Relationship between glomerular hyperfiltration and ACE insertion/deletion polymorphism in type 1 diabetic children and adolescents.
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OBJECTIVE: Glomerular hyperfiltration may predict diabetic nephropathy in type 1 diabetes, and some studies suggest that the ACE D allele is associated with diabetic nephropathy. The aim of this study was to examine a possible relationship between glomerular hyperfiltration and ACE insertion/deletion (I/D) polymorphism in type 1 diabetic children and adolescents. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted to examine the relationship between glomerular hyperfiltration and ACE (I/D) polymorphism in 76 type 1 diabetic children and adolescents without diabetic nephropathy (mean +/- SD: age 16 +/- 3 years; diabetes duration 7 +/- 4 years; age at diabetes onset 9 +/- 4 years; HbA1c 9.5 +/- 1.9%). Glomerular hyperfiltration (defined as a glomerular filtration rate [GFR] > or = 135 ml.min-1. 1.73 m-2 and by 51Cr-labeled EDTA plasma disappearance technique) and ACE I/D genotypes and plasma levels (enzyme-linked immunosorbent assay [ELISA] method) were determined. RESULTS: Of the patients, 29 (38%) displayed glomerular hyperfiltration. An association between glomerular hyperfiltration and ACE (I/D) polymorphism was observed (chi 2 = 7.09, P = 0.029) because of a reduced proportion of DD genotypes among patients with glomerular hyperfiltration (4 vs. 19; chi 2 = 6.03, P = 0.014) and not because of an excess of the II genotype (5 vs. 9; chi 2 = 0.04, P = 0.83). Age, diabetes duration, age at diabetes onset, and HbA1c were not different according to genotype. Patients with glomerular hyperfiltration had low plasma ACE levels, compared with those with normal glomerular filtration (457 +/- 157 vs. 553 +/- 186 micrograms/l; P = 0.027). CONCLUSIONS: These results suggest an unexpected association between glomerular hyperfiltration and ACE (I/D) polymorphism, characterized by a defect of the DD genotype among type 1 diabetic children and adolescents with glomerular hyperfiltration. (+info)
In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha.
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The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- alpha receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4(+) T cells to establish insulitis and subsequently destroy islet beta cells. These results argue that islet cells play a TNF-alpha-dependent role in their own demise. (+info)
Noncommunicable disease management in resource-poor settings: a primary care model from rural South Africa.
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Noncommunicable diseases (NCDs) such as hypertension, asthma, diabetes and epilepsy are placing an increasing burden on clinical services in developing countries and innovative strategies are therefore needed to optimize existing services. This article describes the design and implementation of a nurse-led NCD service based on clinical protocols in a resource-poor area of South Africa. Diagnostic and treatment protocols were designed and introduced at all primary care clinics in the district, using only essential drugs and appropriate technology; the convenience of management for the patient was highlighted. The protocols enabled the nurses to control the clinical condition of 68% of patients with hypertension, 82% of those with non-insulin-dependent diabetes, and 84% of those with asthma. The management of NCDs of 79% of patients who came from areas served by village or mobile clinics was transferred from the district hospital to such clinics. Patient-reported adherence to treatment increased from 79% to 87% (P = 0.03) over the 2 years that the service was operating. The use of simple protocols and treatment strategies that were responsive to the local situation enabled the majority of patients to receive convenient and appropriate management of their NCD at their local primary care facility. (+info)
Social disadvantage, family composition, and diabetes mellitus: prevalence and outcome.
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OBJECTIVE: To investigate the relation between social disadvantage and family composition on diabetes prevalence and diabetes care outcome. DESIGN: Retrospective audit in the south west of England of 801 children with diabetes mellitus. MAIN OUTCOME MEASURES: Prevalence of diabetes in relation to the Townsend index. Admissions to hospital with diabetes related problems, glycated haemoglobin, time spent in hospital, outpatient attendance rates. RESULTS: There was no association between social status and diabetes prevalence. Social deprivation increased the likelihood of admission for hypoglycaemia. Children living with a single parent were more likely to be admitted to hospital with a diabetes related problem and stay in hospital longer. Having either a parent with diabetes or a single parent increased the rates of clinic non-attendance. No association was identified between medium term diabetes control and either social disadvantage or single parent status. CONCLUSIONS: Social disadvantage has no effect on diabetes prevalence and little on diabetes outcome in childhood. Family structure and parental diabetes have adverse effects on some aspects of diabetes outcome. (+info)
Interferon-gamma plays a role in pancreatic islet-cell destruction of reovirus type 2-induced diabetes-like syndrome in DBA/1 suckling mice.
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Reovirus type 2 (Reo-2) infection in DBA/1 suckling mice causes insulitis, which leads to pancreatic islet-cell destruction, resulting in a diabetes-like syndrome. T-helper (Th) 1 cytokines are thought to play a key role in islet inflammation in insulin-dependent diabetes mellitus. We examined this hypothesis in the Reo-2-induced diabetes-like syndrome. We used reverse transcriptase polymerase chain reaction (PCR) and quantitative PCR techniques to examine mRNA expression of interferon (IFN)-gamma (Th1 type cytokine), and interleukin (IL)-4 (Th2 type cytokine) in splenic cells. We observed that in Reo-2 infected mice the level of IFN-gamma expression increases with the development of insulitis, whereas expression of message for IL-4 is minimal to detectable with the immuno-inflammatory process 10 days after infection. The treatment of monoclonal antibody (mAb) against mouse IFN-gamma during the expansion phase of insulitis (5-9 days after infection) inhibited the development of insulitis and the elevation of blood glucose concentrations in a dose dependent manner. Furthermore altered CD4+/CD8+ cell ratio compared with uninfected mice in the splenic cells by the infection was recovered to the ratio of uninfected mice by the treatment of mAb against mouse IFN-gamma, suggesting normalization of T cell balance in immune system. These results suggest that Reo-2-triggered autoimmune insulitis may be mediated by Th1 lymphocytes and IFN-gamma may play a role in islet inflammation leading to islet cell destruction. (+info)
Evidence for control of tumour necrosis factor-alpha (TNF-alpha) activity by TNF receptors in patients with proliferative diabetic retinopathy.
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TNF-alpha has been implicated in the pathogenesis of insulin- dependent diabetes mellitus (IDDM). At present there are no studies linking serum levels of soluble TNF receptors (sTNF-R) to the development of diabetic microvascular complications such as proliferative diabetic retinopathy (PDR), or to the production of TNF-alpha in these patients. We investigated serum levels of sTNF receptors (sTNF-RI and sTNF-RII) in IDDM patients with or without PDR, and related these to the in vitro production of TNF-alpha upon activation of whole blood and isolated mononuclear cells (MNC). We observed higher serum levels of sTNF-RI in IDDM patients with active (range 945-6630 pg/ml; P = 0.029) or quiescent PDR (range 1675-4970 pg/ml; P = 0.00092) than in individuals with IDDM without retinopathy (range 657-2617 pg/ml) or healthy controls (range 710-1819 pg/ml; P = 0.0092 and 0.0023, respectively). Increased serum levels of sTNF-RII were also seen in IDDM patients with active PDR (range 1749-5218 pg/ml; P = 0.034) or quiescent PDR (range 1494-5249 pg/ml; P = 0.0084) when compared with disease controls (range 1259-4210 pg/ml) or healthy subjects (range 1237-4283 pg/ml). Whole blood production of biologically active TNF-alpha was lower in PDR patients than in disease (P = 0.04) and healthy controls (P < 0.005), contrasting with a higher production of TNF-alpha by lipopolysaccharide (LPS)-activated MNC from PDR patients (P = 0.013). Inhibition of TNF-alpha by TNF-R in plasma supernatants of activated blood from PDR patients was demonstrated by increase of TNF-alpha activity in the presence of anti-TNF-RI and anti-TNF-RII antibodies. These observations suggest that abnormalities in TNF-alpha production and control may operate during the development of microvascular complications of diabetes mellitus. (+info)
Induction of prostaglandin release from macrophages by bacterial endotoxin.
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This review summarizes the role of the monocytic responses to lipopolysaccharide as it relates to periodontal disease severity. Data are presented which illustrate that the levels of prostaglandin E2 (PGE2) secreted by systemic peripheral blood monocytes in culture, in the presence of bacterial endotoxins, are highly correlated with the levels observed in the gingival crevicular fluid. Furthermore, the different periodontal diagnostic categories have varying levels of monocytic and crevicular fluid PGE2, in juxtaposition with clinical disease severity. These data are consistent with the concept that there is close synchrony between the systemic responsiveness of peripheral blood monocytes with regard to prostanoid synthesis and the local levels of mediator present within the gingival crevice. (+info)
Long-term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy.
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AIM: To determine if children born to mothers with diabetes mellitus during pregnancy, who subsequently developed neonatal hypoglycaemia, experienced long-term neurological dysfunction. METHODS: Thirteen children with, and 15 without, neonatal hypoglycaemia (blood glucose < 1.5 mmol/l) were randomly selected from a larger cohort and investigated at the age of 8 years. They were also compared with 28 age matched healthy controls. RESULTS: Children with neonatal hypoglycaemia had significantly more difficulties in a validated screening test for minimal brain dysfunction than controls and were also more often reported to be hyperactive, impulsive, and easily distracted. On psychological assessment, they had a lower total development score than normoglycaemic children born to diabetic mothers, and control children. CONCLUSIONS: Neonatal hypoglycaemia in diabetic pregnancy was associated with long-term neurological dysfunction related to minimal brain dysfunction/deficits in attention, motor control, and perception. (+info)