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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Destruction of pancreatic beta cells has been implicted in the progression to hyperglycemia in type 1 diabetes. While there is evidence of beta-cell loss in type 2 diabetes, its contribution to the development of the diabetic state is undecided. Nicotinamide has defensive effects against toxic insults to the pancreatic islets and confers protection in both human and animal models of type 1 diabetes, but its effects on type 2 diabetes are less well documented. This report describes a comparison of the outcome of chronic oral administration of nicotinamide on the development of diabetes in obese diabetic (db/db) and non-obese diabetic (NOD) mice models of type 2 and type 1 diabetes, respectively. Nicotinamide was administered in the diet (5 g/kg diet) for 12 (db/db) or 24 (NOD) weeks. Over the 12 weeks of the study, control diabetic (db/db) mice became progressively more hyperglycemic and glycosuric, while serum and pancreatic insulin levels decreased compared with those on day 0. In mice treated with nicotinamide, there was a pronounced acceleration in the development of hyperglycemia and glycosuria, as well as a decrease in pancreatic insulin levels, compared with time-matched controls. In addition, the morphology of the pancreatic islets of nicotinamide-treated diabetic (db/db) mice showed an enhanced islet disorganization. By comparison, in NOD mice, nicotinamide prevented the decline in serum and pancreatic insulin levels and maintained normal islet architecture and insulin content. Our data shows that in contrast to its preventative effects on the development of autoimmune diabetes in NOD mice, chronic nicotinamide administration to obese diabetic (db/db) mice markedly accelerated the progression of diabetes. The results of our study caution against the use of nicotinamide in insulin-resistant states, such as type 2 diabetes.
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PMID:Acceleration of the development of diabetes in obese diabetic (db/db) mice by nicotinamide: a comparison with its antidiabetic effects in non-obese diabetic mice. 1114 15

The general population risk of developing type 1 diabetes mellitus (DM), 1/300, is magnified 15-20 fold in first-degree relatives of affected individuals. Because a combination of immunologic, metabolic, and genetic markers can be used to predict the disease, multicenter prevention trials in the US (DPT-1) and Europe (ENDIT) were initiated in relatives. In the DPT-1 over 80,000 relatives under 45 years of age will be screened for ICA and then 'staged' to assess risk. High-risk subjects (>50% over 5 yr) are randomized either to 4 days intravenous insulin infusion annually followed by b.i.d. low doses of subcutaneous ultralente insulin, or to close observation. To date (September 2000), 331/340 (97%) high-risk subjects have been enrolled with the intention of detecting a 35% decrease in disease over 5 years (80% power). 280/490 (57%) of intermediate risk subjects (25-50% over 5 yr) have been randomized to oral insulin or placebo. A 50% treatment difference is sought. Anticipated enrolment for the high-risk arm will be completed by year 2001, and by 2003 for the oral arm. The ENDIT study will prospectively address whether nicotinamide will reduce the rate of progression to DM in relatives. 40,000 first-degree relatives (5-40 yr) have been screened with 552 subjects (ICA titers > or = 20 JDF U) randomized to nicotinamide or placebo. This study is designed with 90% power to detect a 35% reduction in disease (placebo group estimated at 40% risk over 5 years). Analysis of data is expected in 2003.
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PMID:Update on major trials for the prevention of type 1 diabetes mellitus: the American Diabetes Prevention Trial (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT). 1139 53

The prevention of diabetes and its devastating complications is the prime goal of diabetes care. In immune-mediated type 1 diabetes, beta cell destruction can be predicted with increasing confidence both before and after diagnosis, thus allowing the development of preventative strategies. Multicentre clinical trials with the natural products insulin and nicotinamide have been launched, but the results will only be available in a few years time. Meanwhile, observational studies in large representative risk groups can help to refine the selection of subjects with a more homogenous risk for beta cell destruction, thereby reducing the need for large sample sizes. The comparison between biological markers and disease progression will help to define surrogate disease end-points that can be monitored before the hard clinical end-points of hyperglycaemia or remission. These advances will facilitate the start of new pilot trials to identify relatively safe candidate interventions adapted to disease stage.
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PMID:Prospects for predicting and stopping the development of type 1 of diabetes. 1155 77

The poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that detects and binds DNA strand breaks. Excessive PARP activation leads to the death of mice islet beta-cells by depleting cellular energy reserves. On the other hand, PARP-mutant mice are resistant to streptozotocine-induced diabetes, and in the non-obese diabetic (NOD) mouse model, treatment with nicotinamide, a PARP inhibitor, protects islet cells against cytotoxic actions in vitro and results in a decreased incidence of type 1 diabetes. PARP gene in human is located within a recently identified type 1 diabetes-susceptibility region on chromosome 1q41-42, and contains a polymorphic CA dinucleotide repeat in the promoter region. To consider the putative involvement of PARP polymorphism in predisposition to type 1 diabetes, we performed genotyping for the various alleles of the CA dinucleotide repeat in 158 unrelated French Caucasian patients with type 1 diabetes and 193 ethnically-matched healthy controls. We found no significant difference of PARP alleles distribution between patients and controls, even after stratification of the patients according to HLA class II genotype or to age at disease onset. Our results suggest that this PARP polymorphism does not influence susceptibility to type 1 diabetes in French Caucasians.
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PMID:A dinucleotide repeat polymorphism at the poly(ADP-ribose) polymerase gene is not associated with predisposition to type 1 diabetes in French Caucasians. 1159 Nov 22

Type 1 diabetes mellitus (DM) is characterized by selective and progressive autoimmune destruction of beta-cells of the pancreas in genetically susceptible individuals. This autoimmune process takes years before the patient eventually develops clinical DM. Over the course of the disease, some patients regain their ability to secrete endogenous insulin to some extent for a period of few months to years. This partial remission phase has drawn a lot of attention since it offers a window of opportunity to intervene in an attempt to restore pancreatic beta-cell function or to prevent development of the disease in the prediabetic population at risk. Several factors, including age, sex, pubertal status, metabolic findings at the time of presentation, HLA types, presence of diabetes-associated autoantibodies, have been recognized to affect the likelihood of partial or complete remission in children with type 1 DM. Several interventions in patients with new-onset type 1 DM have been tried, including oral nicotinamide and immunomodulatory and immunosuppressive treatments, in an attempt to preserve beta-cell function and to promote or prolong the remission phase, but no conclusive data have been obtained so far. This review summarizes current knowledge on the factors that possibly influence the remission phase in children with type 1 DM.
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PMID:Factors influencing remission phase in children with type 1 diabetes mellitus. 1179 51

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic beta-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced beta-cell death.
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PMID:Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-Ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes. 1197 44

The expression of IL-1beta in the NOD mouse pancreas was examined following disease acceleration with cyclophosphamide (Cy). Female NOD mice were injected with Cy at day 95 and the pancreas examined immunohistochemically at days 0, 4, 7, 11, and 14 (Cy group). Cyclophosphamide was also administered to NOD mice that were given oral nicotinamide from day 21. At day 0 (Cy group), IL-1beta was expressed in selective intraislet macrophages but showed an increase from day 7 onwards in macrophages, a few beta cells, and somatostatin cells. Peak expression was seen at day 11, when it was significantly higher than in day-11 mice given nicotinamide. In the Cy group a proportion of macrophages coexpressed IL-1beta and inducible nitric oxide synthase (iNOS). IL-1beta expressed within the islet macrophages may act in concert with other cytokines, promote free radical generation including NO, and promote beta cell death during IDDM.
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PMID:IL-1beta expression in islet cells of the NOD mouse and its spatial relationship to beta cells and inducible nitric oxide synthase. 1202 Nov 4

ENDIT ("European Nicotinamide Diabetes Intervention Trial") is a large placebo-controlled randomised clinical trial that aimed at studying the efficacy of nicotinamide in the prevention of type 1 diabetes mellitus among first-degree relatives of type 1 diabetic patients with positive islet cell antibodies (ICA). The results presented at the last congress of the European Association for the Study of Diabetes (EASD) in Budapest do not evidence any significant difference in the risk of developing overt diabetes mellitus in the patients treated with nicotinamide (n = 274) as compared to those receiving placebo (n = 275) after 5 years of follow-up. Despite these negative results, positive lessons could be drawn from ENDIT: 1) the feasibility of a large long-standing multicentre European trial in a difficult research area; 2) the importance of large randomised controlled clinical trials to bring the evidence requested by "Evidence-Based Medicine"; 3) the predictive value of various risk markers to progress toward type 1 diabetes in first-degree relatives, especially the number of positive auto-antibodies; and 4) the urgent need to continue intensive research in this important field of preventive medicine.
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PMID:[Info-congress. Study of the prevention of type 1 diabetes with nicotinamide: positive lessons of a negative clinical trial (ENDIT)]. 1248 73

The clinical manifestation of type 1 diabetes mellitus is preceded by an asymptomatic prodromal period called prediabetes or preclinical diabetes. It may last from a few months to several years, during which the autoimmune destruction of the insulin-producing beta-cells in the pancreas progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections are the most likely environmental factors contributing to the etiopathogenesis. T cells are thought to be the effector cells for the beta-cell destruction, and glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin represent the three major autoantigens. Autoantibodies are early detectable markers of an ongoing disease process and are used to diagnose prediabetes. Among first-degree relatives of patients with type 1 diabetes, the risk for clinical disease can be graded from <5% in those with one or no antibodies to >90% in individuals who carry the HLA-DQB1*02/0302 risk genotype and are positive for multiple autoantibodies. beta-Cell function may also be tested in autoantibody-positive individuals and low first-phase insulin response is highly predictive for rapid progression to the clinical disease. However, dynamic course and individual variation of the disease process complicates the disease prediction, and it is not known whether all individuals with signs of prediabetes will inevitably progress to clinical type 1 diabetes. Until clinically applicable prevention for the condition exists, the screening for the risk markers of type 1 diabetes should actively be undertaken only in the context of research projects. Several major national and international multicenter studies are ongoing to test the potential of various agents (e.g. insulin and nicotinamide) or early elimination of dietary compounds (e.g. cow's milk proteins) to delay or prevent the onset of clinical type 1 diabetes.
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PMID:Prediabetes in children: natural history, diagnosis, and preventive strategies. 1266 17

The incidence of type 1 diabetes continues to increase worldwide. Despite major strides in the daily care of patients with the disease, the patients' contribution to overall morbidity and mortality statistics and health care economic burden to society is disproportionately large because of the high rate of microvascular and macrovascular complications. The quest for prevention of type 1 diabetes has been made feasible by the unraveling of the immunogenetics of the disease and the identification of at-risk subjects by an enhanced understanding of the natural history of the prediabetic period. A combination of immunologic, metabolic, and genetic markers can be used to accurately predict the disease in higher-risk relatives and the general population. This has enabled initiation of worldwide trials (Diabetes Prevention Trial-Type 1, European Nicotinamide Diabetes Intervention Trial, and Trial to Prevent Diabetes in Genetically at Risk) aimed at the prevention of the disease. Various promising agents are being considered for use in different at-risk populations in the near future.
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PMID:Prediction and prevention of type 1 diabetes. 1276 54


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