 diabetes mellitus and latent autoimmune diabetes of adults.
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Cernea S, Dobreanu M. Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. Biochem Med (Zagreb) 2013; 23:266-80. [PMID: 24266296 PMCID: PMC3900074 DOI: 10.11613/bm.2013.033] [Citation(s) in RCA: 133] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Diabetes is a complex, heterogeneous condition that has beta cell dysfunction at its core. Many factors (e.g. hyperglycemia/glucotoxicity, lipotoxicity, autoimmunity, inflammation, adipokines, islet amyloid, incretins and insulin resistance) influence the function of pancreatic beta cells. Chronic hyperglycaemia may result in detrimental effects on insulin synthesis/secretion, cell survival and insulin sensitivity through multiple mechanisms: gradual loss of insulin gene expression and other beta-cell specific genes; chronic endoplasmic reticulum stress and oxidative stress; changes in mitochondrial number, morphology and function; disruption in calcium homeostasis. In the presence of hyperglycaemia, prolonged exposure to increased free fatty acids result in accumulation of toxic metabolites in the cells (“lipotoxicity”), finally causing decreased insulin gene expression and impairment of insulin secretion. The rest of the factors/mechanisms which impact on the course of the disease are also discusses in detail. The correct assessment of beta cell function requires a concomitant quantification of insulin secretion and insulin sensitivity, because the two variables are closely interrelated. In order to better understand the fundamental pathogenetic mechanisms that contribute to disease development in a certain individual with diabetes, additional markers could be used, apart from those that evaluate beta cell function. The aim of the paper was to overview the relevant mechanisms/factors that influence beta cell function and to discuss the available methods of its assessment. In addition, clinical considerations are made regarding the therapeutical options that have potential protective effects on beta cell function/mass by targeting various underlying factors and mechanisms with a role in disease progression.
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Affiliation(s)
- Simona Cernea
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania.
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Harrison LC, Wentworth JM, Zhang Y, Bandala-Sanchez E, Böhmer RM, Neale AM, Stone NL, Naselli G, Bosco JJ, Auyeung P, Rashidi M, Augstein P, Morahan G. Antigen-based vaccination and prevention of type 1 diabetes. Curr Diab Rep 2013; 13:616-23. [PMID: 23888323 DOI: 10.1007/s11892-013-0415-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Insulin-dependent or type 1 diabetes (T1D) is a paradigm for prevention of autoimmune disease: Pancreatic β-cell autoantigens are defined, at-risk individuals can be identified before the onset of symptoms, and autoimmune diabetes is preventable in rodent models. Intervention in asymptomatic individuals before or after the onset of subclinical islet autoimmunity places a premium on safety, a requirement met only by lifestyle-dietary approaches or autoantigen-based vaccination to induce protective immune tolerance. Insulin is the key driver of autoimmune β-cell destruction in the nonobese diabetic (NOD) mouse model of T1D and is an early autoimmune target in children at risk for T1D. In the NOD mouse, mucosal administration of insulin induces regulatory T cells that protect against diabetes. The promise of autoantigen-specific vaccination in humans has yet to be realized, but recent trials of oral and nasal insulin vaccination in at-risk humans provide grounds for cautious optimism.
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Affiliation(s)
- Leonard C Harrison
- Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia,
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Andersen CD, Bennet L, Nyström L, Lindblad U, Lindholm E, Groop L, Rolandsson O. Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy. Diabetologia 2013; 56:252-8. [PMID: 23096095 DOI: 10.1007/s00125-012-2759-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Accepted: 09/24/2012] [Indexed: 10/27/2022]
Abstract
AIMS/HYPOTHESIS Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy. METHODS We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35-80 years) from Swedish cohorts from Skåne (n = 272) and Västerbotten (n = 100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin-OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA(1c) ≥7.0% (≥53 mmol/mol) at follow-up. RESULTS The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m(2); p < 0.001) and follow-up (BMI 27.9 vs 30.2 kg/m(2); p < 0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p < 0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p < 0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR = 1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA(1c), BMI at diagnosis, follow-up time and duration of insulin treatment. CONCLUSIONS/INTERPRETATION Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.
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Affiliation(s)
- C D Andersen
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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Brophy S, Davies H, Mannan S, Brunt H, Williams R. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database Syst Rev 2011; 2011:CD006165. [PMID: 21901702 PMCID: PMC6486159 DOI: 10.1002/14651858.cd006165.pub3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Latent autoimmune diabetes in adults (LADA) is a slowly developing type 1 diabetes. OBJECTIVES To compare interventions used for LADA. SEARCH STRATEGY Studies were obtained from searches of electronic databases, supplemented by handsearches, conference proceedings and consultation with experts. Date of last search was December 2010. SELECTION CRITERIA Randomised controlled trials (RCT) and controlled clinical trials (CCT) evaluating interventions for LADA or type 2 diabetes with antibodies were included. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed risk of bias. Studies were summarised using meta-analysis or descriptive methods. MAIN RESULTS Searches identified 13,306 citations. Fifteen publications (ten studies) were included, involving 1019 participants who were followed between three months to 10 years (1060 randomised). All studies had a high risk of bias. Sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone at three months (one study, n = 15) and at 12 months (one study, n = 14) of treatment and follow-up. SU (with or without metformin) gave poorer metabolic control compared to insulin alone (mean difference in glycosylated haemoglobin A1c (HbA1c) from baseline to end of study, for insulin compared to oral therapy: -1.3% (95% confidence interval (CI) -2.4 to -0.1; P = 0.03, 160 participants, four studies, follow-up/duration of therapy: 12, 30, 36 and 60 months; however, heterogeneity was considerable). In addition, there was evidence that SU caused earlier insulin dependence (proportion requiring insulin at two years was 30% in the SU group compared to 5% in conventional care group (P < 0.001); patients classified as insulin dependent was 64% (SU group) and 12.5% (insulin group, P = 0.007). No intervention influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5)). In a five year follow-up of GAD65 (glutamic acid decarboxylase formulated with aluminium hydroxide), improvements in fasting and stimulated C-peptide levels (20 μg group) were maintained after five years. Short term (three months) follow-up in one study (n = 74) using Chinese remedies did not demonstrate a significant difference in improving fasting C-peptide levels compared to insulin alone (0.07 µg/L (95% CI -0.05 to 0.19). One study using vitamin D with insulin showed steady fasting C-peptide levels in the vitamin D group but declining fasting C-peptide levels (368 to 179 pmol/L, P = 0.006) in the insulin alone group at 12 months follow-up. Comparing studies was difficult as there was a great deal of heterogeneity in the studies and in their selection criteria. There was no information regarding health-related quality of life, complications of diabetes, cost or health service utilisation, mortality and limited evidence on adverse events (studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic episodes). AUTHORS' CONCLUSIONS Two studies show SU leading to earlier insulin dependence and a meta-analysis of four studies with considerable heterogeneity showed poorer metabolic control if SU is prescribed for patients with LADA compared to insulin. One study showed that vitamin D with insulin may protect pancreatic beta cells in LADA. Novel treatments such as GAD65 in certain doses (20 μg) have been suggested to maintain fasting and stimulated C-peptide levels. However, there is no significant evidence for or against other lines of treatment of LADA.
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Affiliation(s)
- Sinead Brophy
- University of Wales, SwanseaCollege of MedicineSingleton ParkSwanseaWalesUKSA2 8PP
| | - Helen Davies
- University of Wales, SwanseaSchool of MedicineSingleton ParkSwanseaWalesUKSA2 8PP
| | - Sopna Mannan
- University of Wales, SwanseaSchool of MedicineSingleton ParkSwanseaWalesUKSA2 8PP
| | - Huw Brunt
- National Public Health Service for WalesNational Public Health Service for WalesMid & West Wales Region, Job's Well RoadCarmarthenSouth WalesUKSA31 3WY
| | - Rhys Williams
- University of Wales, SwanseaSchool of MedicineSingleton ParkSwanseaWalesUKSA2 8PP
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Thunander M, Thorgeirsson H, Törn C, Petersson C, Landin-Olsson M. β-cell function and metabolic control in latent autoimmune diabetes in adults with early insulin versus conventional treatment: a 3-year follow-up. Eur J Endocrinol 2011; 164:239-45. [PMID: 21088056 PMCID: PMC3022338 DOI: 10.1530/eje-10-0901] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES The optimal treatment of latent autoimmune diabetes in adults (LADA) is not established. We explored whether early insulin treatment, which has shown beneficial effects in rodents and in human pilot studies, would result in better preservation of β-cell function or metabolic control, compared with conventional treatment. SUBJECTS AND METHODS Glucagon-stimulated C-peptide and HbAlc were evaluated at baseline and after 12, 24 and 36 months in 37 patients recently diagnosed with diabetes, aged ≥ 30 years, non-insulin-requiring and GADAb and/or ICA positive. Twenty patients received early insulin and 17 received conventional treatment (diet ± oral hypoglycaemic agents (OHA), metformin, some and/or sulfonylurea) and insulin when necessary. RESULTS Level of metabolic control, HbAlc, was preserved in the early insulin treated, while it significantly deteriorated in the conventionally treated. There was no significant difference between the groups in C-peptide after 12, 24 or 36 months, or in the decline of C-peptide. Only baseline C-peptide predicted a C-peptide of ≥ 0.5 nmol/l at 36 months. Gender, body mass index, antibody titres or HbAlc did not influence the levels of C-peptide or HbAlc at baseline or end-of-study, or the decline in C-peptide. Among the diet ± OHA-treated, 5/17 (30%) developed insulin dependency during the follow-up. No major hypoglycaemic events occurred. CONCLUSIONS Early insulin treatment in LADA leads to better preservation of metabolic control and was safe. Superior preservation of C-peptide could not be significantly demonstrated. Only baseline level of C-peptide significantly influenced C-peptide level after 3 years. Further studies exploring the best treatment in LADA are warranted.
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Affiliation(s)
- Maria Thunander
- Department of Endocrinology and Diabetology, Lund University Hospital, Lund, Sweden.
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Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care 2009; 32 Suppl 2:S246-52. [PMID: 19875559 PMCID: PMC2811444 DOI: 10.2337/dc09-s317] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Simona Cernea
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
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Affiliation(s)
- A Lernmark
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
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Skyler JS. Latent autoimmune diabetes in adults: the search for interventions continues. NATURE CLINICAL PRACTICE. ENDOCRINOLOGY & METABOLISM 2008; 4:600-601. [PMID: 18762790 DOI: 10.1038/ncpendmet0949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Accepted: 07/14/2008] [Indexed: 05/26/2023]
Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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Brophy S, Davies H, Bain S, Stephens JW, Cheung WY, Richards K, Wareham K, Beaverstock C, Lloyd J, Page D, Williams M, Russell I, Williams R. Randomized, controlled, parallel-group prospective study to investigate the clinical effectiveness of early insulin treatment in patients with latent autoimmune diabetes in adults. BMC Endocr Disord 2008; 8:8. [PMID: 18652676 PMCID: PMC2496905 DOI: 10.1186/1472-6823-8-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2007] [Accepted: 07/24/2008] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Latent autoimmune diabetes in adults [LADA] is a type 1 diabetes that is slowly developing. This means many people are treated as having type 2 diabetes at diagnosis as they are adults who are not immediately insulin dependent. LADA can be distinguished from type 2 diabetes by antibody tests. Patients who are antibody positive have an autoimmune reaction which is similar to that of type 1 diabetes and is not found in type 2 diabetes. We would like to examine the best way of treating LADA in the early phase of the conditions, with tablets (similar to type 2 diabetes) or with insulin (similar to type 1 diabetes). METHODS/DESIGN This is an open parallel group prospective randomised trial. Participants need to have a GAD antibody test results of 101 WHO units or more and a diagnosis of diabetes not requiring insulin at diagnosis. Participants will need to have been diagnosed within 12 months and not treated with insulin at study entry. They will be randomised to receive either insulin (NovoMix 30) or tablets (diet treated followed by metformin followed by glitazone (with or without metformin) followed by insulin). Primary outcome assessment will be for change in HbA1c and change in fasting C-peptide over 24 months. Secondary outcome measures will include Quality of life, GAD antibody levels, adverse events, inflammatory markers, insulin resistance, and markers of the metabolic syndrome. DISCUSSION This study seeks the best treatment for early LADA in terms of maintaining glycaemic control and maintaining natural insulin production. TRIAL REGISTRATION ISRCTN63815121.
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Affiliation(s)
- Sinead Brophy
- School of Medicine, Swansea University, Swansea, Wales, UK
| | - Helen Davies
- School of Medicine, Swansea University, Swansea, Wales, UK
| | - Stephen Bain
- School of Medicine, Swansea University, Swansea, Wales, UK
| | | | - Wei-yee Cheung
- School of Medicine, Swansea University, Swansea, Wales, UK
| | - Kez Richards
- Clinical Research Unit, Swansea NHS Trust. Swansea, Wales, UK
| | - Kathie Wareham
- Clinical Research Unit, Swansea NHS Trust. Swansea, Wales, UK
| | | | - Janet Lloyd
- Diabetes UK Cymru, Argyle House Castlebridge, Cowbridge, Cardiff, CF11 9AB, UK
| | - Don Page
- Diabetes UK Cymru, Argyle House Castlebridge, Cowbridge, Cardiff, CF11 9AB, UK
| | - Meurig Williams
- Diabetes Centre, Prince Philip Hospital, Llanelli, Carmarthenshire, Wales, UK
| | - Ian Russell
- Institute for Medical and Social Care Research, University of Wales, Bangor, Wales, UK
| | - Rhys Williams
- School of Medicine, Swansea University, Swansea, Wales, UK
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Maruyama T, Tanaka S, Shimada A, Funae O, Kasuga A, Kanatsuka A, Takei I, Yamada S, Harii N, Shimura H, Kobayashi T. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab 2008; 93:2115-21. [PMID: 18397986 DOI: 10.1210/jc.2007-2267] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
OBJECTIVE We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve beta-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults. METHODS This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (SigmaC-peptide) less than 4 ng/ml (1.32 nmol/liter). RESULTS The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that SigmaC-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [> or =10 U/ml (180 World Health Organization U/ml)] and preserved beta-cell function [SigmaC-peptide > or = 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study. CONCLUSIONS Insulin intervention to preserve beta-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.
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Affiliation(s)
- Taro Maruyama
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan
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Rosário PWS, Reis JS, Fagundes TA, Calsolari MR, Amim R, Silva SC, Purisch S. Latent autoimmune diabetes in adults (LADA): usefulness of anti-GAD antibody titers and benefit of early insulinization. ACTA ACUST UNITED AC 2008; 51:52-8. [PMID: 17435855 DOI: 10.1590/s0004-27302007000100009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2006] [Accepted: 08/31/2006] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To determine the clinical and laboratory parameters and the progression to insulin requirement in two groups of LADA patients separated according to GADA titers, and to evaluate the benefit of early insulinization in patients at high risk of premature beta-cell failure (high GADA titers). METHODS Among the diabetic adults seen at our service and screened for GADA at diagnosis, 54 were diagnosed with LADA and classified as having low (> 1 U/ml and < 17.2 U/ml) or high (> 17.2 U/ml) GADA titers. Fifty-four patients with type 2 diabetes (GADA-) were selected for comparison. In addition, 24 patients who had GADA titers > 20 U/ml and who were not initially insulinized were compared to 16 patients who were insulinized at diagnosis. RESULTS Insulin resistance was higher in the GADA- group, followed by patients with low GADA titers. BMI and the frequency of arterial hypertension, elevated triglycerides and reduced HDL cholesterol were lower in the high GADA+ group, with no difference between the GADA- or low GADA+ groups. The high GADA+ group showed a greater reduction and lower levels of C-peptide and required insulin earlier during follow-up. Patients with GADA titers > 20 U/ml and insulinized early presented no significant variation in C-peptide levels, had better glycemic control and required a lower insulin dose than patients who were insulinized later. CONCLUSION We agree that patients with LADA should be differentiated on the basis of GADA titers and that patients with GADA titers > 20 U/ml benefit from early insulinization.
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Calsolari MR, Rosário PWSD, Reis JS, Silva SCD, Purisch S. Diabetes auto-imune latente do adulto ou diabetes melito tipo 2 magro? ACTA ACUST UNITED AC 2008; 52:315-21. [DOI: 10.1590/s0004-27302008000200019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Accepted: 12/03/2007] [Indexed: 11/22/2022]
Abstract
A prevalência do diabetes auto-imune latente do adulto (LADA) varia em virtude da população estudada, dos critérios usados e dos anticorpos avaliados. Em 256 pacientes com menos de 25 anos, encontramos 26 (10,2%) com anticorpos anti-GAD (GADA) positivos, dos quais 16 (6,3%) evoluíram sem necessidade de insulina inicialmente. Embora exista controvérsias, sugere-se como critérios diagnósticos de LADA: idade entre 25 e 65 anos; ausência de cetoacidose ou hiperglicemia sintomática no diagnóstico ou imediatamente após, sem necessidade de insulina por 6 a 12 meses; e presença de auto-anticorpos (especialmente GADA). A auto-imunidade e a resistência insulínica coexistem no LADA, e a contribuição desses fatores parece estar refletida nos títulos de GADA. Um subgrupo similar aos diabéticos tipo 2, fenotipicamente e na progressão para necessidade de insulina, parece ser melhor identificado pela presença de baixos títulos de GADA, sobretudo isolados. Por outro lado, indivíduos com altos títulos de GADA e múltiplos anticorpos apresentam fenótipo mais próximo do diabetes melito do tipo 1 (DM1) clássico e são de maior risco para falência prematura das células-beta. Comparados aos diabéticos GADA-negativos, pacientes com LADA apresentam maior prevalência de outros auto-anticorpos (anti-TPO, anti-21-hidroxilase e associados à doença celíaca) e maior freqüência de genótipos e haplótipos de risco para DM1. Pacientes com altos títulos de GADA podem ser beneficiados, retardando a falência das células-beta, com a insulinização precoce e evitando-se o uso de sulfoniluréias. Em oposição, pacientes com baixos títulos de GADA aparentemente não teriam prejuízos em serem conduzidos da mesma forma que pacientes portadores de diabetes melito tipo 2 (DM2) (GADA-negativos).
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Brophy S, Yderstraede K, Mauricio D, Hunter S, Hawa M, Pozzilli P, Schernthaner G, Schloot N, Buzzetti R, Davies H, Leslie D, Williams R. Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults. Diabetes Care 2008; 31:439-41. [PMID: 18083788 DOI: 10.2337/dc07-1308] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Latent autoimmune diabetes in adults is type 1 diabetes presenting as non-insulin dependent diabetes. One feature of the selection criteria is time independent of insulin treatment. We examine the validity of this criterion. RESEARCH DESIGN AND METHODS Patients were recruited in nine European centers, and clinicians reported on criteria for initiating insulin. All patients were tested for GAD antibodies (GADAs) in a central laboratory. We examined time to insulin treatment for GADA-positive patients in six participating centers. RESULTS There was intercenter variation in the criteria used to initiate insulin. Median time to insulin was 16.15 months (interqartile range 6.7-25.5) in centers with GADA testing compared with 45.6 months (29.5-61.8) in centers without routine GADA testing (P < 0.002). CONCLUSION Time to insulin should not be used to define patients with LADA because it is dependent on local clinical judgment and the use of laboratory tests for GADA.
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Affiliation(s)
- Sinead Brophy
- School of Medicine, Swansea University, Swansea SA2 8PP, UK.
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Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological responses to exogenous insulin. Endocr Rev 2007; 28:625-52. [PMID: 17785428 DOI: 10.1210/er.2007-0002] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Regardless of purity and origin, therapeutic insulins continue to be immunogenic in humans. However, severe immunological complications occur rarely, and less severe events affect a small minority of patients. Insulin autoantibodies (IAAs) may be detectable in insulin-naive individuals who have a high likelihood of developing type 1 diabetes or in patients who have had viral disorders, have been treated with various drugs, or have autoimmune disorders or paraneoplastic syndromes. This suggests that under certain circumstances, immune tolerance to insulin can be overcome. Factors that can lead to more or less susceptibility to humoral responses to exogenous insulin include the recipient's immune response genes, age, the presence of sufficient circulating autologous insulin, and the site of insulin delivery. Little proof exists, however, that the development of insulin antibodies (IAs) to exogenous insulin therapy affects integrated glucose control, insulin dose requirements, and incidence of hypoglycemia, or contributes to beta-cell failure or to long-term complications of diabetes. Studies in which pregnant women with diabetes were monitored for glycemic control argue against a connection between IAs and fetal risk. Although studies have shown increased levels of immune complexes in patients with diabetic microangiopathic complications, these immune complexes often do not contain insulin or IAs, and insulin administration does not contribute to their formation. The majority of studies have shown no relationship between IAs and diabetic angiopathic complications, including nephropathy, retinopathy, and neuropathy. With the advent of novel insulin formulations and delivery systems, such as insulin pumps and inhaled insulin, examination of these issues is increasingly relevant.
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Affiliation(s)
- S Edwin Fineberg
- Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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Brophy S, Brunt H, Davies H, Mannan S, Williams R. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database Syst Rev 2007:CD006165. [PMID: 17636829 DOI: 10.1002/14651858.cd006165.pub2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Latent autoimmune diabetes in Adults (LADA) is a slowly developing type 1 diabetes which presents as non-insulin dependent diabetes and progresses to insulin dependence. However, the best treatment strategy for LADA is unclear. OBJECTIVES To compare interventions used for LADA. SEARCH STRATEGY Studies were obtained from searches of electronic databases (including MEDLINE, EMBASE), supplemented by hand searches, conference proceedings and consultation with experts. SELECTION CRITERIA Selection was in duplicate by two independent reviewers. RCT and controlled clinical trials evaluating interventions for LADA or type 2 diabetes with antibodies were included. DATA COLLECTION AND ANALYSIS Two reviewers independently extracted data and assessed study quality. Studies were summarised in a descriptive manner. MAIN RESULTS Searches identified 8067 citations. Eight publications (seven studies) were included, involving 735 participants. All studies had high risk of bias. There were no data on use of metformin or glitazones alone. Rosiglitazone or sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone. SU alone gave either poorer (one study, mean difference in HbA1c 2.8% (95% confidence interval (CI) 0.9 to 4.7) or equivalent metabolic control compared to insulin alone (two studies). There was evidence that SU caused earlier insulin dependence (insulin treated at two years: 60% (SU) and 5% (conventional care) (P < 0.001); classified insulin dependent: 64% (SU) and 12.5% (insulin group) (P = 0.007)). No interventions influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5) and insulin with rosiglitazone was superior to insulin alone (one study) at maintaining stimulated C-peptide. A pilot study showed better metabolic control at six months with subcutaneously administered glutamic acid decarboxylase (GAD) GAD65, a major autoantigen in autoimmune diabetes, compared to placebo. There was no information regarding quality of life, mortality, complications or costs in any of the publications. Time from diagnosis varied between recruitment at diagnosis to recruitment at nine years of disease duration and there was a great deal of variation in the selection criteria for LADA patients, making it difficult to generalise findings from these studies. AUTHORS' CONCLUSIONS There are few studies on this topic and existing studies have a high risk of bias. However, there does seem to be an indication that SU should not be a first line treatment for antibody positive type 2 diabetes. There is no significant evidence for or against other lines of treatment of LADA.
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Affiliation(s)
- S Brophy
- University of Wales, Swansea, Swansea School of Medicine, Grove Building, Sigleton Park, Swansea, UK, SA2 8PP.
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Kobayashi T, Tanaka S, Harii N, Aida K, Shimura H, Ohmori M, Kanesige M, Shimada A, Maruyama T. Immunopathological and Genetic Features in Slowly Progressive Insulin-Dependent Diabetes Mellitus and Latent Autoimmune Diabetes in Adults. Ann N Y Acad Sci 2006; 1079:60-6. [PMID: 17130533 DOI: 10.1196/annals.1375.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
In 1982 we proposed the presence of a subtype of type 1 diabetes [slowly progressive insulin-dependent diabetes mellitus (SPIDDM)], which was characterized by persistently positive islet cell antibody, late age of onset, noninsulin-dependent diabetes, and slowly progressive beta cell failure. Since then many studies demonstrated that this subtype of type 1 diabetes is prevalent in many ethnic groups and was later called the latent autoimmune diabetes in adults (LADA). Recent epidemiological studies reported that about 10% of patients with apparent type 2 diabetes have at least one autoantibodies against islet-specific antigen with high potential to progress to insulin-dependent state. Between SPIDDM and LADA some differences are reported in terms of some genetic predispositions including HLA class II and class I genes, vitamin D receptor gene, and CTLA4 genes. Common features in SPIDDM and LADA including preserved beta cells at the onset of diabetes and weak T cell response to residual beta cells suggest that these subtypes of type 1 diabetes are suitable candidates for prevention treatment for further progression of beta cell failure.
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Affiliation(s)
- Tetsuro Kobayashi
- Third Department of Internal Medicine, School of Medicine, University of Yamanashi, Tamaho, Yamanashi 409-3898, Japan.
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Brophy S, Davies H, Mannan S, Williams R. Interventions for latent autoimmune diabetes in adults (LADA). THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2006. [DOI: 10.1002/14651858.cd006165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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TANAKA SHOICHIRO, KOBAYASHI TETSURO, NAKANISHI KOJI, OKUBO MINORU, ODAWARA MASATO, MURASE TOSHIO, HASHIMOTO MASAJI, WATANABE GORO, MATSUSHITA HIROSHI, INOKO HIDETOSHI, TAKEUCHI KAZUO. Corticosteroid-Responsive Diabetes Mellitus Associated with Autoimmune Pancreatitis. Ann N Y Acad Sci 2006. [DOI: 10.1111/j.1749-6632.2002.tb02959.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Stenström G, Gottsäter A, Bakhtadze E, Berger B, Sundkvist G. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes 2005; 54 Suppl 2:S68-72. [PMID: 16306343 DOI: 10.2337/diabetes.54.suppl_2.s68] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Latent autoimmune diabetes in adults (LADA) is a disorder in which, despite the presence of islet antibodies at diagnosis of diabetes, the progression of autoimmune beta-cell failure is slow. LADA patients are therefore not insulin requiring, at least during the first 6 months after diagnosis of diabetes. Among patients with phenotypic type 2 diabetes, LADA occurs in 10% of individuals older than 35 years and in 25% below that age. Prospective studies of beta-cell function show that LADA patients with multiple islet antibodies develop beta-cell failure within 5 years, whereas those with only GAD antibodies (GADAs) or only islet cell antibodies (ICAs) mostly develop beta-cell failure after 5 years. Even though it may take up to 12 years until beta-cell failure occurs in some patients, impairments in the beta-cell response to intravenous glucose and glucagon can be detected at diagnosis of diabetes. Consequently, LADA is not a latent disease; therefore, autoimmune diabetes in adults with slowly progressive beta-cell failure might be a more adequate concept. In agreement with proved impaired beta-cell function at diagnosis of diabetes, insulin is the treatment of choice.
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Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP, Rolandsson O, Colman PG, Harrison LC. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 2005; 48:2206-12. [PMID: 16193284 DOI: 10.1007/s00125-005-1960-7] [Citation(s) in RCA: 226] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2005] [Accepted: 05/11/2005] [Indexed: 12/15/2022]
Abstract
'Latent autoimmune diabetes in adults' (LADA) is the term coined to describe adults who have a slowly progressive form of autoimmune or type 1 diabetes that can be treated initially without insulin injections. The diagnosis of LADA is currently based on three clinical criteria: (1) adult age at onset of diabetes; (2) the presence of circulating islet autoantibodies, which distinguishes LADA from type 2 diabetes; and (3) insulin independence at diagnosis, which distinguishes LADA from classic type 1 diabetes. The prevalence of LADA in adults presenting with non-insulin-requiring diabetes is approximately 10%. Recognition of LADA expands the concept and prevalence of autoimmune diabetes, but LADA remains poorly understood at both a clinical and research level. In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes.
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Affiliation(s)
- S Fourlanos
- Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
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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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Unnikrishnan AG, Singh SK, Sanjeevi CB. Prevalence of GAD65 antibodies in lean subjects with type 2 diabetes. Ann N Y Acad Sci 2005; 1037:118-21. [PMID: 15699503 DOI: 10.1196/annals.1337.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
While type 2 diabetic subjects in developed countries are predominantly obese or overweight, those in India are often nonobese or lean. The reasons for leanness in these subjects has not been well understood. We assessed the prevalence of pancreatic islet autoimmunity in 83 lean adult subjects (BMI < 18.5 kg/m(2)) with type 2 diabetes by measuring antibodies to glutamic acid decarboxylase-65 (GAD Abs). Positivity to GAD Ab was present in 21 (25.3%) subjects. In addition, subjects with GAD Ab positivity were younger and had lower beta cell function (homeostasis model assessment, HOMA) as compared to the GAD Ab-negative group. This suggests that the antibody-positive group could have a slowly progressive form of type 1 diabetes.
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Affiliation(s)
- A G Unnikrishnan
- Department of Endocrinology, Amrita Institute of Medical Sciences, Cochin, Kerala, India.
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Zhou Z, Li X, Huang G, Peng J, Yang L, Yan X, Wang J. Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA). Diabetes Metab Res Rev 2005; 21:203-8. [PMID: 15386806 DOI: 10.1002/dmrr.503] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND LADA is thought to result from the chronic autoimmune destruction of the insulin-producing pancreatic beta cells. In addition to antidiabetic effects, the newly developed insulin sensitizer-thiazolidinediones have the potential to increase the insulin content of islet cells by downregulating local inflammation and autoimmune response. Therefore, we hypothesized that LADA patients might benefit from thiazolidinediones treatment. METHODS LADA patients, with a fasting C-peptide (FCP) of 0.3 nmol/L or more, were enrolled and randomly assigned to receive subcutaneous insulin alone (insulin group, n = 12) or rosiglitazone plus insulin (insulin + RSG group, n = 11) to compare the impacts on islet beta cell function. Plasma glucose, HbA 1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucose load (PCP) were determined every 6 months. GAD-Ab and C-peptide were measured with radioimmune assays. Islet beta cell function was evaluated by PCP and DeltaCP(DeltaCP = PCP-FCP). RESULTS All of the 23 patients have been followed up for 6 months, 17 cases for 12 months and 14 for 18 months. (1) During 6 months' follow-up, there were no significant changes for DeltaCP and PCP levels in both groups. (2) PCP and DeltaCP levels in insulin + RSG group patients stayed steady during the 12 months' observation (P = 0.161 for both PCP and DeltaCP), while in the insulin alone group, both FCP (P = 0.021) and PCP (P = 0.028) levels decreased significantly. Furthermore, PCP (P = 0.004) and DeltaCP(P = 0.015) differences between 12th month and baseline were higher in insulin + RSG group than those in the insulin group. (3) When observed up to 18 months, PCP and DeltaCP levels in insulin + RSG group patients still stayed steady, while PCP and DeltaCP levels decreased more in the insulin alone group. CONCLUSIONS This pilot study suggests that rosiglitazone combined with insulin may preserve islet beta cell function in LADA patients.
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Affiliation(s)
- Zhiguang Zhou
- Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, China.
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Abstract
The sulphonylureas act by triggering insulin release from the pancreatic beta cell. A specific site on the adenosine triphosphate (ATP)-sensitive potassium channels is occupied by sulphonylureas leading to closure of the potassium channels and subsequent opening of calcium channels. This results in exocytosis of insulin. The meglitinides are not sulphonylureas but also occupy the sulphonylurea receptor unit coupled to the ATP-sensitive potassium channel. Glibenclamide (glyburide), gliclazide, glipizide and glimepiride are the primary sulphonylureas in current clinical use for type 2 diabetes mellitus. Glibenclamide has a higher frequency of hypoglycaemia than the other agents. With long-term use, there is a progressive decrease in the effectiveness of sulphonylureas. This loss of effect is the result of a reduction in insulin-producing capacity by the pancreatic beta cell and is also seen with other antihyperglycaemic agents. The major adverse effect of sulphonylureas is hypoglycaemia. There is a theoretical concern that sulphonylureas may affect cardiac potassium channels resulting in a diminished response to ischaemia. There are now many choices for initial therapy of type 2 diabetes in addition to sulphonylureas. Metformin and thiazolidinediones affect insulin sensitivity by independent mechanisms. Disaccharidase inhibitors reduce rapid carbohydrate absorption. No single agent appears capable of achieving target glucose levels in the majority of patients with type 2 diabetes. Combinations of agents are successful in lowering glycosylated haemoglobin levels more than with a single agent. Sulphonylureas are particularly beneficial when combined with agents such as metformin that decrease insulin resistance. Sulphonylureas can also be given with a basal insulin injection to provide enhanced endogenous insulin secretion after meals. Sulphonylureas will continue to be used both primarily and as part of combined therapy for most patients with type 2 diabetes.
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Affiliation(s)
- Marc Rendell
- Creighton Diabetes Center, 601 North 30th Street, Omaha, NE 68131, USA.
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Tanaka S, Endo T, Aida K, Shimura H, Yokomori N, Kaneshige M, Furuya F, Amemiya S, Mochizuki M, Nakanishi K, Kobayashi T. Distinct diagnostic criteria of fulminant type 1 diabetes based on serum C-peptide response and HbA1c levels at onset. Diabetes Care 2004; 27:1936-41. [PMID: 15277420 DOI: 10.2337/diacare.27.8.1936] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Diagnostic criteria in fulminant type 1 diabetes, a novel subtype of type 1 diabetes, remain unclear. RESEARCH DESIGN AND METHODS We analyzed basal and longitudinal changes of serum C-peptide levels during a 75-g oral glucose tolerance test (OGTT) in 125 consecutively recruited patients with type 1 diabetes including fulminant type 1 diabetes (n = 25) and acute-onset type 1 diabetes (n = 100). Discriminating criteria of fulminant type 1 diabetes were examined using receiver-operating characteristic curve analysis and multiple logistic regression analysis. RESULTS The integrated values of serum C-peptide response during OGTT (SigmaC-peptide) in fulminant type 1 diabetes at onset, 1 year, and 2 years after onset were markedly lower than those in acute-onset type 1 diabetes. None of the patients with fulminant type 1 diabetes had improvement of C-peptide response to OGTT. Fasting C-peptide values at onset in fulminant type 1 diabetes were significantly lower than those in acute-onset type 1 diabetes. We established diagnostic criteria of serum C-peptide and HbA(1c) levels at onset that discriminate fulminant type 1 diabetes from acute-onset type 1 diabetes with high sensitivity and specificity: a criterion in which the levels of both the fasting C-peptide is <or=0.033 nmol/l and HbA(1c) is <or=8.0% or a criterion in which the levels of both the SigmaC-peptide is <or=0.540 nmol/l and HbA(1c) is <or=8.0%. CONCLUSIONS Fulminant type 1 diabetes has extremely low beta-cell function at onset that rarely recovers after onset. Sensitive and specific diagnostic criteria were established for detection of fulminant type 1 diabetes based on serum C-peptide and HbA(1c) levels at onset.
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Affiliation(s)
- Shoichiro Tanaka
- Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Tamaho, Yamanashi 409-3898, Japan
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Affiliation(s)
- H K Chiu
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, VA Puget Sound Health Care System, Seattle, WA, USA.
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Kanungo A, Sanjeevi CB. IA-2 autoantibodies are predominant in latent autoimmune diabetes in adults patients from eastern India. Ann N Y Acad Sci 2004; 1005:390-4. [PMID: 14679098 DOI: 10.1196/annals.1288.065] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Autoimmune diabetes or latent autoimmune diabetes in adults (LADA) among the clinically diagnosed type 2 diabetes patients from Cuttack in Eastern India was studied. GAD65 and IA-2 autoantibodies were measured by radioligand binding assay using recombinant human GAD65 and IA-2. The frequency of GAD65 was not significantly different between patients and controls. However, IA-2 antibodies were predominant in LADA patients and there were two distinct peaks, one in the age group of 20 to 30 years and another in the age group of 50 to 60 years. The data suggest that LADA is more frequent in Eastern Indian T2DM patients and the IA-2 is the predominant autoantibody in this population.
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Affiliation(s)
- Alok Kanungo
- Cuttack Diabetes Research Foundation, Cuttack, Orissa, India
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