Immune intervention at diagnosis--should we treat children to preserve beta-cell function?
ABSTRACT Type 1 diabetes (T1D) is characterized by loss of beta-cell function. If beta-cell function can be preserved, it will lead to improved metabolic balance with improved quality of life and fewer acute and late complications, and if residual insulin secretion improves well enough, then that could lead to complete remission and even cure of the disease. Several efforts to save residual beta-cell function have been made for more than three decades without success. Proof of principle has been possible, and it seems clear that immune suppression or immune modulation, in fact, can stop the destructive process and thereby preserve beta-cell function. However, the effect seen in adult patients with T1D have been minimal or absent in diabetic children who seem to have another or at least more aggressive disease process. Furthermore, the immune interventions have had too serious and common adverse events in comparison to the scarce-positive effect. Recent more specific immune modulation with anti-CD3 monoclonal antibodies seems more encouraging with at least postponement of the C-peptide decline, but unfortunately still with common and quite threatening adverse effects. Even more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown good results with impressive preservation of residual insulin secretion in 10- to 18-year-old type 1 diabetic patients with recent onset. In patients with short diabetes duration at intervention the effect was remarkable. Furthermore, these effects were achieved with no adverse events. Future studies will show whether the good effect seen so far can be confirmed. If so there is hope that GAD vaccination will cause remission and even cure and prevention of T1D will then no longer be just a dream.
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ABSTRACT: Loss of pancreatic islet function and insulin-producing beta cell mass is a central hallmark in the pathogenesis of both type 1 and type 2 diabetes. While in type 1 diabetes this phenomenon is due to an extensive destruction of beta cells caused by an autoimmune process, the mechanisms resulting in beta cell failure in type 2 diabetes are different and less clear. Also, beta cell destruction in type 1 diabetes occurs early and is the initial step in the pathogenetic process, while beta cell loss in type 2 diabetes after an initial phase of hyperinsulinemia due to the underlying insulin resistance occurs relatively late and it is less pronounced. Since diabetes mellitus is the most frequent endocrine disease, with an increasing high prevalence worldwide, huge efforts have been made over the past many decades to identify predisposing genetic, environmental, and nutritional factors in order to develop effective strategies to prevent the disease. In parallel, extensive studies in different cell systems and animal models have helped to elucidate our understanding of the physiologic function of islets and to gain insight into the immunological and non-immunological mechanisms of beta cell destruction and failure. Furthermore, currently emerging concepts of beta cell regeneration (e.g., the restoration of the beta cell pool by regenerative, proliferative and antiapoptotic processes, and recovery of physiologic islet function) apparently is yielding the first promising results. Recent insights into the complex endocrine and paracrine mechanisms regulating the physiologic function of pancreatic islets, as well as beta cell life and death, constitute an essential part of this new and exciting area of diabetology. For example, understanding of the physiological role of glucagon-like peptide 1 has resulted in the successful clinical implementation of incretin-based therapies over the last years. Further, recent data suggesting paracrine effects of growth hormone-releasing hormone and corticotropin-releasing hormone on the regulation of pancreatic islet function, survival, and proliferation as well as on local glucocorticoid metabolism provide evidence for a potential role of the pancreatic islet-stress axis in the pathophysiology of diabetes mellitus. In this chapter, we provide a comprehensive overview of current preventive and regenerative concepts as a basis for the development of novel therapeutic approaches to the treatment of diabetes mellitus. A particular focus is given on the potential of the pancreatic islet-stress axis in the development of novel regenerative strategies.Vitamins & Hormones 01/2014; 95:195-222. · 1.78 Impact Factor
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ABSTRACT: Type 1 diabetes is a multifactorial disease with an early age of onset, in which the insulin producing ß cell of the pancreas are destroyed because of autoimmunity. It is the second most common chronic disease in children and account for 5% to 10% of all diagnosed cases of diabetes. India is having an incidence of 10.6 cases/ year/100,000, and recent studies indicate that the prevalence of type 1 diabetes in India is increasing. However in view of poor health care network, there is no monitoring system in the country. Of the 18 genomic intervals implicated for the risk to develop type 1 diabetes, the major histocompatibility complex (MHC) region on chromosome 6p21.31 has been the major contributor estimated to account for 40-50%, followed by 10% frequency of INS-VNTR at 5 anking region of the insulin gene on chromosome 11p15.5. However, population studies suggest that > 95% of type 1 diabetes have HLA-DR3 or DR4, or both, and in family studies, sibling pairs affected with type 1 diabetes have a non-random distribution of shared HLA haplotypes. As predisposing genetic factors such as HLA alleles are known, immunological interventions to prevent type 1 diabetes are of great interest. In the present study we have reviewed the status of molecular genetics of the disease and the approaches that need to be adopted in terms of developing patient and suitable control cohorts in the country.International Journal of Diabetes in Developing Countries 04/2009; 29(2):85-101. · 0.37 Impact Factor
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ABSTRACT: Objective The Environmental Determinants of Diabetes in the Young (TEDDY) study is designed to identify environmental exposures triggering islet autoimmunity and type 1 diabetes (T1D) in genetically high-risk children. We describe the first 100 participants diagnosed with T1D, hypothesizing that (i) they are diagnosed at an early stage of disease, (ii) a high proportion are diagnosed by an oral glucose tolerance test (OGTT), and (iii) risk for early T1D is related to country, population, human leukocyte antigen (HLA)-genotypes and immunological markers.Methods Autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2) and insulin (IAA) were analyzed from 3 months of age in children with genetic risk. Symptoms and laboratory values at diagnosis were obtained and reviewed for ADA criteria.ResultsThe first 100 children to develop T1D, 33 first-degree relatives (FDRs), with a median age 2.3 yr (0.69–6.27), were diagnosed between September 2005 and November 2011. Although young, 36% had no symptoms and ketoacidosis was rare (8%). An OGTT diagnosed 9/30 (30%) children above 3 yr of age but only 4/70 (5.7%) below the age of 3 yr. FDRs had higher cumulative incidence than children from the general population (p < 0.0001). Appearance of all three autoantibodies at seroconversion was associated with the most rapid development of T1D (HR = 4.52, p = 0.014), followed by the combination of GADA and IAA (HR = 2.82, p < 0.0001).Conclusions Close follow-up of children with genetic risk enables early detection of T1D. Risk factors for rapid development of diabetes in this young population were FDR status and initial positivity for GADA, IA-2, and IAA or a combination of GADA and IAA.Pediatric Diabetes 03/2014; 15(2). · 2.13 Impact Factor