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

Nicotinamide is being used in trials to prevent or delay the development of clinical IDDM. A related compound, niacin, has been shown to cause insulin resistance in normal subjects, resulting in increased insulin secretion. This study was designed to answer the question: Does the short-term administration of nicotinamide cause insulin resistance in subjects who have a high risk of developing IDDM? Eight islet cell antibody-positive (ICA+) relatives of IDDM patients were given nicotinamide at a dose of 2 g/day for 2 weeks. Measurements of first-phase insulin release, insulin sensitivity, glucose effectiveness, and the constant for glucose disappearance (Kg) were measured at baseline, at the end of 2 weeks of therapy, and after subjects had been off therapy for at least 2 weeks. Nicotinamide administration caused a 23.6% decrease in insulin sensitivity (P = 0.02). This decrease was associated with a fall in Kg despite increased insulin secretion. Our data suggest that the use of nicotinamide in subjects who are at risk of developing IDDM may be complicated by the drug's effects on insulin sensitivity. By inducing insulin resistance, a therapeutic effect of nicotinamide on the diabetes disease process may be missed, and the interpretation of insulin secretion measurements that are obtained during the intervention trials using nicotinamide may be complicated by the changes in insulin secretion that are caused by the increased insulin resistance. Therefore, we strongly support the recommendation that at least one subgroup of subjects enrolled in clinical trials to prevent IDDM have regular measurements of both insulin sensitivity and insulin secretion performed. This subgroup should be randomly assigned and large enough for statistical analysis to interpret properly the changes in insulin secretion that may occur.
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PMID:Nicotinamide's effects on glucose metabolism in subjects at risk for IDDM. 886 71

Autoimmune processes are involved in pancreatic beta cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against protein tyrosine phosphatase/IA2 (IA2-Ab) appear in the circulation years before clinical onset and permit increasingly precise disease prediction. Increasing knowledge of the pathogenesis of type 1 diabetes in animal models and humans suggests that progression to disease is not inevitable in those with indications of autoimmune processes directed against islet beta cells, and that these processes may prove vulnerable to intervention. The conditions therefore exist for screening and attempted intervention in pre-type 1 diabetes. This review will discuss the theoretical and practical background to a major controlled trial using one of a number of interventions currently under consideration. Nicotinamide, a soluble B group vitamin, has for many years been known to protect beta cells against a variety of noxious stimuli. It is at high doses a free radical scavenger, a potent inhibitor of the enzyme poly (ADP-ribose) polymerase (PARP), and prevents depletion of intracellular NAD. Although its benefits have been marginal or absent in recently diagnosed patients, promising pilot studies have been performed in ICA positive first degree relatives and schoolchildren. No serious side effects have been reported from its use at the doses proposed in man or other species. There is therefore a sound case for submitting this agent to a controlled clinical trial, which, in view of the numbers involved, has necessarily been launched on an international collaborative basis.
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PMID:Theory and practice of nicotinamide trials in pre-type 1 diabetes. 888 46

It has been postulated that treatment with nicotinamide may prevent or delay the onset of insulin dependent diabetes mellitus. We report the findings of a population based diabetes prevention trial which tests this hypothesis. 33,658 school children aged 5-7.9 years were randomly selected (by school) from a total population of 81,993 of such children in the Auckland (New Zealand) region. They were offered testing for islet cell antibodies. 20,195 (60%) consented to testing. Of these 185 had islet cell antibodies and met the criteria for treatment with nicotinamide. 173 received this treatment. The study population has an average follow up time of 7.1 years. The diabetes incidence of the untested controls was: 16.07 (12.4-20.5 95% CI) /100,000 person years at risk; in the group who were tested and treated when deemed appropriate: 7.14 (3.1-14.1 95% CI); and in the group offered testing but who did not consent ("refusers'): 18.48 (10.1-31.0 95% CI). The tested group had a rate of diabetes of 41% (20-85 95% CI) of the other groups combined after an age adjustment, which is significant (p = 0.008). The tested group combined with the "refuser' group (i.e. "intention to treat') also has a lower incidence than the control group (p = 0.12). Nicotinamide has a protective effect against the development of insulin dependent diabetes in this setting but the size of the effect has a wide confidence interval. Further follow up may define the magnitude of the protective effect within narrower limits.
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PMID:A population based strategy to prevent insulin-dependent diabetes using nicotinamide. 896 Nov 25

This article focuses on recent developments that have defined the autoimmune nature of this entity and its genetic basis, especially the crucial roles of aspartic acid at position 57 of the DQ beta chain and arginine at position 52 of the DQ alpha chain of the HLA complex on chromosome 6 in conferring susceptibility; other genetic markers on other genes are mentioned. These genetic markers help to explain the worldwide differences in prevalence and incidence of type 1 diabetes. Because the autoimmune process may be gradual, markers of beta pancreatic cell damage, such as islet cell antibodies, glutamic acid decarboxylase antibodies, and insulin autoantibodies, coupled with evidence of progressive failure of insulin secretion may be used to predict the future onset of disease. In turn, accurate prediction may permit preventive intervention. Two intervention trials are mentioned: (1) Diabetes Prevention Trial for Type 1, a multicenter trial in the United States using insulin; and (2) European Nicotinamide Diabetes Intervention Trial in Europe using nicotinamide as the preventive or delaying agent. These first steps reflect the remarkable progress and understanding of this major problem of childhood and the hopes for its future prevention.
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PMID:Aspects of the etiology, prediction, and prevention of insulin-dependent diabetes mellitus in childhood. 913 Sep 20

The radical nitric oxide (NO) may be a mediator of beta-cell damage in IDDM. The cytokines IFN-gamma and IL-1beta are required for expression of the enzyme nitric oxide synthase (iNOS), and NO production by human pancreatic islets. In this study, possible mechanisms by which IFN-gamma participates in iNOS messenger RNA (mRNA) expression were evaluated in both rodent and human islets cells. Addition of IFN-gamma, before or after arrest of IL-1beta-induced iNOS gene transcription by actinomycin D, did not prolong iNOS mRNA half life in the rat insulin-producing cell line RINm5F (RIN cells). IFN-gamma also failed to modify IL-1beta-induced activation of the transcription factor kappaB (NF-kappaB) in RIN cells, as determined by electrophoretic mobility shift assay. However, IFN-gamma induced an early (30 min(-1) h) increase in interferon regulatory factor-1 (IRF-1) mRNA expression and a later (2 h) 19-fold increase in RIN cell nuclear IRF-1 protein content, an effect further potentiated by IL-1beta. The total cellular content of IRF-1 protein increased by 30- to 50-fold in human islets exposed for 2-8h to IFN-gamma or IFN-gamma + IL-1beta. IL-1beta alone induced a marginal and transient increase in IRF-1. It has been previously reported that nicotinamide prevents IL-1beta-induced IRF-1 expression in rat pancreatic islets. However, nicotinamide (20 mM) presently failed to prevent IL-1beta + IFN-gamma-induced IRF-1 protein expression in human pancreatic islets. In conclusion, the effects of IFN-gamma on iNOS expression can neither be explained by iNOS mRNA stabilization nor increased NF-kappaB activation. However, IFN-gamma induces an early increase in cellular IRF-1 content, and this may contribute to increased iNOS mRNA expression.
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PMID:Interferon-gamma-induced interferon regulatory factor-1 (IRF-1) expression in rodent and human islet cells precedes nitric oxide production. 920 13

At the present time, there are markers which we can use to identify individuals with a high susceptibility of developing insulin-dependent diabetes mellitus (IDDM) years before the onset of the disease. Insulin-dependent diabetes mellitus is an autoimmune disease strongly associated with HLA antigens DR3 and DR4. In this manuscript, we discuss the usefulness of several markers, such as islet cell antibodies, insulin autoantibodies and glutamic acid decarboxylase antibodies, to identify individuals with a high susceptibility to IDDM before the disease is clinically evident. Monitoring first phase insulin release during intravenous glucose administration is a useful index of residual beta cell function that can be used to detect individuals who are close to insulin dependence. Several drugs have been used to prevent the development of IDDM. These include immunodepressors, anti-inflammatory agents, non-specific immunomodulators and free radical scavengers. Due to their toxicity, studies employing aziothioprine and cyclosporin were discontinued. Other agents, such as tetrandrin and lymphotoxin, are now restricted to non-human trials. Currently, two large-scale multicentric human trials, one in Europe using nicotinamide (European Nicotinamide Diabetes Intervention Trial, ENDIT) and the other in the USA using insulin (Diabetes Prevention Trial), are now in full activity and will test the benefits of these drugs in the prophylaxis of IDDM in highly susceptible individuals.
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PMID:[The prevention of insulin-dependent diabetes mellitus]. 925 34

On the basis of the positive outcome of animal experiments, several large placebo-controlled trials are underway and aiming for the first time at the prevention of an immune-mediated disease, type 1 diabetes. The first of these trials, The Deutsche Nicotinamide Intervention Study (DENIS), evaluated the clinical efficacy of high doses of nicotinamide in children at high risk for IDDM. Nicotinamide has been shown to protect beta-cells from inflammatory insults and to improve residual beta-cell function in patients after onset of IDDM. Individuals at high risk for developing IDDM within 3 years were identified by screening the siblings (age 3-12 years) of patients with IDDM for the presence of high titer (> or =20 Juvenile Diabetes Foundation [JDF] U) islet cell antibodies. Probands (n = 55) were randomized into placebo and nicotinamide (slow release, 1.2 g x m(-2) x day(-1)) receiving groups and followed prospectively in a controlled clinical trial using a sequential design. Rates of diabetes onset were similar in both groups throughout the observation period (maximum 3.8 years, median 2.1 years). This sequential design provides a 10% probability of a type II error against a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% by nicotinamide. The trial was terminated when the second sequential interim analysis after the eleventh case of diabetes showed that the trial had failed to detect a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% (P = 0.97). The group receiving nicotinamide exhibited decreased first-phase insulin secretion in response to intravenous glucose (P = 0.03). No other side effects were observed. We conclude that in this subgroup of diabetes-prone individuals at very high risk and with an assumed rapid disease progression, nicotinamide treatment did not cause a major decrease or delay of diabetes development. However, the data do not exclude the possibility of a less strong, but potentially meaningful, risk reduction in this cohort, or a major clinical effect of nicotinamide in individuals with less risk of progression to IDDM than studied here.
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PMID:The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group. 960 80

Pancreases of untreated and nicotinamide (NIC)-treated pre-diabetic (10-week-old) and overtly diabetic (25-week-old) female NOD (non-obese diabetic) mice and of NON (non-obese non-diabetic) control mice were studied, with the following results. (1) Islets and ducts of overtly diabetic untreated NOD mice (25-week-old) were found to express low levels of MHC class I and II molecules, like NON controls, and high levels of adhesive molecules. (2) NIC was able to slightly affect glycaemia and insulitis, slowing down diabetes progression. Moreover it significantly decreased MHC class II expression (but not class I) in vivo by week 10, and significantly enhanced intercellular adhesion molecule-1 (ICAM-1) expression, mainly by week 25, within the pancreas, where 5-bromo-2'-deoxyuridine positive nuclei and insulin positive cells were present, demonstrating that a stimulation of endocrine cell proliferation occurs. (3) In addition, NIC partly counteracted the fall of superoxide dismutase levels, observed in untreated diabetic NOD animals. (4) In vitro studies demonstrated that NIC: (i) was able to significantly reduce nitrite accumulation and to increase NAD+NADH content significantly, and (ii) was able to increase the levels of interleukin-4, a T helper 2 lymphocyte (Th2) protective cytokine, and of interferon-alpha (IFN-alpha), which is known to be able to induce MHC class I and ICAM-1 but not MHC class II expression, as well as IFN-gamma, which is also known to be able to induce MHC class I and ICAM-1 expression. The latter, although known to be a proinflammatory Th1 cytokine, has also recently been found to exert an anti-diabetogenic role. This study therefore clearly shows that adhesive mechanisms are ongoing during the later periods of diabetes in pancreatic ducts of NOD mice, and suggests they may be involved in a persistence of the immune mechanisms of recognition, adhesion and cytolysis and/or endocrine regeneration or differentiation processes, as both NIC-increased ICAM-1 expression and 5-bromo-2'-deoxyuridine positivity imply. The effects of NIC on MHC class II (i.e. a reduction) but not class I, and, mainly, on ICAM-1 expression (i.e. an increase), together with the increase in Th2 protective cytokine levels are very interesting, and could help to explain its mechanism of action and the reasons for alternate success or failure in protecting against type 1 diabetes development.
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PMID:Nicotinamide decreases MHC class II but not MHC class I expression and increases intercellular adhesion molecule-1 structures in non-obese diabetic mouse pancreas. 1007 85

Over the past decade, a large part of type 1 diabetes research has focused on the possibility of preventing the disease. The objective of this article is to analyze which potential and pitfalls different preventive strategies may involve from the individual, epidemiological, and ethical perspectives. Two potential prevention strategies are considered: l) to try to arrest or delay an already ongoing immune destruction of the beta-cells, and 2) to try to intervene with exposures that may initiate this process. In addition to the potential effects of immune modulation, this prevention strategy depends on screening for risk markers. There are inherent ethical problems with screening because of the introduction of awareness of risk in healthy individuals and also because false positivity, the rate of which differs tremendously in high- and low-risk groups. Because of these latter circumstances, the most promising low-risk preventive treatments presently used in trials, i.e., nicotinamide and insulin, will probably only be feasible in high-risk groups, such as family members, though this group covers only 10-15% of potential cases. The second strategy aiming at eradicating environmental initiators of the beta-cell destruction will avoid the problem of screening and approach a total population at risk. Potential risk factors, such as food components (cow's milk proteins, gliadin or nitroso products) or different viruses, are indicated by animal and epidemiological studies. So far, however, no single environmental risk factor has been proven to be necessary and certainly not sufficient for the disease causation, and the etiological fractions estimated in population-based studies are low. It is concluded that more basic research is warranted before effective and safe prevention can be introduced for type 1 diabetes. Most probably, different preventive strategies must be applied to different groups and populations and in different phases of the beta-cell destruction.
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PMID:Primary and secondary prevention strategies of pre-type 1 diabetes. Potentials and pitfalls. 1009 92

Treatment with high doses of nicotinamide (niacinamide, vitamin B3) prevents or delays insulin-deficient diabetes in several animal models of type 1 diabetes and protects islet cells against cytotoxic actions in vitro. In recent-onset type 1 diabetes, nicotinamide administration improves beta-cell function, without significantly decreased insulin requirements. This review discusses the possible mechanism of action of nicotinamide in vivo. It is proposed that the key target of nicotinamide is the poly(ADP-ribose)polymerase (PARP), and to a lesser extent (mono)ADP-ribosyl transferases (ADPRTs). Suppression of PARP activity by nicotinamide not only decreases consumption of NAD+, the substrate of PARP, but also has major regulatory effects on gene expression, as shown for the major histocompatibility complex class II gene. In addition, PARP activity controls early steps of apoptosis. The possible suppression of ADPRTs by nicotinamide would also affect CD38, a membrane-bound external ADP-ribosyl transferase with potent immunoregulatory properties. Taken together, it is proposed that high doses of nicotinamide primarily affect ADP-ribosylation reactions in beta-cells as well as in immune cells and the endothelium. As a consequence, cell death pathways and gene expression patterns are modified, leading to improved beta-cell survival and an altered immunoregulatory balance.
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PMID:Nicotinamide in type 1 diabetes. Mechanism of action revisited. 1009 94

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