Genetic and humoral autoimmunity markers of type 1 diabetes: from theory to practice

O diabetes melito tipo 1 auto-imune (DM1A) resulta da destruição auto-imune seletiva das células-beta pancreáticas produtoras de insulina. O principal determinante genético de suscetibilidade para o DM1A está em genes do complexo principal de histocompatibilidade, no cromossomo 6p211.3 (locus IDDM1), responsável por 40% ou mais da agregação familiar dessa doença. O maior risco é conferido pelo genótipo do antígeno leucocitário humano HLA-DR3-DQA1* 0501-DQB1*0201/DR4-DQA1*0301-QB1*0302, e o haplótipo HLA-DR15-DQA1* 0102-DQB1*0602 é associado à proteção. Três outros loci relacionados à predisposição a DM1A são o número variável de freqüências repetidas (VNTR) do gene da insulina (IDDM2), que confere 10% da suscetibilidade genética, o antígeno-4 associado ao linfócito T citotóxico (CTLA-4) e o protein tyrosine phosphatasis nonreceptor-type 22 (PTPN22). Muitos outros genes suspeitos de predispor à auto-imunidade estão sendo investigados. O DM1A é freqüentemente associado com doença auto-imune tiroidiana, doença celíaca, doença de Addison e várias outras doenças auto-imunes, caracterizadas por auto-anticorpos órgãos-específicos, relacionados aos mesmos determinantes genéticos. Esses anticorpos são úteis na detecção de auto-imunidade órgão-específica antes do aparecimento da doença clínica, prevenindo comorbidades.Type 1 A diabetes mellitus (T1AD) results from the autoimmune destruction of the insulin producing pancreatic beta-cells. The largest contribution to genetic susceptibility comes from several genes located in the major histocompatibility complex on chromosome 6p21.3 (IDDM1 locus), accounting for at least 40% of the family aggregation of this disease. The highest-risk human leukocyte antigen HLA genotype for T1AD is DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, whereas -DR15-DQA1*0102-DQB1*0602 haplotype is associated with dominant protection. Three other T1D loci associated with predisposition are the Variable Number for Tandem Repeats (VNTR) near the insulin gene (IDDM2), which accounts to 10% of genetic susceptibility, the Cytotoxic T-Lymphocyte-associated Antigen (CTLA-4)(IDDM 12) and the Protein Tyrosine Phosphatasis Nonreceptor-type 22 (PTPN22). Many other gene suspected to predispose to autoimmunity have been investigated. T1AD is frequently associated with autoimmune thyroid disease, celiac disase, Addison´s disease and many other autoimmune diseases, characterized by organ-specific autoantibodies and related to the same genetic background. Using these autoantibodies, organ specific autoimmunity may be detected before the development of clinical disease preventing significant morbidity

Tecido adiposo na encruzilhada no desenvolvimento da síndrome metabólica, inflamação e aterosclerose

The authors analyze insulin resistance, the metabolic syndrome and endothelial dysfunction as consequence of a common antecedent, a low grade inflammation, indicating that in obesity there is a chronically activated inflammatory state of the adipose tissue. Furthermore, the inflammatory signaling is discussed according to the adipose tissue depot, visceral or subcutaneous.Os autores analisam a resistência à insulina, a síndrome metabólica e a disfunção endotelial como consequência de um antecedente comum, a inflamação de baixo nível, o que mostra que a obesidade é um estado inflamatório cronicamente ativado do tecido adiposo. Discute-se, aqui, a sinalização inflamatória de acordo com a localização do tecido adiposo subcutâneo ou visceral

How much information do medical practitioners and endocrinologists have about diabetic retinopathy?

OBJECTIVE: The objective of this study was to use a questionnaire to evaluate knowledge concerning diabetic retinopathy among the physicians present at the 12th Latin American Congress on Diabetes held in São Paulo, Brazil, September 2004. METHODS: A questionnaire about their experience and management of patients with diabetes mellitus and the ophthalmologic examination was administered to 168 endocrinologists attending the meeting. RESULTS: Among the 168 physicians, only 36.9% correctly referred patients with diabetes type 1 to an ophthalmologist, whereas 86.9% referred patients with the type 2 disorder as recommended by the American Academy of Ophthalmology. Regarding the correct indication for screening for diabetic retinopathy, more physicians who had received their degree less than 5 years previously implemented this practice (54.8%), as opposed to those who had received their MD 20 years or more ago (22.6%). Regarding their experience in funduscopy during their specialty training, 52.4% claimed to have experience, but only 21.4% of those interviewed performed this examination on their patients. According to 84.5% of the interviewees, the fundus examination influenced their clinical treatment program. CONCLUSION: Our study demonstrates that medical knowledge among medical practitioners and endocrinologists on preventive measures and periodicity of diabetic retinopathy examinations appears to be far from ideal for diabetes type 1, but satisfactory for diabetes type 2. Therefore, refresher courses emphasizing the correct management of diabetic patients are necessary, because the social and economic impact of retinopathy is significant.OBJETIVO: O objetivo deste estudo foi avaliar através de questionário o conhecimento dos médicos presentes no 12º Congresso Latino Americano de Diabetes Realizado em São Paulo Brasil, Setembro de 2004. MATERIAIS E MÉTODOS: Através de um questionário aplicado a 168 especialistas em endocrinologia presentes no 12º Congresso Latino Americano de Diabetes realizado São Paulo - Brasil em Setembro de 2004, os autores interrogaram sobre a experiência e conduta em relação à Retinopatia Diabética e ao exame oftalmológico. RESULTADOS: Dos 168 médicos, apenas 36,9% encaminhavam corretamente ao oftalmologista os pacientes com diabetes do tipo 1, enquanto 86,9% o faziam de acordo com a Academia Americana de Oftalmologia para os diabéticos do tipo 2. Quanto ao correto encaminhamento dos pacientes para exame de fundo de olho: os médicos com tempo de formação inferior a cinco anos foram os que mais realizam esta prática (54,8%), comparados àqueles com 20 ou mais anos (22,1%). Quanto à experiência em fundoscopia durante a especialização, embora 52,40% afirmassem possuir experiência, apenas 21,4% dos entrevistados realizavam fundo de olho em seus pacientes. Para 84,5% dos entrevistados, o exame de fundo de olho influenciava o tratamento clínico sistemico. CONCLUSÃO: O estudo demonstra que o conhecimento médico das medidas preventivas e de periodicidade do exame da Retinopatia Diabética apresenta-se distante do ideal, para diabéticos tipo 1 e satisfatória para diabéticos tipo 2. Médicos graduados ate 5 anos apresentaram maior porcentagem de correto encaminhamento. A presença de retinopatia diabética no exame de fundo de olho influencia o tratamento clinico sistêmico da maioria dos médicos entrevistados

Quanta informação os médicos gerais e endócrinologistas tem sobre retinopatia diabética?

OBJECTIVE: The objective of this study was to use a questionnaire to evaluate knowledge concerning diabetic retinopathy among the physicians present at the 12th Latin American Congress on Diabetes held in São Paulo, Brazil, September 2004. METHODS: A questionnaire about their experience and management of patients with diabetes mellitus and the ophthalmologic examination was administered to 168 endocrinologists attending the meeting. RESULTS: Among the 168 physicians, only 36.9% correctly referred patients with diabetes type 1 to an ophthalmologist, whereas 86.9% referred patients with the type 2 disorder as recommended by the American Academy of Ophthalmology. Regarding the correct indication for screening for diabetic retinopathy, more physicians who had received their degree less than 5 years previously implemented this practice (54.8%), as opposed to those who had received their MD 20 years or more ago (22.6%). Regarding their experience in funduscopy during their specialty training, 52.4% claimed to have experience, but only 21.4% of those interviewed performed this examination on their patients. According to 84.5% of the interviewees, the fundus examination influenced their clinical treatment program. CONCLUSION: Our study demonstrates that medical knowledge among medical practitioners and endocrinologists on preventive measures and periodicity of diabetic retinopathy examinations appears to be far from ideal for diabetes type 1, but satisfactory for diabetes type 2. Therefore, refresher courses emphasizing the correct management of diabetic patients are necessary, because the social and economic impact of retinopathy is significant.OBJETIVO: O objetivo deste estudo foi avaliar através de questionário o conhecimento dos médicos presentes no 12º Congresso Latino Americano de Diabetes Realizado em São Paulo Brasil, Setembro de 2004. MATERIAIS E MÉTODOS: Através de um questionário aplicado a 168 especialistas em endocrinologia presentes no 12º Congresso Latino Americano de Diabetes realizado São Paulo - Brasil em Setembro de 2004, os autores interrogaram sobre a experiência e conduta em relação à Retinopatia Diabética e ao exame oftalmológico. RESULTADOS: Dos 168 médicos, apenas 36,9% encaminhavam corretamente ao oftalmologista os pacientes com diabetes do tipo 1, enquanto 86,9% o faziam de acordo com a Academia Americana de Oftalmologia para os diabéticos do tipo 2. Quanto ao correto encaminhamento dos pacientes para exame de fundo de olho: os médicos com tempo de formação inferior a cinco anos foram os que mais realizam esta prática (54,8%), comparados àqueles com 20 ou mais anos (22,1%). Quanto à experiência em fundoscopia durante a especialização, embora 52,40% afirmassem possuir experiência, apenas 21,4% dos entrevistados realizavam fundo de olho em seus pacientes. Para 84,5% dos entrevistados, o exame de fundo de olho influenciava o tratamento clínico sistemico. CONCLUSÃO: O estudo demonstra que o conhecimento médico das medidas preventivas e de periodicidade do exame da Retinopatia Diabética apresenta-se distante do ideal, para diabéticos tipo 1 e satisfatória para diabéticos tipo 2. Médicos graduados ate 5 anos apresentaram maior porcentagem de correto encaminhamento. A presença de retinopatia diabética no exame de fundo de olho influencia o tratamento clinico sistêmico da maioria dos médicos entrevistados

Effects of nateglinide and rosiglitazone on pancreatic alpha- and beta-cells, GLP-1 secretion and inflammatory markers in patients with type 2 diabetes: randomized crossover clinical study

Abstract\ud \ud Background\ud To compare the effects of nateglinide and rosiglitazone on inflammatory markers, GLP-1 levels and metabolic profile in patients with type 2 diabetes (DM2).\ud \ud \ud Methods\ud A prospective study was performed in 20 patients with DM2, mean age 51.82 ± 8.05 years, previously treated with dietary intervention. Participants were randomized into rosiglitazone (4–8 mg/day) or nateglinide (120 mg 3 times a day) therapy. After 4 months, the patients were crossed-over with 8 weeks washout period to the alternative treatment for an additional 4-month period on similar dosage schedule. The following variables were assessed before and after 4 months of each treatment period: (1) a test with a standardized 500 calories meal for 5 h including frequent measurements of glucose, insulin, glucagon, proinsulin, GLP-1, free fat acids (FFA), and triglycerides levels was obtained. The lipid profile and HbA1 levels were measured at fasting. (2) Haemostatic and inflammatory markers: platelet aggregation, fibrinogen, PAI-1 activity, C reactive protein (CRP), IL-6, TNF-α, leptin, sICAM and TGFβ levels.\ud \ud \ud Results\ud Both therapy decreased blood glucose levels under the postprandial curve but neither affected glucagon and GLP-1 levels. Nateglinide was associated with higher insulin and pro-insulin secretion, but similar pro-insulin/insulin ratio when compared with rosiglitazone. Only rosiglitazone decreased Homa β, PAI-1 activity, CRP, fibrinogen, TGFβ, FFA and triglyceride levels.\ud \ud \ud Conclusions\ud Nateglinide and rosiglitazone were effective in improving glucose and lipid profile and β cell function, but rosiglitazone afforded a better anti-inflammatory effect. No drug restored alpha cell sensitivity or changed GLP-1 levels. Maintenance of haemostatic factors, inflammatory factors and glucagon levels can be related to the continuously worsening of cardiovascular function and glucose control observed in DM2.To Greci de Paula Souza for procedures assistance. This study was supported\ud by State of São Paulo Research Foundation (Fundação de Amparo à Pesquisa\ud do Estado de São Paulo-FAPESP)

Metformin, but not glimepiride, improves carotid artery diameter and blood flow in patients with type 2 diabetes mellitus

OBJECTIVE: To compare the effects of glimepiride and metformin on vascular reactivity, hemostatic factors and glucose and lipid profiles in patients with type 2 diabetes. METHODS: A prospective study was performed in 16 uncontrolled patients with diabetes previously treated with dietary intervention. The participants were randomized into metformin or glimepiride therapy groups. After four months, the patients were crossed over with no washout period to the alternative treatment for an additional four-month period on similar dosage schedules. The following variables were assessed before and after four months of each treatment: 1) fasting glycemia, insulin, catecholamines, lipid profiles and HbA1 levels; 2) t-PA and PAI-1 (antigen and activity), platelet aggregation and fibrinogen and plasminogen levels; and 3) the flow indices of the carotid and brachial arteries. In addition, at the end of each period, a 12-hour metabolic profile was obtained after fasting and every 2 hours thereafter. RESULTS: Both therapies resulted in similar decreases in fasting glucose, triglyceride and norepinephrine levels, and they increased the fibrinolytic factor plasminogen but decreased t-PA activity. Metformin caused lower insulin and pro-insulin levels and higher glucagon levels and increased systolic carotid diameter and blood flow. Neither metformin nor glimepiride affected endothelial-dependent or endothelial-independent vasodilation of the brachial artery. CONCLUSIONS: Glimepiride and metformin were effective in improving glucose and lipid profiles and norepinephrine levels. Metformin afforded more protection against macrovascular diabetes complications, increased systolic carotid artery diameter and total and systolic blood flow, and decreased insulin levels. As both therapies increased plasminogen levels but reduced t-PA activity, a coagulation process was likely still ongoing

The role of enteric hormone GLP-2 in the response of bone markers to a mixed meal in postmenopausal women with type 2 diabetes mellitus

Abstract\ud \ud Background\ud Type 2 diabetes mellitus (T2D) is a complex disease associated with several chronic complications, including bone fragility and high fracture risk due to mechanisms not yet fully understood. The influence of the gastrointestinal tract and its hormones on bone remodeling has been demonstrated in healthy individuals. Glucagon-like peptide 2 (GLP-2), an enteric hormone secreted in response to nutrient intake, has been implicated as a mediator of nutrient effects on bone remodeling. This study aimed to analyze the dynamics of bone resorption marker C-terminal telopeptide of type I collagen (CTX), bone formation marker osteocalcin, and GLP-2 in response to a mixed meal in diabetic postmenopausal women.\ud \ud \ud Methods\ud Forty-three postmenopausal women with osteopenia or osteoporosis (20 controls – group CO – and 23 diabetic – group T2D) were subjected to a standard mixed meal tolerance test, with determination of serum CTX, plasma osteocalcin and serum GLP-2 concentrations at baseline and 30, 60, 120 and 180 minutes after the meal.\ud \ud \ud Results\ud T2D women had higher body mass index as well as higher femoral neck and total hip bone mineral density. At baseline, luteinizing hormone, follicle-stimulating hormone, osteocalcin and CTX levels were lower in group T2D. In response to the mixed meal, CTX and osteocalcin levels decreased and GLP-2 levels increased in both groups. The expected CTX suppression in response to the mixed meal was lower in group T2D.\ud \ud \ud Conclusions\ud Bone turnover markers were significantly reduced in T2D women at baseline. Confirming the role of nutrient intake as a stimulating factor, GLP-2 increased in response to the mixed meal in both groups. Importantly, CTX variation in response to the mixed meal was reduced in T2D women, suggesting abnormal response of bone remodeling to nutrient intake in T2D.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de nível superior (CAPES

CD226 rs763361 is associated with the susceptibility to type 1 diabetes and greater frequency of GAD65 autoantibody in a brazilian cohort

CD226 rs763361 variant increases susceptibility to type 1 diabetes (T1D) in Caucasians. There is no data about CD226 variants in the very heterogeneous Brazilian population bearing a wide degree of admixture. We investigated its association with T1D susceptibility, clinical phenotypes, and autoimmune manifestations (islet and extrapancreatic autoantibodies). Casuistry. 532 T1D patients and 594 controls in a case-control study. Initially, CD226 coding regions and boundaries were sequenced in a subset of 106 T1D patients and 102 controls. In a second step, two CD226 variants, rs763361 (exon 7) and rs727088 (3′ UTR region), involved with CD226 regulation, were genotyped in the entire cohort. C-peptide and autoantibody levels were determined. No new polymorphic variant was found. The variants rs763361 and rs727088 were in strong linkage disequilibrium. The TT genotype of rs763361 was associated with TID risk (;  95%  –1.991; ), mainly in females , greater frequency of anti-GAD autoantibody (31.9% × 24.5%; ; –2.194; ), and lower C-peptide levels when compared to those with TC + CC genotypes ( ng/dL versus  ng/dL ). Conclusions. The rs763361 variant of CD226 gene (TT genotype) was associated with susceptibility to T1D and with the degree of aggressiveness of the disease in T1D patients from Brazil. Ancestry had no effect.FAPESP 2008-04472-

Prevalence of celiac disease among blood donors in São Paulo: the most populated city in Brazil

OBJECTIVE: Celiac disease is a permanent enteropathy caused by the ingestion of gluten, which leads to an immunemediated inflammation of the small intestine mucosa. The prevalence of celiac disease varies among different nations and ethnic backgrounds, and its diversity is determined by genetic and environmental factors. São Paulo city is one of the largest cities in the world, with a vast population and an important history of internal migratory flow from other Brazilian regions, as well as immigration from other, primarily European, countries, resulting in significant miscegenation. The aim of the present study was to estimate the prevalence of adults with undiagnosed celiac disease among blood donors of São Paulo by collecting information on the ancestry of the population studied. METHODS: The prevalence of celiac disease was assessed by screening for positive IgA transglutaminase and IgA endomysium antibodies in 4,000 donors (volunteers) in the Fundação Pró-Sangue Blood Center of São Paulo, São Paulo, Brazil. The antibody-positive subjects were asked to undergo a small bowel biopsy. RESULTS: Of the 4,000 subjects, twenty-four had positive tests, although both antibody tests were not always concordant. For example, ten subjects were positive for IgA tissue transglutaminase only. In twenty-one positive patients, duodenal biopsies were performed, and the diagnosis of celiac disease was confirmed in fourteen patients (Marsh criteria modified by Oberhuber). In this group, 67% claimed to have European ancestry, mainly from Italy, Portugal and Spain. CONCLUSION: The prevalence of celiac disease is at least 1:286 among supposedly healthy blood bank volunteers in São Paulo, Brazil