I-interleukin-2 scintigraphy: a new approach to assess disease activity in autoimmunity.
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Abdomen↗
Biomedical subjects
P Pozzilli
Publications and source records attributed to P Pozzilli.
Beta-cell markers and autoantigen expression by a human insulinoma cell line: similarities to native beta cells.
In the present study we have evaluated the expression of different beta-cell markers, islet molecules and auto-antigens relevant in diabetes autoimmunity by a human insulinoma cell line (CM) in order to define its similarities with native beta cells and to discover whether it could be considered as a model for studies on immunological aspects of Type 1 diabetes. First, the positivity of the CM cell line for known markers of neuroendocrine derivation was determined by means of immunocytochemical analysis using different anti-islet monoclonal antibodies including A2B5 and 3G5 reacting with islet gangliosides, and HISL19 binding to an islet glycoprotein. Secondly, the expression and characteristics of glutamic acid decarboxylase (GAD) and of GM2-1 ganglioside, both known to be islet autoantigens in diabetes autoimmunity and expressed by human native beta cells, were investigated in the CM cell line. The pattern of ganglioside expression in comparison to that of native beta cells was also evaluated. Thirdly, the binding of diabetic sera to CM cells reacting with islet cytoplasmic antigens (ICA) was studied by immunohistochemistry. The results of this study showed that beta cell markers identified by anti-islet monoclonal antibodies A2B5, 3G5 and HISL-19 are expressed by CM cells; similarly, islet molecules such as GAD and GM2-1 ganglioside are present and possess similar characteristics to those found in native beta cells; the pattern of expression of other gangliosides by CM cells is also identical to human pancreatic islets; beta cell autoantigen(s) reacting with antibodies present in islet cell antibodies (ICA) positive diabetic sera identified by ICA binding are also detectable in this insulinoma cell line. We conclude that CM cells show close similarities to native beta cells with respect to the expression of neuro-endocrine markers, relevant beta cell autoantigens in Type 1 diabetes (GAD, GM2-1, ICA antigen), and other gangliosides. Therefore, this insulinoma cell line may be considered as an ideal model for studies aimed at investigating autoimmune phenomena occurring in Type 1 diabetes.
Autoantigens↗
A 5-year (1989-1993) prospective study of the incidence of IDDM in Rome and the Lazio region in the age-group 0-14 years.
OBJECTIVE: To provide data on the incidence of IDDM in Rome and the Lazio region evaluated prospectively from 1989 to 1993 for a total of > 5 million subjects younger than 15 years. RESEARCH DESIGN AND METHODS: All patients with newly discovered IDDM diagnosed between 1 January 1989 and 31 December 1993 among residents in Rome and its region were recorded. Primary ascertainment was based in diabetes clinics and specialized hospitals in the region, whereas the secondary independent source was taken from the archives of the region where patients are registered to obtain exemption from paying for medications. RESULTS: We identified 330 new patients with a degree of ascertainment of 85%. Overall the incidence rate of the disease was 7.9 per 100,000 per year (95% CI 7.1-8.8). The incidence was higher in the 5- to 9-year-old age-group (10.4 per 100,000) and in winter (36.2%). The cumulative risk for the disease is on the order of 1.18 per 1,000 subjects < 15 years of age. No significant differences in incidence were observed between boys and girls. There were 14 instances of coma at diagnosis (4.3%), but hyperglycemia without ketonuria was diagnosed in 35% of patients, suggesting an early diagnosis. DISCUSSION: Compared with the other continental Italian regions for which data are available for a single year, the IDDM incidence rate in Rome is similar. We conclude that the IDDM incidence rate in Rome and its region is comparable to that in other Southern European countries and remained stable over the 5-year observation period.
Adolescent↗
Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM. The Nicotinamide Trialists.
OBJECTIVE: Nicotinamide, a vitamin of the B group, has in vitro actions capable of interfering with the pathogenetic process leading to IDDM. Since 1987, several studies have evaluated nicotinamide as a means of protecting beta-cells from end-stage destruction in insulin-treated patients with newly diagnosed IDDM. The aim of the study was to determine whether nicotinamide protects residual beta-cell function when given at IDDM diagnosis. RESEARCH DESIGN AND METHODS: We performed a meta-analysis of the integrated parameters of metabolic control (C-peptide, glycosylated hemoglobin, insulin dose) in 10 randomized (5 of which were placebo) controlled trials conducted in recent-onset IDDM patients for a total of 211 nicotinamide-treated patients. Data on the adverse effects of nicotinamide were also collected from an additional four trials to yield a grand total of 291 nicotinamide-receiving patients. RESULTS: One year after diagnosis, baseline C-peptide was significantly higher in nicotinamide-treated patients, compared with control patients (0.73 +/- 0.65 vs. 0.32 +/- 0.56 ng/ml, P < 0.005). This statistical difference remained also when the five placebo-controlled trials only were considered (P < 0.05). No differences were observed in the insulin dose required or glycosylated hemoglobin values between nicotinamide and control patients. Adverse effects were reported in few patients (transient elevation of transaminase, n = 2; skin rash, n = 2; recurrent hypoglycemia, n = 2). CONCLUSIONS: This combined analysis demonstrates a therapeutic effect of nicotinamide in preserving residual beta-cell function when given at IDDM diagnosis in addition to insulin. Since adverse effects were negligible, we suggest that prolonged use of nicotinamide after IDDM diagnosis should be tested to see whether residual beta-cell function can be preserved for longer periods.
Adolescent↗
Standardizing experiments with NOD mice.
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Adoptive Transfer↗
Effect of metformin on liver insulin metabolism and regional blood flow.
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Animals↗
Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the non-obese diabetic mouse.
Glutamic acid decarboxylase (GAD) is the enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA). GAD has been identified as a 64-kDa antigen expressed in pancreatic beta-cells, to which autoantibodies are generated prior to the onset of type 1 (insulin-dependent) diabetes mellitus. GAD may therefore be an initiating factor in beta-cell destruction. We administered baclofen, a GABA-B receptor agonist, to non-obese diabetic (NOD) mice in an attempt to down-regulate GAD expression and thereby reduce the incidence of diabetes. Twenty-four female NOD mice were given baclofen in their drinking water at a final dose of 50 mg/kg body weight daily from weaning to 30 weeks of age. Twenty-four sex- and litter-matched mice were used as controls. At 30 weeks there was no difference in the incidence of diabetes in the treated group compared with the controls. However, there was a significant delay in the onset of diabetes in the treated group (P < 0.001, parallelism test). The degree of insulitis and the GAD activity in the pancreas per mg of protein were unchanged by baclofen treatment with respect to controls. These results suggest that baclofen may be effective in delaying diabetes onset in NOD mice by stimulating GABA activity, as this neurotransmitter, localised in the islets, may modulate insulin secretion and the antigen expression associated with it.
Aging↗
Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study).
Nicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels 6.7 +/- 1.8% nicotinamide vs 7.1 +/- 0.6% placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
New and old trends for treating organ-specific autoimmune endocrinopathies.
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Antibodies↗
Retroviruses and diabetes in animal models: hypotheses for the induction of the disease.
This review examines the association between retroviruses and diabetes in the mouse model, the role of retroviruses in the pathogenesis of Type 1 diabetes and the mechanisms by which retroviruses can induce an autoimmune reaction. Three putative mechanisms are considered: the expression of retroviral protein(s) on the beta-cell surface as the first step in immune response against beta cells; the homology of a retroviral product with a self antigen inducing a cross-reacting autoimmune response (molecular mimicry); and a retroviral product showing homology with interleukin-2 and inducing T-cell activation against beta-cell antigens and loss of tolerance. These findings are discussed for their possible implications in the pathogenesis of human Type 1 diabetes.
Animals↗
Adjuvant therapy in recent onset type 1 diabetes at diagnosis and insulin requirement after 2 years.
Partial recovery of beta-cell function in type 1 diabetes is common after diagnosis by intensive insulin therapy. Residual beta-cell function can be improved by other therapies. Cyclosporin (CyA) and nicotinamide (NA), alone or in combination, can preserve this function, as indicated by the parameters of metabolic control (insulin dose, HbA1C). After suspension of CyA, insulin requirement returns to control values, suggesting loss of residual beta-cell function. The effects induced by withdrawal of NA after 1 year are not known. For the first time, we studied 27 type 1 diabetes patients treated with NA for 12 months and then followed up for 1 year after discontinuance of NA. Another 25 patients treated with NA + CyA and 28 control patients were followed up similarly. Insulin requirement doubled 12 months after discontinuance of NA or NA + CyA, becoming identical to that of controls. As patients showed HbA1C values similar to control subjects, it is likely that beta-cell function deteriorated after discontinuance of therapy. As NA is safer than other agents and its effects are beneficial, longer studies are warranted to investigate NA in prolonged treatments since this compound is also being considered for prevention of type 1 diabetes.
Adjuvants, Pharmaceutic↗
Serum angiotensin-converting enzyme levels in patients with recent-onset insulin-dependent diabetes after one year of low-dose cyclosporin therapy. IMDIAB Study Group.
Cyclosporin A (CyA) is today used for the treatment of autoimmune diseases and in the past was given also to patients with recent-onset insulin-dependent diabetes mellitus (IDDM). Hypertension is a major hazard in patients receiving CyA. In this study we have evaluated the effect of CyA administered to IDDM patients on blood pressure and serum angiotensin-converting enzyme (SACE), an endopeptidase that is an integral part of the renin-angiotensin and bradykinin systems. Sera from patients affected by recent-onset IDDM who were treated with CyA at the dose of 5 mg/kg body weight in addition to insulin therapy were included in the study (n = 13). Sera from 9 IDDM patients with the same clinical characteristics and followed up for 12 months represented the control group (insulin therapy only). SACE levels were measured at diagnosis and after 12 months. The results showed that SACE levels were elevated in IDDM patients at diagnosis and remained significantly high at 12 months in CyA-treated patients as compared to control patients (P < 0.006). Systolic and diastolic blood pressure were increased at 12 months in CyA-treated patients (p < 0.005 and p < 0.05, respectively). CyA therapy administered even at low doses to IDDM patients may increase SACE levels and also blood pressure. These findings should be considered when CyA is used for therapy of autoimmune diseases.
Adolescent↗
Affected sib-pair analysis of the GLUT1 glucose transporter gene locus in non-insulin-dependent diabetes mellitus (NIDDM): evidence for no linkage.
Despite the strong evidence for a major role played by genetic factors in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), the genes involved are still unknown. Association studies of candidate genes for the inheritance of NIDDM have so far yielded inconclusive results. Some evidence exists for an association between NIDDM and the glucose transporter gene GLUT1, involved in basal glucose transport, although this has not been confirmed. In the present study we have tested the hypothesis of linkage between NIDDM and the GLUT1 gene, using affected sib-pairs. With this method the concordance observed for a given gene marker is compared with that expected under the assumption of no linkage between that marker and the disease. Fifty-four pedigrees (22 Italians and 32 British), for a total of 82 sib-pairs were studied by the affected sib-pair method proposed by Weeks and Lange, using two restriction fragment length polymorphisms (RFLPs) at the GLUT1 locus, the MspI RFLP, at an estimated 0.171 recombination frequency from the GLUT1 gene, and the XbaI RFLP, located within the GLUT1 gene and previously shown to be associated with the disease. Results showed that the MspI marker and NIDDM segregate independently; for the XbaI RFLP, linkage could be shown only if the results were weighted by the allele frequency [f(p) = 1/p], and only in the Italian and the combined (Italian and British) sib-pair groups. Multilocus analysis with both markers was also negative. We conclude that the GLUT1 gene is very unlikely to play a major role in the aetiology of NIDDM, although an accessory role cannot be excluded, and studies of the gene sequence should help to clarify this question.
Chromosome Mapping↗
Histological study of pancreatic beta-cell loss in relation to the insulitis process in the non-obese diabetic mouse.
Non-obese diabetic (NOD) mice spontaneously develop an autoimmune diabetes with higher incidence in females than in males. In order to elucidate possible factors involved in the different incidence of diabetes between male and female mice, we studied the progression of pancreatic beta-cell loss in relation to mononuclear cell infiltration of the pancreas (insulitis). We examined the pancreas of 76 NOD mice (39 males and 37 females) of different ages. The beta-cell content was assessed by immunoperoxidase staining of sections with an anti-insulin serum and the severity of insulitis was determined by haematoxylin staining of the same sections. A semi-quantitative criterion was used to grade both parameters. The results showed that females have a faster loss of beta-cell mass, which progressively decreases with the increase of severity of insulitis. In males, a medium to severe degree of insulitis is required before initial loss of beta cells occurs. Under the age of 10 weeks there was a significantly lower content of beta cells in females than males (2.84 +/- 0.03 vs 2.67 +/- 0.07; P = 0.02). Since we never observed a significant difference in the degree of mononuclear cell infiltration in age-matched males and females, these data support the hypothesis of weaker beta-cell resistance to immunological attack in female mice. Thus beta-cell sensitivity, in addition to immunological activity, is an important factor in the pathogenesis of insulin dependent diabetes.
Aging↗
Vitamin E delays diabetes onset in the non-obese diabetic mouse.
Vitamin E was administered to non-obese diabetic (NOD) mice to determine if the selective destruction of pancreatic beta cells leading to Type 1 (insulin dependent) diabetes mellitus could be halted by virtue of this vitamin's free oxygen radical scavenger activity. Two groups of NOD mice were treated from 3 weeks of age until 30 weeks of age with either diet supplemented with vitamin E or control diet. Diabetes incidence was recorded as well as the degree of lymphocytic infiltration of the pancreas (insulitis) in animals which did not develop diabetes. Vitamin E did not reduce the incidence of diabetes by 30 weeks of age, however it did significantly delay the onset of the disease (p < 0.01--parallelism test). There were no differences in the degree of insulitis with respect to control mice. We conclude that antioxidant therapy with Vitamin E delays diabetes onset in NOD mice without having an apparent effect on the autoimmune process.
Animals↗
Cytokines and autoimmunity.
Although the immunopathology of most autoimmune diseases has been well defined, the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of systemic and organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of cytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases.
Animals↗
Lymphocytic traffic and homing into target tissue and the generation of endocrine autoimmunity.
Endocrine autoimmunity is known to be characterized by the presence of specific autoantibodies and from the histopathological point of view by lymphocytic infiltration in the target tissue. The presence of mononuclear cell infiltrates is the pathological hallmark of most endocrine diseases characterized by an autoimmune process directed against antigens expressed on endocrine cells. Infiltrating cells can usually be detected by biopsy or by using other, non-invasive, techniques. However, in endocrine tissue such as the islets of Langerhans and the adrenal glands it is difficult to perform biopsies and diagnosis of the autoimmune process is dependent mainly upon detection of specific autoantibodies. A crucial aspect of endocrine autoimmunity and of all processes of organ specific autoimmunity is why and how lymphocytes migrate from primary lymphoid tissue to their specific targets. This occurs mainly through contact with specific adhesion molecules which enable lymphocytes to adhere to the endothelial vessels in close proximity to the target tissue. In this review we discuss the homing of peripheral mononuclear cells into target endocrine tissues and the mediating role of adhesion molecules.
Autoantibodies↗
Infections and diabetes: mechanisms and prospects for prevention.
Infections remain a serious hazard for the diabetic patient. Good metabolic control is a major factor in limiting the development and spread of infections and, most importantly, the development of diabetic complications which predispose to infections. In some patients recurrent infections can pose a problem, particularly if there is evidence of secondary immunodeficiency. In these patients adjuvant therapies, including Biological Responses Modifiers (BRMS) should be considered. Several factors could predispose diabetic patients to infections. These factors include: genetic susceptibility to infection; altered cellular and humoral immune defense mechanisms; local factors including poor blood supply and nerve damage, and alterations in metabolism associated with diabetes. In the context of a diabetic patient all or some of these factors may operate. The purpose of this review is to assess the relative contribution of these potential mechanisms in leading to infection in patients with diabetes.
Adult↗