Decreased Incidence Of Diabetes Research Articles

Socioeconomic conditions and type 1 diabetes in childhood in North Rhine–Westphalia, Germany

The aim of the study was to investigate the relationships between childhood type 1 diabetes and socioeconomic conditions, which might provide clues to the aetiology of the disease. In an ecological study, we investigated the relationships between socioeconomic conditions and the incidence of type 1 diabetes incidence among children aged 0-14 years in North Rhine-Westphalia (NRW), Germany, between 1996 and 2000 at the level of the 33 districts. Incidence data were obtained from the population-based NRW diabetes register and regional socioeconomic data from official statistics. Associations were assessed by Poisson regression models and Bayesian conditionally autoregressive regression models (CAR). In simple Poisson regression, population density, proportion of non-German nationals in the population, measures of income, education and professional training, and deprivation scores were significantly associated with diabetes risk (p < 0.01). An increase of about one interquartile range (IQR) in population density, proportion of non-German nationals or household income was associated with a 9-12% decrease in diabetes incidence. A rise of about one IQR in income ratio, measures of education and professional training, or in deprivation score (high values correspond to high deprivation) was associated with an 8-12% incidence increase. There was a significantly 'linear' increasing incidence trend across five deprivation classes (relative risk: 1.06; 95% CI: 1.03-1.09). All associations were confirmed when overdispersion and spatial autocorrelation were accounted for in Poisson and CAR models. The results raise the possibility that the risk for type 1 diabetes is higher for children living in socially deprived and less densely populated areas. Subsequent investigations are necessary to verify the observed ecological relations at the individual level and to identify the causal factors behind the socioeconomic indicators.

Long-term non-pharmacological weight loss interventions for adults with prediabetes

Most persons with prediabetes (impaired glucose tolerance or impaired fasting glucose) are overweight, and obesity worsens the metabolic and physiologic abnormalities associated with this condition. Prediabetes is an important risk factor for the development of type 2 diabetes. The objective of this review was to assess the effectiveness of dietary, physical activity, and behavioral weight loss, and weight control interventions for adults with prediabetes. Studies were obtained from computerized searches of multiple electronic bibliographic databases, supplemented by hand searches of selected journals, and consultation with experts in obesity research. The last search was conducted May, 2004. Studies were included if they were published or unpublished randomized controlled trials in any language and examined weight loss or weight control strategies using one or more dietary, physical activity, or behavioral interventions, with a follow-up interval of at least 12 months. Effects were combined using a random-effects model. Nine studies were identified, with a total of 5,168 participants. Follow-up ranged from 1 to 10 years. Quantitative synthesis was limited by the heterogeneity of populations, settings, and interventions and by the small number of studies that examined outcomes other than weight. Overall, in comparisons with usual care, four studies with a follow-up of one year reduced weight by 2.8 kg (95 % confidence interval (CI) 1.0 to 4.7) (3.3% of baseline body weight) and decreased body mass index by 1.3 kg/m(2) (95% CI 0.8 to 1.9). Weight loss at two years was 2.6 kg (95% CI 1.9 to 3.3) (three studies). Modest improvements were noted in the few studies that examined glycemic control, blood pressure, or lipid concentrations (P > 0.05). No data on quality of life or mortality were found. The incidence of diabetes was significantly lower in the intervention groups versus the controls in three of five studies examining this outcome at 3 to 6 years follow-up. Overall, weight loss strategies using dietary, physical activity, or behavioral interventions produced significant improvements in weight among persons with prediabetes and a significant decrease in diabetes incidence. Further work is needed on the long-term effects of these interventions on morbidity and mortality and on how to implement these interventions in diverse community settings.

A Systematic Review of Drug Therapy to Delay or Prevent Type 2 Diabetes

To systematically review the evidence for the prevention of type 2 diabetes by pharmacological therapies. Randomized controlled trials and cohort studies examining the effect of oral hypoglycemic agents, antiobesity agents, antihypertensive agents, statins, fibrates, and estrogen on the incidence of type 2 diabetes were identified from MEDLINE, EMBASE, the Cochrane Controlled Trials Registry, and searches of reference lists. Two reviewers independently assessed studies for inclusion and performed data extraction. Ten studies of oral hypoglycemic agents and 15 studies of nonoral hypoglycemic agents were found. Oral hypoglycemic agents and orlistat are the only drugs that have been studied in randomized controlled trials with diabetes incidence as the primary end point. In the largest studies of 2.5-4.0 years' duration, metformin (relative risk [RR] 0.69, 95% CI 0.57-0.83), acarbose (0.75, 0.63-0.90), troglitazone (0.45, 0.25-0.83), and orlistat (hazard ratio [HR] 0.63, 95% CI 0.46-0.86) have all been shown to decrease diabetes incidence compared with placebo; however, follow-up rates varied from 43 to 96%. Current evidence for statins, fibrates, antihypertensive agents, and estrogen is inconclusive. In addition, the critical question of whether drugs are preventing, or simply delaying, onset of diabetes remains unresolved. Currently, no single agent can be definitively recommended for diabetes prevention. Future studies should be designed with diabetes incidence as the primary outcome and should be of sufficient duration to differentiate between genuine diabetes prevention as opposed to simple delay or masking of this condition.

1,25-Dihydroxyvitamin D3 Modulates Expression of Chemokines and Cytokines in Pancreatic Islets: Implications for Prevention of Diabetes in Nonobese Diabetic Mice

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is an immune modulator that prevents experimental autoimmune diseases. Receptors for 1,25-(OH)(2)D(3) are present in pancreatic beta-cells, the target of an autoimmune assault in nonobese diabetic (NOD) mice. The aim of this study was to investigate the in vivo and in vitro effects of 1,25-(OH)(2)D(3) on beta-cell gene expression and death and correlate these findings to in vivo diabetes development in NOD mice. When female NOD mice were treated with 1,25-(OH)(2)D(3) (5 microg/kg per 2 d), there was a decrease in islet cytokine and chemokine expression, which was accompanied by less insulitis. Complementing these findings, we observed that exposure to 1,25-(OH)(2)D(3) in three cell systems INS-1(E) cell line, fluorescence-activated cell sorting purified rat beta-cells, and NOD-severe combined immunodeficient islets) suppressed IP-10 and IL-15 expression in the beta-cell itself but did not prevent cytokine-induced beta-cell death. This 1,25-(OH)(2)D(3)-induced inhibition of chemokine expression in beta-cells was associated with a decreased diabetes incidence in some treatment windows targeting early insulitis. Thus, although a short and early intervention with 1,25-(OH)(2)D(3) (3-14 wk of age) reduced diabetes incidence (35 vs. 58%, P < or = 0.05), a late intervention (from 14 wk of age, when insulitis is present) failed to prevent disease. Of note, only early and long-term treatment (3-28 wk of age) prevented disease to a major extent (more than 30% decrease in diabetes incidence). We conclude that 1,25-(OH)(2)D(3) monotherapy is most effective in preventing diabetes in NOD mice when applied early. This beneficial effect of 1,25-(OH)(2)D(3) is associated with decreased chemokine and cytokine expression by the pancreatic islets.

Screening and interventions for obesity in adults: summary of the evidence for the U.S. Preventive Services Task Force.

Obesity poses a considerable and growing health burden. This review examines evidence for screening and treating obesity in adults. MEDLINE and Cochrane Library (January 1994 through February 2003). Systematic reviews; randomized, controlled trials; and observational studies of obesity's health outcomes or efficacy of obesity treatment. Two reviewers independently abstracted data on study design, sample, sample size, treatment, outcomes, and quality. No trials evaluated mass screening for obesity, so the authors evaluated indirect evidence for efficacy. Pharmacotherapy or counseling interventions produced modest (generally 3 to 5 kg) weight loss over at least 6 or 12 months, respectively. Counseling was most effective when intensive and combined with behavioral therapy. Maintenance strategies helped retain weight loss. Selected surgical patients lost substantial weight (10 to 159 kg over 1 to 5 years). Weight reduction improved blood pressure, lipid levels, and glucose metabolism and decreased diabetes incidence. The internal validity of the treatment trials was fair to good, and external validity was limited by the minimal ethnic or gender diversity of volunteer participants. No data evaluated counseling harms. Primary adverse drug effects included hypertension with sibutramine (mean increase, 0 mm Hg to 3.5 mm Hg) and gastrointestinal distress with orlistat (1% to 37% of patients). Fewer than 1% (pooled samples) of surgical patients died; up to 25% needed surgery again over 5 years. Counseling and pharmacotherapy can promote modest sustained weight loss, improving clinical outcomes. Pharmacotherapy appears safe in the short term; long-term safety has not been as strongly established. In selected patients, surgery promotes large amounts of weight loss with rare but sometimes severe complications.

Three Loci on Mouse Chromosome 6 Influence Onset and Final Incidence of Type I Diabetes in NOD.C3H Congenic Strains

The development of insulin-dependent diabetes mellitus in both human and mouse is dependent on the interaction between genetic and environmental factors. The analysis of newly created NOD.C3H congenic strains for spontaneous and cyclophosphamide-induced diabetes has allowed the definition of three controlling genetic loci on mouse chromosome 6. A NOD-derived susceptibility allele at the Idd6 locus strongly influences the onset of diabetes in spontaneous diabetes. A NOD-derived resistance allele at the Idd19 locus affects the final diabetes incidence observed in both models, while a novel locus, provisionally termed Idd20, appears to control Idd19 in an epistatic manner. Decreased diabetes incidence is observed in CY-induced diabetes when Idd20 is homozygous for the C3H allele, while heterozygosity is associated with an increase in diabetes incidence. The Idd20, Idd19, and Idd6 candidate regions fall respectively within genetically defined intervals of 4, 7, and 4.5 cM on mouse chromosome 6. From our YAC contig, Idd6 would appear to localize within a ca. 1.5-Mb region on distal chromosome 6.

An Inhibitor of Inducible Nitric Oxide Synthase and Scavenger of Peroxynitrite Prevents Diabetes Development in NOD Mice

Peroxynitrite (ONOO−) is a highly reactive oxidant produced by the interaction of the free radicals superoxide (O•−2) and nitric oxide (NO•). In a previous study, we found that peroxynitrite is formed in islet β-cells of nonobese diabetic (NOD) mice. Here, we report that guanidinoethyldisulphide (GED), a selective inhibitor of inducible nitric oxide synthase (iNOS) and scavenger of peroxynitrite prevents diabetes in NOD mice. GED treatment of female NOD mice, starting at age 5 weeks, delayed diabetes onset (from age 12 to 22 weeks) and significantly decreased diabetes incidence at 30 weeks (from 80% to 17%). GED did not prevent pancreatic islet infiltration by leukocytes; however, β-cells that stained positive for nitrotyrosine (a marker of peroxynitrite) were significantly decreased in islets of GED-treated mice (1±1%) compared with vehicle-treated mice (30±9%). In addition, GED significantly inhibited nitric oxide and nitrotyrosine formation and decreased destruction of β-cells in NOD mouse islets incubated in vitro with the combination of proinflammatory cytokines interleukin 1-beta (IL-1β), tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). These findings indicate that both superoxide and nitric oxide radicals contribute to islet β-cell destruction in autoimmune diabetes via peroxynitrite formation in the β-cells.

Both CD4+and CD8+T cells are Required for IFN-γ Gene Expression in Pancreatic Islets and Autoimmune Diabetes Development in Biobreeding Rats

To study the relative roles of CD4+and CD8+T cells and their cytokine products in autoimmune diabetes development, we selectively depleted CD4+and CD8+T cells in autoimmune diabetes-prone (DP) biobreeding (BB) rats, by administrations of anti-CD2 and anti-CD8 monoclonal antibody (mAb) respectively. We then analysed cytokine mRNA expression, by PCR assay, in mononuclear leukocytes isolated from islets and spleens of control and mAb-treated DP-BB rats. Depletion of CD4+T cells (by anti-CD2mAb) in blood, spleen and islets prevented diabetes development in DP-BB rats, and depletion of CD8+T cells (by anti-CD8mAb) delayed and significantly decreased diabetes incidence. Depletion of either CD4+or CD8+T cells completely prevented IFN-γ mRNA upregulation in islets of DP-BB rats above the low level expressed in islets of diabetes-resistant (DR) BB rats. Also, IL-10mRNA levels in islets of DP-BB rats were significantly decreased by depletion of either CD4+or CD8+T cells, whereas the effects of the anti-T cell mAb on mRNA levels of other cytokines in islets (IL-2, IL-4, IL-12p40, and TNF-α) were discordant. In contrast, both mAb treatments significantly upregulated IL-4 and TNF-α mRNA levels in spleens of DP-BB rats. These results demonstrate that islet infiltration by both CD4+and CD8+T cells is required for IFN-γ and IL-10 production in islets and β-cell destruction. Depletion of either CD4+or CD8+T cells may prevent β-cell destruction by decreasing IFN-γ and IL-10 production in islets and increasing IL-4 and TNF-α production systemically.

Prevention of a Th1 disease by a Th1 cytokine: IL-12 and diabetes in NOD mice.

The effects of interleukin-12 on autoimmune diabetes in nonobese diabetic mice was examined. IL-12 was given, intraperitoneally, to NOD females in two different treatment protocols: three times a week, for 2 weeks beginning at 9 weeks of age and a single weekly injection, for 15 weeks, beginning at 9 weeks of age. A significant decrease in diabetes incidence was observed with multidose/short-term IL-12 treatment. Age of disease onset, however, was unchanged. Weekly administration of IL-12 was more effective in preventing onset of diabetes. Only 20% of female NOD mice become diabetic by 30 weeks of age, with a later age of onset. In spite of the decrease in diabetes incidence, no differences were seen in islet histology with treated mice compared to controls. Furthermore, IL-12 treatment of recipient mice did not prevent induction of diabetes using spleen cells from diabetic mice in adoptive transfer experiments. These observations are in contrast to reported data in which treatment of NOD mice with daily doses of IL-12 exacerbated disease incidence and hastened diabetes onset.

Tumor Necrosis Factor Mediates the Protective Effect of Freund's Adjuvant against Autoimmune Diabetes in BB Rats

In previous studies we reported that a single injection of complete Freund's adjuvant (CFA) in early life inhibits the development of autoimmune diabetes in BB diabetes-prone (DP) rats, and that CFA upregulates tumor necrosis factor-alpha (TNFα) production by macrophages of DP rats. In this study, we asked if CFA-induced prevention of diabetes in DP rats might be mediated by TNFα. Chronic intraperitoneal injection of TNFα, 20μg daily from age 50 to 110 days, significantly decreased diabetes incidence in DP rats from 83% (15 of 18) to 37% (seven of 19) at age 110 days. Similarly, a single intraperitoneal injection of CFA, 100μl at age 26 days, significantly decreased diabetes incidence from 80% (16 of 20) to 50% (10 of 20) at age 110 days. Prevention by either TNFα or CFA was associated with decreased insulitis and preservation of islet β-cells. By contrast, treatment of DP rats with CFA, plus antiserum to TNFα three times a week from age 26 to 110 days, obviated CFA-induced protection against β-cell destructive insulitis and diabetes. Thus, diabetes incidence was 75% (18 of 24) in DP rats treated with CFA plus anti-TNFα antiserum, similar to that in untreated DP rats (80%), but only 44% (eight of 18) in DP rats treated with CFA plus control serum, similar to that in DP rats with CFA alone (50%). These results suggest that TNFα may be a mediator of the protective effects of CFA against autoimmune diabetes development in BB rats.

Prevention of diabetes and induction of non-specific suppressor cell activity in the BB rat by an immunomodulatory azaspirane, SK&F 106610.

Immunomodulatory azaspirane compounds have immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis. The mechanism of action of azaspiranes appears to be the induction of antigen non-specific (natural) suppressor cell activity. In this study, we tested the azaspirane, SK&F 106610 in an animal model of autoimmune (type 1) diabetes, the BB rat. Oral administration of SK&F 106610 (15 mg/kg/day) to diabetes-prone BB rats, from age 30 days, significantly decreased diabetes incidence at 100 days from 80% (24 of 30 control rats) to 32% (10 of 31 drug-treated rats, P < 0.001). Protection from diabetes by SK&F 106610 was accompanied by decreased lymphocytic infiltration of the pancreatic islets (insulitis). No changes occurred in splenic T cell, B cell or macrophage subsets, or in proliferative responses to the mitogens lipopolysaccharide and concanavalin A (Con-A). Cell mixing experiments in vitro, however, revealed increased antigen non-specific suppressor activity (suppression of splenic lymphoproliferative response to Con-A) in spleens of SK&F 106610-treated rats. The suppressor cell activity was enriched in a low density fraction of splenic cells relatively depleted of T cells, B cells, macrophages and natural killer cells. These results indicate that the azaspirane compound, SK&F 106610 can prevent insulitis and autoimmune diabetes in BB rats and that these actions may be related to the activation of non-specific (natural) suppressor cells.

Combination therapy with an antioxidant and a corticosteroid prevents autoimmune diabetes in NOD mice

Oxygen free radicals have been implicated as mediators of pancreatic islet β cell damage in autoimmune, insulin-dependent diabetes mellitus (IDDM). In this study, we show that the antioxidant, probucol, produced only a small decrease in diabetes incidence in nonobese diabetic (NOD) mice, an animal model for human IDDM. However, combination of probucol with the anti- inflammatory corticosteroid, deflazacort, produced an early synergistic effect, delaying diabetes onset by 3 weeks, and a later additive effect, decreasing diabetes incidence from 68% (17 of 25 mice) to 23% (6 of 26 mice, p<0.005). Protection against diabetes by the combination of probucol and deflazacort was associated with a significant decrease in pancreatic islet infiltration by macrophages/lymphocytes (insulitis) and prevention of islet β cell loss.

Prevention and suppression of autoimmune pancreatic Beta-cell destruction in BB rats by syngeneic lymphocytes obtained from long-term normoglycaemic donors

To prove whether a cell-mediated mechanism is responsible for maintaining long-term normoglycaemia in BB/OK rats with a proved immune attack (insulitis, reduced Beta-cell volume), we transferred lymphocytes obtained from those rats into normoglycaemic diabetes-prone BB/OK rats or into diabetic BB/OK rats receiving a simultaneous syngeneic islet graft. Our results show the presence of a lymphocyte population in the long-term normoglycaemic BB/OK rats, which is able to arrest pancreatic Beta-cell destruction in diabetes-prone BB/OK rats detected by a decreased diabetes incidence following single lymphocyte transfusion. Syngeneic islets were destroyed by recurrence of the autoimmune process when transplanted into diabetic BB/OK rats. Lymphocytes obtained from long-term normoglycaemic BB/OK rats were able to protect the syngeneic BB/OK islet graft from autoimmune destruction in diabetic BB/OK rats, whereas allogeneic islet destruction was not prevented. The phenotype of the effective lymphocyte population is not yet clear, but it is negative for RT6. We conclude that the mechanism responsible for maintaining normoglycaemia in long-term normoglycaemic BB/OK rats is cell mediated, because this property can be transferred to prevent autoimmune destruction of pancreatic Beta cells.

Prevention of diabetes in BB rats. I. Evidence suggesting a requirement for mature T cells in bone marrow inoculum of neonatally injected rats.

Injection of major histocompatibility complex (MHC)-compatible bone marrow cells from normal animals into neonatal BB rats resulted in a striking decrease in incidence of diabetes and restoration of concanavalin A (ConA) and mixed lymphocyte responses. However, injection of bone marrow cells pretreated with anti-rat thymocyte antiserum plus complement to remove mature T cells had no effect on incidence of disease, suggesting that mature T cells in the bone marrow inoculum were responsible for prevention of diabetes. Because the decreased incidence of diabetes in rats injected with untreated bone marrow appeared to be unrelated to the extent of lymphopenia in these animals, the involvement of T cells in the onset of diabetes must reflect a defect in the normal function of these cells rather than their absolute number. Approximately 50% of the W3/13+ cells in the spleens of BB rats lacked the OX-8 and W3/25 T cell subset markers. The identity of this W3/13+, OX-8-, W3/25- blank subset remains to be established. Our results, interpreted in light of studies from the other laboratories, suggest the existence of multiple abnormalities in the BB rat, including the presence of T cells as effector or helper cells that augment onset of disease and the absence of a regulatory T cell circuit that could prevent the disease.