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Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

IDDM patients with incipient and overt nephropathy have been found to exhibit an overactivity of RBC sodium-lithium countertransport. To explore the physiological relevance of this finding, we measured the activity of Na+/H+ antiport in serially passaged cultured skin fibroblasts from IDDM patients with and without nephropathy and from normal, nondiabetic control subjects. Na+/H+ antiport activity (measured as the rate of amiloride-sensitive Na+ influx at pH1 = 6.4, extracellular pH = 8.0, and [Na+] = 1 mM) was elevated significantly in IDDM patients with nephropathy compared with IDDM patients without nephropathy and nondiabetic control subjects (13.35 ± 3.8 vs. 8.54 ± 2.0 vs. 7.33 ± 2.3 nmol Na+ · mg protein−1 · min−1; P < 0.006 and P < 0.001, respectively). A kinetic analysis of Na+/H+ antiport activity showed that the raised activity in IDDM patients with nephropathy was caused by an increased Vmax for extracellular Na+. Km values were similar in the three groups. pH-stimulated amiloride-sensitive Na+ influx also was higher under baseline conditions and after serum stimulation in cells from IDDM patients with nephropathy. pHI values were significantly higher, both during active proliferation and after 10-min exposure to serum, in cells from IDDM patients with nephropathy, compared with IDDM patients without nephropathy and nondiabetic control subjects. Serum-stimulated incorporation of [3H]thymidine into DNA was greater in IDDM patients with nephropathy than in the other two groups (35.7 ± 18.9- vs. 17.4 ± 7.5- vs. 11.9 ± 8.7-fold stimulation above baseline; P < 0.01 for both). These data from cultured skin fibroblasts suggest that intrinsic abnormalities in cell function, independent of the metabolic disturbances of diabetes, are characteristic of IDDM patients who develop nephropathy.

O artigo tem como objetivo principal caracterizar os perfis glicêmicos domiciliares de pacientes com diabetes mellitus tipo1, a partir de um esquema de monitorização proposto, e adotá-los como estratégia de ajuste nas doses de insulina. Foram realizados 3259 testes, 781 antes do café, 752 antes do almoço, 765 antes do jantar, 740 antes de deitar e 221 pela madrugada. A média das glicemias nestes períodos ultrapassaram os limites superiores satisfatórios em 6,87%, 3,83%, 11,37%, 30,50% e 19,28% respectivamente. Estes dados forneceram subsídios para ajustes nos esquemas insulinoterápicos. Os níveis HbA1c não mudaram de forma significante com os ajustes realizados porém, foram mantidos em 10%. The goal of this paper is to characterize the glycemic profiles of patients with type 1 diabetes mellitus like a strategy in insulin adjustments. A total of 3259 tests were realized being 781 before breakfast, 752 before lunch, 765 before dinner and 740 before bed and 221 in the dawn. The average of the blood glucose tests in these periods oversteped the superior limits in 6,87%, 3,83%, 11,37%, 30,50% e 19,28% respectively. These data gave the conditons to make the insulin adjustments. The HbA1c levels evidenced that there was no significant statistical difference in the metabolic control, but they remained in 10%. El objetivo principal de este artículo consiste en caracterizar los perfiles glicémicos domiciliares de los pacientes con diabetes mellitus tipo 1, a partir de un esquema propuesto de monitorización, para aplicarlo como estrategia, en los ajustes de las dosis de insulina. Fueron realizados 3.259 tests, de los cuales 781se hicieron antes del desayuno, 752 se realizaron antes del almuerzo, 765 antes de la merienda, 740 se hicieron antes de dormir y los 221 se hicieron en la madarugada. La media de las glicemias en estos períodos ultrapasaron los límites superiores satisfactorios em 6,8%, 3,83%, 11,37%, 30,50% y 19,28% respectivamente. Estos datos ofrecieron subsidios para poder ajustar los esquemas insulinoterápicos. Los niveles de HbA1c no variaron de forma significativa com los ajustes realizados y se mantuvieron em 10%.

OBJECTIVE: To estimate the incidence rate of type 1 diabetes in the urban area of Santiago, Chile, from March 21, 1997 to March 20, 1998, and to assess the spatio-temporal clustering of cases during that period. METHODS: All sixty-one incident cases were located temporally (day of diagnosis) and spatially (place of residence) in the area of study. Knox's method was used to assess spatio-temporal clustering of incident cases. RESULTS: The overall incidence rate of type 1 diabetes was 4.11 cases per 100,000 children aged less than 15 years per year (95% confidence interval: 3.06--5.14). The incidence rate seems to have increased since the last estimate of the incidence calculated for the years 1986--1992 in the metropolitan region of Santiago. Different combinations of space-time intervals have been evaluated to assess spatio-temporal clustering. The smallest p-value was found for the combination of critical distances of 750 meters and 60 days (uncorrected p-value = 0.048). CONCLUSIONS: Although these are preliminary results regarding space-time clustering in Santiago, exploratory analysis of the data method would suggest a possible aggregation of incident cases in space-time coordinates.

Background: Advanced glycation end products are associated with chronic complications of diabetes mellitus. This glycation process renders many proteins immunogenic. Aim: To detect the presence of antibodies against albumin, collagen and low density lipoprotein glycation products in boys and teenagers with diabetes mellitus. Patients and methods: Thirty one patients with diabetes mellitus type I, aged 11±3.8 years and with a mean duration of disease of 3.7±2.7 years and 31 healthy controls aged 12.4±5.3 years were studied. Antibodies against glycation end products were detected by ELISA and results were expressed as a ratio of the optical density of the glycated protein/optical density of the native protein. Results: Diabetic patients and healthy controls did not have antibodies against albumin glycation end products. Diabetics had higher levels of antibodies than controls for collagen glycation end products (2.6±0.4 and 1.8±0.2 respectively, p< 0.01) and low density lipoprotein glycation end products (3.07±0.92 and 2.2±0.72 respectively, p< 0.05). Conclusions: The biological role of these antibodies is not clear. They could be a depuration mechanism for glycation end products or contribute to chronic complications of diabetes mellitus (Rev Méd Chile 2001; 129: 141-48).

It has been suggested that breastfeeding is a protective factor against Type 1 DM due to anti-infection properties or delay in exposure to other agents in the diet. A descriptive study was carried out using data from the Cuban National Registry of Childhood-Onset Diabetes Mellitus (CNRDM). The goal of the study was to determine the frequency and duration of breast-feeding in Cuban children with Type 1 DM. Four hundred and eighty-six children were registered in the CNRDM between January 1, 1988, and December 31, 1993. Breast-feeding data was obtained from two hundred and sixty three (54.1%) of the total registered children. Of these children, two hundred and one (76.4%) were breastfed. The median duration of breast-feeding was three months (Total range 144 months). No statistically significant association was found between the mean age at DM or the clinical profile at diagnosis and the breast-feeding duration groups (p >0.05, respectively). In conclusion, Cuban children with Type 1 DM have relatively low frequency of breast-feeding. When breast-feeding is studied without stratifying for different types of breast-feeding (e.g. exclusive and non-exclusive), there is no association found with the age at DM diagnosis or the clinical profiles at diagnosis. Há evidências de que o aleitamento materno age como um fator protetor contra o DM Tipo 1 devido a propriedades antiinfecciosas ou porque retarda a exposição a outros agentes na dieta. Foi realizado um estudo descritivo com dados do Registro Nacional Cubanas de Diabetes Mellitus na Infância (CNRDM). O objetivo desse estudo era determinar a freqüência e duração do aleitamento materno em crianças cubanas com DM Tipo 1. Quatrocentas e oitenta e seis crianças foram cadastradas no CNRDM entre 1 de janeiro de 1988 e 31 de dezembro de 1993. Os dados sobre aleitamento materno foram obtidos de duzentas e sessenta e três crianças (54.1%) do total registrado. Dessas crianças, duzentas e uma (76.4%) foram amamentadas. A duração média do aleitamento materno foi de (3) meses (Variação total entre 1 e 44 meses). Não foi encontrada nenhuma diferença estatisticamente significante entre a idade média de início e os grupos de duração do aleitamento materno (p >0.05). Concluindo, as crianças cubanas com DM Tipo 1 apresentam uma freqüência relativamente baixa tanto do aleitamento materno exclusivo como não exclusivo. Quando o aleitamento materno é estudado sem estratificação em diferentes tipos (ex. exclusivo e não exclusivo), não encontra-se associação com a idade ou perfil clínico no momento do diagnóstico.

•Background: The study was performed in order to ascertain whether electrophysiological abnormalities in visual function exist in newly diagnosed diabetic patients. •Methods: Visual evoked potentials (VEPs) were assessed under basal conditions and after photostress in normal control subjects and in newly diagnosed diabetic patients free of any fluorescein angiography signs of retinopathy. • Results: In basal conditions VEP P100 latency was significantly increased in the diabetic patients compared to controls (P

Visual evoked potentials (VEPs) were assessed under basal conditions and after photostress in normal control subjects, in insulin-dependent diabetic patients with retinopathy (IDDPWR) and in insulin-dependent diabetic patients without retinopathy (IDDP). The VEPs recorded under basal conditions showed a P100 latency significantly higher in IDDP and IDDPWR eyes than in control eyes and in IDDPWR than in IDDP eyes (P

OBJECTIVE A nationwide retrospective study was conducted to assess the incidence of type I diabetes in The Netherlands among children RESEARCH DESIGN AND METHODS The capture recapture census method was chosen for analysis of the data. A questionnaire was sent to all Dutch pediatricians and internists, and for the ascertainment, a similar questionnaire was sent out separately to members of the Dutch Diabetes Association, which is the national patient association. RESULTS The average achieved ascertainment rate was 81%. The ascertainmentadjusted annual incidence was 13.2/100,000 for 0- to 19-year-old children, indicating an increase of 23% compared with the 1978–1980 survey; for 0- to 14-year-olds, the increase amounted to 17%. CONCLUSIONS This study suggests a sustained increase of type I diabetes in The Netherlands because the cumulative incidence studied previously in the 1960–1970 birth cohorts of male army conscripts 18 years of age was also found to rise. In contrast to Northern European countries, an increase in incidence for the age category 0–4 years could not be found.

The Na+-pumping activity of the erythrocyte plasma membrane in diabetic subjects was studied together with the lipid composition. Insulin-dependent diabetes mellitus (IDDM) patients (n = 25) were divided into young (28.1 ± 7.4 yr old, mean ± SD; n = 16) and old (71.7 ± 9.8 yr old; n = 10) subjects; the age of non-insulin-dependent (NIDDM) patients was 70.7 ± 11.5 yr (n = 10). The Na+-pumping activity, estimated from both Na+-K+-ATPase and ouabain binding, was significantly decreased in IDDM and NIDDM subjects, but its insulin sensitivity was retained only in young IDDM subjects. The total cholesterol and phospholipid content of the erythrocyte plasma membrane was lowered in IDDM subjects, and cholesterol-to-phospholipid molar ratio was significantly decreased. In NIDDM subjects the significant decrease of the two lipid components did not alter their ratio. The analysis of major phospholipid components of erythrocyte membranes revealed that only phosphatidylcholine is significantly increased in young diabetic subjects. The fatty acid composition of major phospholipid classes was significantly altered in all cases: the unsaturation index appeared to be increased in phosphatidylserine and sphingomyelin for both IDDM and NIDDM subjects and was also increased in phosphatidylcholine in the latter group.

The incidence of childhood diabetes (0–19 years of age) in The Netherlands, where there is no nationalized health-care system, was investigated retrospectively in the years 1978 to 1980 inclusive. The method chosen was a questionnaire among all Dutch paediatricians and internal physicians acting as consultants. Ascertainment was by the same questionnaire held separately among the large Dutch membership of the Dutch Diabetes Association, employing the capture-recapture census method for calculation. For paediatricians the ascertainment was 94%, for specialists in internal medicine 75%. Before correction for ascertainment 1271 children were registered in the two surveys. The ascertainment-corrected annual incidence was 10.95/100000 for 0–19-year-old children, lower than in any other ascertained survey in north-western Europe published so far. The male: female ratio was the same as in other studies and no local geographical differences were found. Seasonal variation was absent in children 0–10 years old in the month the first insulin injection was administered. The data support the influence of unknown exogenous factors associated with the clinical onset of childhood diabetes.

Chemicals/CAS: Autoantibodies; islet cell antibody; Mumps Vaccine