Association between different levels of dysglycemia and metabolic syndrome in pregnancy.

BACKGROUND: In this study, we sought to evaluate the prevalence of metabolic syndrome (MS) in a cohort of pregnant women with a wide range of glucose tolerance, prepregnancy risk factors for MS during pregnancy, and the effects of MS in the outcomes in the mother and in the newborn. METHODS: One hundred and thirty six women with positive screening for gestational diabetes mellitus (GDM) were classified by two diagnostic methods: glycemic profile and 100 g OGTT as normoglycemic, mild gestational hyperglycemic, GDM, and overt GDM. Markers of MS were measured between 2428th during the screening. RESULTS: The prevalence of MS was: 0%; 20.0%; 23.5% and 36.4% in normoglycemic, mild hyperglycemic, GDM, and overt GDM groups, respectively. Previous history of GDM with or without insulin use, BMI >/= 25, hypertension, family history of diabetes in first degree relatives, non-Caucasian ethnicity, history of prematurity and polihydramnios were statistically significant prepregnancy predictors for MS in the index pregnancy, that by its turn increased the adverse outcomes in the mother and in the newborn. CONCLUSION: The prevalence of MS increases with the worsening of glucose tolerance; impaired glycemic profile identifies pregnancies with important metabolic abnormalities even in the presence of a normal OGTT, in patients that are not classified as having GDM.

Surgery for nonobese type 2 diabetic patients: an interventional study with duodenal-jejunal exclusion.

BACKGROUND: A 24-week interventional prospective trial was performed to compare the benefits of open duodenal-jejunal exclusion surgery (GJB) with a matched control group on standard medical care. METHODS: One-hundred eighty patients were screened for the surgical approach. Twelve patients accepted to be operated and presented the full eligibility criteria for surgery that includes overweight BMI (25-29.9 kg/m2), T2DM diagnosis for less than 15 years, insulin-treated patients, no history of major complications, preserved beta-cell function, and absence of autoimmunity. A matched control group (CG) of patients whom refused surgical treatment was placed to receive standard care. Patients had age of 50 (5) years, time of diagnosis 9 years (range, 3 to 15 years), time of insulin usage 6 months (range, 3 to 48 months), fasting glucose (FG), 9.8 (2.5) mg/dL, and glycated hemoglobin (A1C) 8.90 (2.12)%. RESULTS: At 24 weeks after surgery, patients experienced greater reductions on FG (14% vs. 7% on CG), A1C (from 8.78 to 7.84 in GJB-p<0.01 and 8.93 to 8.71 in CG; p<0.05 between groups) and reductions on average daily insulin requirement (93% vs. 29%, p<0.01). Ten patients stopped insulin usage in GJB but they remain taking oral medications. No differences were observed in both groups regarding BMI, body distribution and composition, blood pressure, and lipids. CONCLUSIONS: In conclusion, duodenal-jejunal exclusion was an effective treatment for nonobese T2DM subjects. GJB was superior to standard care in achieving better glycemic control along with reduction in insulin requirements.

The effect of Roux-en-Y gastric bypass on zinc nutritional status.

BACKGROUND: Researchers have found that zinc nutritional status in obese and diabetic subjects is altered: low zinc concentrations in plasma and erythrocytes, with high urinary zinc excretion, were observed. This study evaluated the effect of Roux-en-Y gastric bypass (RYGBP) on plasma, erythrocyte and urinary zinc concentration. METHODS: 22 morbidly obese patients were studied before and 6 months after RYGBP. Fasting blood sample and 24-hour urine were collected in the pre- and postoperative phases. A software analyzed the diet information from 3-day food records after RYGBP. Zinc nutritional status was evaluated by determination of the concentration of this mineral in plasma and erythrocytes, and the urinary excretion of zinc / 24 hours by atomic absorption spectrophotometry. RESULTS: The diets consumed by the patients had adequate average concentrations of zinc. Zinc concentration in plasma, erythrocytes and urine were within the values of normality before RYGBP, with mean values of 93.25 +/- 19.34 microg/dL, 43.85 +/- 7.76 microg Zn/gHb and 583.05 +/- 359.30 microg Zn/24 hours, respectively. At 6 months after RYGBP, there was a change in these parameters to 69.82 +/- 10.95 microg/dL, 51.80 +/- 6.92 microg Zn/gHb, 535.29 +/- 216.40 microg Zn/24 hours in the concentration of plasma, erythrocyte and urinary zinc. CONCLUSION: These results suggest that RYGBP promoted, besides change in body composition, an alteration in the zinc plasma and erythrocytes concentrations which in the medium and long term, could cause problems for these patients.

Effect of zinc supplementation on serum leptin levels and insulin resistance of obese women.

Leptin is thought to be a lipostatic signal that contributes to body weight regulation. Zinc might play an important role in appetite regulation and its administration stimulates leptin production. However, there are few reports in the literature on its role on leptin levels in the obese population. The present work assesses the effect of zinc supplementation on serum leptin levels in insulin resistance (IR). A prospective double-blind, randomized, clinical, placebo-controlled study was conducted. Fifty-six normal glucose-tolerant obese women (age: 25-45 yr, body mass index [BMI] = 36.2 +/- 2.3 kg/m2) were randomized for treatment with 30 mg zinc daily for 4 wk. Baseline values of both groups were similar for age, BMI, caloric intake, insulin concentration, insulin resistance, and zinc concentration in diet, plasma, urine, and erythrocytes. Insulin and leptin were measured by radioimmunoassay and IR was estimated by the homeostasis model assessment (HOMA). The determinations of zinc in plasma, erythrocytes, and 24- h urine were performed by using atomic absorption spectrophotometry. After 4 wk, BMI, fasting glucose, and zinc concentration in plasma and erythrocyte did not change in either group, although zinc concentration in the urine increased from 385.9 +/- 259.3 to 470.2 +/- 241.2 +/- microg/24 h in the group with zinc supplementation (p < 0.05). Insulin did not change in the placebo group, whereas there was a significant decrease of this hormone in the supplemented group. HOMA also decreased from 5.8 +/- 2.6 to 4.3 +/- 1.7 (p < 0.05) in the zinc-supplemented group but did not change in the placebo group. Leptin did not change in the placebo group. In the zinc group, leptin was 23.6 +/- 12.3 microg/L and did not change. More human data from a unique population of obese individuals with documented insulin resistance would be useful in guiding future studies on zinc supplementation (with higher doses or longer intervals) or different measures.

Pancytopenia in untreated patients with Graves' disease.

Severe pancytopenia is a rare but severe complication of thyrotoxicosis. In this report, we describe four patients with Graves' disease who presented with pancytopenia at diagnosis. Methimazole (30-40 mg/d) or propylthiouracil (400 mg/d) restored normal hematopoiesis in three of the patients. The remaining patient evolved to aplastic anemia under therapy with methimazole (60 mg/d), but had an increased peripheral blood count that almost reached normal values after radioiodinetherapy and standard immunosuppressive treatment with antithymocyte globulin (700 mg/d, intravenous infusion for 5 days), oral cyclosporin (400 mg/d), prednisone (30-60 mg/d), and granulocyte colony-stimulating factor (150 microg subcutaneous injection, 3 times per week). We conclude that: (1) a hematologic evaluation of all patients with Graves' disease should be performed before administering antithyroid drugs, (2) antithyroid drugs may be administered to patients with pancytopenia and bone marrow hypercellularity but a reevaluation of the bone marrow must be done if there is no recovery of the peripheral blood cell count when euthyroidism state is achieved, (3) standard immunosuppressive treatment of aplastic anemia caused by antithyroid drugs restores normal hematopoiesis, and (4) a thyroid evaluation of patients with pancytopenia should be done, even though no related symptoms are found.

[Nationwide multicenter study on the prevalence of overweight and obesity in type 2 diabetes mellitus in the Brazilian population]. / Prevalência de sobrepeso e obesidade em pacientes com diabetes mellitus do tipo 2 no Brasil: estudo multicêntrico nacional.

AIM: To evaluate the prevalence of overweight and obesity in type 2 diabetic (DM2) outpatients from different regions of Brazil. PATIENTS AND METHODS: We studied 2,519 randomly selected patients, from 11 hospitals, 2 endocrine and one general public care clinics from 10 cities. Overweight was defined as body-mass index (BMI) > 25 and obesity as BMI > 30 kg/m2. Glycemic control (GC) was evaluated by GC index (GCI = patient's HbA1 or HbA1c/upper limit of normal for the method x 100). RESULTS: 39% of the population studied was male, the mean age was 58.8 +/- 11.6 y, the duration from clinical diagnosis of DM2 was 9.0 +/- 7.3y, and BMI was 28.3 +/- 5.2 kg/m2. No measurements of BMI were recorded from 265 patients (10.5%). Patients from the Northeast presented lower BMI as compared with those from the Midwest, Southeast and South areas, respectively (26.4 +/- 4.7 vs. 27.9 +/- 4.8 vs. 29.2 +/- 5.1 vs. 29.4 +/- 5.4 kg/m2; p < 0.001). A greater prevalence of obesity was observed in the Southeast and South areas as compared to the Northeast (p < 0.001), as well as in the female group, respectively (69% vs. 31%; p < 0.001). Normal weight patients presented lower GCI. Patients being treated with two or more oral drugs and an association of insulin plus oral drug presented greater BMI values than those being treated with diet, oral hypoglycemic agents and insulin p < 0.001. The BMI of patients treated by a specialist did not differ from those treated by a generalist. CONCLUSIONS: 75% of our sample was out of adequate BMI and 30% was obese. The percentage of patients with overweight and obesity was comparable to those found in similar European studies but still lower than those found in the USA. The prevalence of obesity in diabetic patients was three times higher than in the overall Brazilian population according to data from the Brazilian Institute of Geography and Statistics (IBGE).

Prevalência de sobrepeso e obesidade em pacientes com diabetes mellitus do tipo 2 no Brasil: estudo multicêntrico nacional / Nationwide multicenter study on the prevalence of overweight and obesity in type 2 diabetes mellitus in the Brazilian population

OBJETIVO: Avaliar a prevalência de sobrepeso e obesidade em pacientes ambulatoriais com diabetes mellitus tipo 2 (DM2) em diferentes regiões do Brasil. PACIENTES E MÉTODOS: Avaliamos aleatoriamente 2.519 pacientes em 11 hospitais, 2 ambulatórios especializados e um posto de saúde em 10 cidades brasileiras. Consideramos sobrepeso um índice de massa corporal (IMC) > 25 e obesidade um IMC > 30 kg/m². O controle glicêmico (CG) foi avaliado pelo índice de CG [ICG= HbA1 e ou HbA1c do paciente/limite superior de normalidade do método x 100]. RESULTADOS: Os pacientes tinham idade de 58,8 ± 11,6 anos, tempo de diagnóstico clínico de DM de 9,0 ± 7,3 anos, IMC de 28,3 ± 5,2 kg/m², e 39 por cento eram do sexo masculino. Do total da amostra, 265 pacientes (10,5 por cento) não apresentavam avaliação do IMC. Os pacientes da região Nordeste apresentaram menor IMC em comparação com os das regiões Centro-Oeste, Sudeste e Sul, respectivamente (26,4 ± 4,7 vs. 27,9 ± 4,8 vs. 29,2 ± 5,1 vs. 29,4 ± 5,4 kg/m²; p< 0,001). Houve maior prevalência de obesidade na região Sudeste e Sul em comparação à região Nordeste (p< 0,001) e nos pacientes do sexo feminino, respectivamente (69 vs. 31 por cento; p< 0,001). Os pacientes com peso normal apresentaram menor ICG. Aqueles em tratamento com associação de duas ou mais drogas orais e associação de insulina + droga oral apresentaram maior IMC do que aqueles em tratamento com dieta, hipoglicemiante oral e insulina; p< 0,001. O IMC não diferiu entre os pacientes assistidos ou não por especialistas. CONCLUSÕES: Da população estudada, 75 por cento não estava na faixa de peso ideal, sendo que um terço tinha obesidade. Nossos dados indicam que o sobrepeso e a obesidade já atingem um percentual de pacientes com DM2 no Brasil semelhante ao relatado em estudos europeus, mas ainda menor do que o observado nos EUA. A prevalência de obesidade nos pacientes diabéticos foi três vezes maior do que a observada na população brasileira em geral de acordo com os dados do IBGE.

High pre-therapy [99mTc]pertechnetate thyroid uptake, thyroid size and thyrostatic drugs: predictive factors of failure in [131I]iodide therapy in Graves' disease.

BACKGROUND AND OBJECTIVE: Several factors may interfere with the success rate of radioiodine therapy (RIT) in Graves' disease. Our aim was to evaluate, retrospectively, some of these factors in the outcome of RIT. METHODS: Patient gender, age at diagnosis, ophthalmopathy, disease duration, thyroid size, drug used as clinical treatment, thionamide withdrawal period during RIT preparation, FT4, TSH and [99mTc]pertechnetate thyroid uptake prior to RIT were studied as potential interference factors for RIT success. Eighty-two Graves' disease patients were submitted to RIT after thionamide treatment failure. Prior to RIT, 67 patients were receiving methimazole and 15 propylthiouracil. Thirty-three patients received thionamides during RIT; in 49 patients the medication was withdrawn for 2-30 days. [99mTc]pertechnetate thyroid uptake was determined before RIT. Fixed doses of 370 MBq of [131I]iodide were administered to all patients. RESULTS: Eleven patients became euthyroid; 40 became hypothyroid and 31 remained hyperthyroid. There was no association between outcome and age at diagnosis, gender, ophthalmopathy, pre-RIT FT4, TSH, antithyroid antibodies or thyrostatic drug. Multiple logistic regression showed higher probability of treatment success in patients with thyroid mass <53 g (odds ratio (OR)=8.9), with pre-RIT thyroid uptake <12.5% (OR=4.1) and in patients who withdrew thionamide before RIT (OR=4.9). CONCLUSIONS: Fixed doses of 370 MBq of radioiodine seem to be practical and effective for treating Graves' disease patients with [99mTc]pertechnetate uptake <12.5% and thyroid mass <53 g. This treatment is clearly not recommended for patients with large goitre. In contrast to what could be expected, patients with a high pre-RIT thyroid uptake presented a higher rate of RIT failure.

Endocrine-metabolic effects of the treatment with pioglitazone in obese patients with polycystic ovary syndrome.

The hyperandrogenism found in polycystic ovary syndrome (PCOS) can be a consequence of hyperinsulinemia as a result of peripheral insulin resistance. Metformin and insulin sensitizers have become a potential therapeutic tool for treating these patients; however, there are few studies with pioglitazone in PCOS. Elevated luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratios and LH hyper-responsivity to stimulation with gonadotropin-releasing hormone (GnRH) are common findings in PCOS. The reason why hyperinsulinemia produces hyperandrogenism and whether insulin action on the pituitary alters gonadotropin liberation remain unknown. In the present study, we evaluated the effect of pioglitazone (30 mg/day for 2 months) on insulin response to an oral glucose tolerance test (OGTT), serum levels of androgens and sex hormone-binding globulin (SHBG), and pituitary gonadotropin response to GnRH stimulation in 15 obese PCOS women. We found a significant decrease in insulin response to the OGTT and also in total and free testosterone levels, an increase in SHBG and a reduction in the LH response to GnRH stimulation after pioglitazone treatment. In conclusion, this short-term treatment with pioglitazone decreased hyperinsulinemia and hyperandrogenemia in obese PCOS patients, and there was a significant reduction in LH response to GnRH stimulation. Further research should be carried out to establish the risks and benefits of pioglitazone, which would assist in the physiopathologic comprehension of PCOS.

[Leptin as a marker of sexual dimorphism in newborn infants]. / Leptina como marcadora do dimorfismo sexual em recém-nascidos.

OBJECTIVE: To determine cord blood leptin levels in newborns appropriate for gestational age, according to gender, birth weight, birth height and ponderal index. METHODS: A cross-sectional study was carried out with 132 term newborns appropriate for gestational age (68 females, 64 males), gestational age between 35-42 weeks. Data were collected through interviews with the mothers at the maternity, anthropometrycal study of the newborns, and cord blood estradiol, testosterone and leptin assays obtained immediately after birth. RESULTS: The levels of leptin were significantly higher in females than in males (8.34+/-0.65 ng/ml versus 6.06+/-0.71 ng/ml; p = 0.000). The concentrations of estradiol and testosterone did not differ between males and females. Leptin levels were positively correlated with gestational age (r = 0.394, p < 0.01), birth weight (r = 0.466, p < 0.01), birth length (r = 0.335, p < 0.01) and ponderal index (r = 0.326, p < 0.01). CONCLUSIONS: Leptin concentration in the umbilical cord is positively correlated with gestational age, birth weight, birth height, and ponderal index, suggesting its participation in the neonatal growth process. In addition, a gender difference with higher levels of leptin in females neonates was observed, suggesting that the sexual dimorphism in relation to body composition already exists in newborns.

Leptina como marcadora do dimorfismo sexual em recém-nascidos / Leptin as a marker of sexual dimorphism in newborn infants

OBJETIVO: Avaliar os níveis de leptina do cordão umbilical em recém-nascidos adequados para a idade gestacional conforme sexo, peso, comprimento e índice ponderal de nascimento. MÉTODO: Estudo tipo transversal, envolvendo 132 recém-nascidos adequados para idade gestacional (68 do sexo feminino, 64 do sexo masculino), com idade gestacional de 35-42 semanas. Os dados foram obtidos mediante entrevista com as mães na maternidade, pelo estudo antropométrico dos recém-nascidos e pela dosagem de leptina, estradiol e testosterona no cordão umbilical por meio da coleta imediata após o parto. RESULTADOS: Os recém-nascidos do sexo feminino apresentaram níveis de leptina significativamente maiores que os do sexo masculino (8,34±0,65 ng/ml versus 6,06±0,71 ng/ml; p = 0,000). Os níveis de estradiol e testosterona não variaram conforme o sexo. A leptina se correlacionou positivamente com idade gestacional (r = 0,394, p < 0,01), peso (r = 0,466, p < 0,01), comprimento (r = 0,335, p < 0,01) e índice ponderal (r = 0,326, p < 0,01) dos recém-nascidos. CONCLUSÕES: A leptina do cordão umbilical se correlaciona positivamente com idade gestacional, peso, comprimento e índice ponderal do recém-nascido, sugerindo sua participação no processo de crescimento neonatal. Além disso, os recém-nascidos do sexo feminino têm níveis séricos de leptina maiores que os do sexo masculino, sugerindo que o dimorfismo sexual relacionado à composição corporal já possa existir em recém-nascidos.

Participação do zinco na resistência à insulina / Participation of zinc in insulin resistance

Essa revisão relata os aspectos etiológicos da resistência à insulina, bem como a participação do zinco nesse processo. O zinco participa de vias metabólicas que envolvem a síntese de proteínas, metabolismo de carboidratos, de lipídeos e de ácidos nucléicos. Esse mineral tem sido relacionado com a interação entre hormônios e seus receptores, e com melhoras no estímulo pós-receptor. Estudos in vitro apontam que a insulina pode se ligar com o zinco, melhorando a solubilidade deste hormônio nas células beta do pâncreas, e, ainda, pode aumentar a capacidade de ligação da insulina ao seu receptor. Na obesidade e resistência à insulina, têm sido detectadas alterações na concentração e na distribuição de zinco nos tecidos, bem como melhora da sensibilidade à insulina após a suplementação com esse mineral. Portanto, o papel metabólico do zinco na síndrome de resistência insulínica deve ser mais pesquisado, tendo em vista que esse mineral pode contribuir no controle das alterações metabólicas comumente presentes em pacientes obesos.

Hyperadiponectinemia in newborns: relationship with leptin levels and birth weight.

OBJECTIVE: Adiponectin is the only adipose-specific hormone that, despite its exclusive production by adipose tissue, is reduced in obesity and is inversely correlated with leptin levels in adults. The aim of this study was to evaluate the adiponectin concentration in umbilical cord blood at different gestational ages and to investigate its possible associations with leptin levels and birth weight. RESEARCH METHODS AND PROCEDURES: Umbilical cord blood was obtained from 132 newborns (male = 65, female = 67, gestational age: 35 to 42 weeks). The anthropometric variables of the newborns studied were birth weight, birth length, body weight/body length, and ponderal index. Adiponectin, insulin, and leptin levels were measured by radioimmunoassay methods. RESULTS: Adiponectin levels in males were not different from those in females (24.10 +/- 0.81 vs. 25.62 +/- 0.84 micro g/mL, p = 0.280). Adiponectin concentrations were positively correlated with birth weight (p < 0.05), birth length (p < 0.05), body weight/body length (p < 0.05), gestational age (p < 0.01), and leptin levels (p < 0.01). DISCUSSION: These findings indicate that adiponectin is present in umbilical cord blood after 35 to 42 weeks of gestation, with higher levels than those usually found in adults, no gender differences, and a positive correlation with birth weight and leptin. These results suggest that not only could neonatal hyperadiponectinemia be associated with the increase of adiponectin production by fetal adipose tissue but also with a possible reduction in an unknown mechanism related to the suppression of adiponectin observed in adults.

[Role of zinc in insulin resistance]. / Participação do zinco na resistência à insulina.

This review reports the etiological aspects of insulin resistance as well as the participation of zinc in this process. Zinc participates in the metabolic pathways involving protein synthesis, and the metabolism of carbohydrate, lipid and nucleic acid. This element has been associated with the interaction between hormones and their receptors and to the improvement in the post-receptor stimulus. In vitro studies show that insulin may form a complex with zinc improving the solubility of this hormone in the pancreatic beta cells and also increasing the binding ability of insulin to its receptor. Regarding obesity and insulin resistance, alterations in zinc concentration and distribution in tissues, as well as improvement in sensitivity to insulin after supplementation with this element, have been detected. Thus, the metabolic role of zinc in the insulin resistance syndrome should be further investigated having in mind that this element may contribute to the control of the usual metabolic alterations present in obese patients.

Ghrelin: a gut-brain hormone: effect of gastric bypass surgery.

BACKGROUND: Ghrelin is a newly recognized gastric hormone with orexigenic and adipogenic properties, produced primarily by the stomach. Ghrelin is reduced in obesity. Weight loss is associated with an increase in fasting plasma ghrelin. We assessed the effect of massive weight loss on plasma ghrelin concentrations and its correlation with serum leptin levels and the presence of type 2 diabetes mellitus (DM) in severely obese patients. METHODS: A prospective study was conducted on 28 morbidly obese women (BMI 56.3 +/- 10.2 kg/m2) who underwent gastric bypass, divided into 2 groups: 14 non-diabetics (NGT) and 14 type 2 diabetics (DM2). Ghrelin and leptin were evaluated before silastic ring transected vertical gastric bypass, and again 12 months postoperatively. RESULTS: Fasting plasma ghrelin concentrations were 56% lower in NGT and 59% lower in DM2 compared with a lean control group (P < 0.001). There was no difference in ghrelin levels between NGT and DM2 groups before and after surgery (P > 0.05). Ghrelin was negatively correlated with leptin before gastric bypass surgery (r = 0.51, P < 0.01). The mean plasma ghrelin concentration decreased significantly after surgery in both groups (P < 0.001). CONCLUSION: Ghrelin was inversely related to leptin concentrations. Presence of diabetes did not affect the ghrelin pattern. Reduced production of ghrelin after gastric bypass could be partly responsible for the lack of hyperphagia and thus for the weight loss.

Alteraçöes cardiovasculares no hipotiroidismo / Cardiovascular alterations in hypothyroidism

O amplo espectro de sintomas de hipotiroidismo clínico sugere que as alteraçöes cardivasculares desempenham papel importante na manifestaçäo dessa doença. As células cardíacas sofrem influência da açäo dos hormônios tiroideanos, particularmente a decorrente da contratilidade muscular. Além do desempenho cardíaco, encontra-se alterada a resistência vascular sistêmica, a hipertensäo, a cardiomegalia e o potencial de aceleraçäo da aterosclerose. Os achados eletrocardiográficos incluem complexos d baixa voltagem e alteraçös de repolarizaçäo ventricular, que podem ser reversíveis ou mesmo fazer parte de um quadro de cardiopatia isquêmica, induzida pelas alteraçöes do hipotiroidismo. O tratamento do hipotiroidismo, que se baseia na reposiçäo hormonal com 1-tiroxina, deve ser feito com cautela, utilizando-se pequenas doses, com aumentos progressivos, com acompanhamento clínico rigoroso e com o auxílio das dosagens das enzimas musculares e do eletrocardiograma. A dose ideal de tiroxina é a dose necessária para a normalizaçäo dos níveis de T4 e TSH.

Diabetes mellitus insulino-dependente: história natural de uma síndrome auto-imune / Diabetes mellitus insulin-dependent: natural history of an autoimmune syndrome

O Diabetes Mellitus Insulino-dependente (DMID) é uma doença predominantemente auto-imune, causada pela perda de tolerância dos linfócitos T a constituintes da célula beta pancreática, insulino-secretora. O auto-antígeno primário, do DMID, ainda nao está definido, tendo sido identificados vários candidatos, como: GAD ("glutamic acid decarboxylase"), insulina e outros componentes granulares. Estudos de dois modelos experimentais espontâneos, o camundongo (NOD) ("non obese diabetic") e o rato BB ("Bio breeding"), demonstraram que, a origem do DMID depende de fatores que promoveriam desequilíbrio entre subpopulaçoes T CD4+, executoras e protetoras da auto-reatividade antiilhota. Estas subpopulaçoes foram envolvidas, diretamente, na induçao e inibiçao da transferência do DMID, através de linfócitos, in vivo. Sao células T CD4+ as primariamente responsáveis pelo início da insulite, emobora a participaçao de células T CD8+ seja necessária para o desenvolvimento do DMID clínico. A patogênese da doença implica o sistema imunológico (distúrbios da manutençao da tolerância fisiológica), e a célula beta (maior suscetibilidade a agressoes). Ambos mecanismos sao modulados por vários genes, sobretudo os que codificam proteínas relacionadas com a apresentaçao antigênica (HLA), e fatores ambientais (dieta, infecçoes virais e bacterianas). A história natural do DMID compreende duas fases: 1) pré-diabetes clínico, longo período de desenvolvimento da insulite, detectado pela presença de marcadores imunológicos, como auto-anticorpos circulantes (ICA, antiGAD, IAA), e metabólicos (diminuiçao da primeira fase de insulino-secreçao), e 2) diabetes clínico, caracterizado por predomínio de insulite invasivo-destrutiva e aparecimento de síndrome hiperglicêmica.

Mecanismos gerais de tolerância imunológica e auto-imunidade / General mechanisms of immunologic tolerance and autoimmunity

A tolerância imunológica a antígenos próprios do organismo é um estado fisiológico, adquirido ao longo do desenvolvimento, envolvendo vários mecanismos, para preservar os tecidos do indivíduo. Ambos repertórios, de linfócitos T e B, sao tolerizados por mecanismos interconectados, que ocorrem em dois níveis: 1) órgaos linfóides primários (tolerância central), e 2) órgaos linfóides periféricos e sangue circulante (tolerância periférica). A deleçao, por apoptose, de clones Te B imaturos, em timo e medula óssea, respectivamente, constitui o principal mecanismo de tolerância, através da seleçao negativa de células com potencial de auto-reatividade. Este processo é influenciado por diversos fatores: grau de afinidade, pelo ligando, do receptor específico para o antígeno, dos linfócitos T e B; concentraçao e natureza do antígeno reconhecido; interaçao de co-receptores e de moléculas de adesao. A detecçao de clones T e B auto-reativos, no repertório periférico normal, confirma a possibilidade de escape à deleçao clonal. Por um lado, linfócitos maduros podem ser potencialmente auto-agressivos, e ainda tolerizados, em periferia, através de mecanismos descritos principalmente para o compartimento T: deleçao clonal, anergia clonal (ocupaçao do receptor, em ausência de co-estimulaçao) e imunossupressao (por células ou citocínas). Por outro lado, o conceito de auto-reatividade fisiológica é introduzido, para se diferenciar de doença auto-imune (auto-reatividade patológica). As doenças auto-imunes se desenvolvem por falhas na manutençao da tolerância, cujas causas sao múltiplas: terreno genético individual, sobretudo genes que regulam a apresentaçao e reconhecimento antigênicos, e fatores ambientais (dieta, infecçoes virais ou bacterianas).