Prevalence of people at risk of developing type 2 diabetes mellitus and the involvement of community pharmacies in a national screening campaign: a pioneer action in Brazil.

BACKGROUND: Brazil is one of top 10 countries with the highest number of people with diabetes mellitus (DM), affecting 16.8 million peoples. It is estimated that 7.7 million people (20-79 years) in the country have not yet been diagnosed, representing an under-diagnosis rate of 46.0%. Herein we aimed to screen people for high blood glucose or risk for developing type 2 DM (T2DM) through community pharmacies in Brazil. METHODS: A cross-sectional study was carried out in November 2018, involving 977 pharmacists from 345 municipalities in Brazil. The study evaluated people between 20 and 79 years old without a previous diagnosis of DM. Glycemia was considered high when its value was ≥ 100 mg/dL fasting and ≥ 140 mg/dL in a casual feeding state. The FINDRISC (Finnish Diabetes Risk Score) was used to estimate the risk for developing T2DM. The prevalence of high blood glucose was estimated and the associated factors were obtained using Poisson's multivariate analysis with robust variance. RESULTS: During the national screening campaign, 17,580 people were tested with the majority of the consultations (78.2%) being carried out in private pharmacies. The population was composed mainly of women (59.5%) and people aged between 20 and 45 years (47.9%). The frequency of participants with high blood glucose was 18.4% (95% CI 17.9-19.0). Considering the FINDRISC, 22.7% of people had a high or very high risk for T2DM. The risk factors associated with high blood glucose were: Body Mass Index > 25 kg/m2, abdominal circumference > 94 cm for men and > 80 cm for women; education level below 15 years of study, no daily intake of vegetables and fruits; previous diagnosis of arterial hypertension; history of high blood glucose and family history of DM. CONCLUSIONS: This is the largest screening study that evaluated the frequency of high blood glucose and its associated factors in a population without a previous diagnosis ever performed in community pharmacies in Brazil. These results may help to improve public health policies and reinforce the role of pharmacists in screening and education actions aimed at this undiagnosed population in a continent-size country such as Brazil.

Short-acting insulin analogues versus regular human insulin on postprandial glucose and hypoglycemia in type 1 diabetes mellitus: a systematic review and meta-analysis.

INTRODUCTION: Strict glucose control using multiple doses of insulin is the standard treatment for type 1 diabetes mellitus (T1DM), but increased risk of hypoglycemia is a frequent drawback. Regular insulin in multiple doses is important for achieving strict glycemic control for T1DM, but short-acting insulin analogues may be better in reducing hypoglycemia and postprandial glucose levels. OBJECTIVE: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effects of short-acting insulin analogues vs regular human insulin on hypoglycemia and postprandial glucose in patients with T1DM. METHODS: Searches were run on the electronic databases MEDLINE, Cochrane-CENTRAL, EMBASE, ClinicalTrials.gov, LILACS, and DARE for RCTs published until August 2017. To be included in the study, the RCTs had to cover a minimum period of 4 weeks and had to assess the effects of short-acting insulin analogues vs regular human insulin on hypoglycemia and postprandial glucose levels in patients with T1DM. Two independent reviewers extracted the data and assessed the quality of the selected studies. The primary outcomes analyzed were hypoglycemia (total episodes, nocturnal hypoglycemia, and severe hypoglycemia) and postprandial glucose (at all times, after breakfast, after lunch, and after dinner). Glycated hemoglobin (HbA1c) levels and quality of life were considered secondary outcomes. The risk of bias of each RCT was assessed using the Cochrane Collaboration Risk of Bias table, while the quality of evidence for each outcome was assessed using the GRADEpro software. The pooled mean difference in the number of hypoglycemic episodes and postprandial glucose between short-acting insulin analogues vs. regular human insulin was calculated using the random-effects model. RESULTS: Of the 2897 articles retrieved, 22 (6235 patients) were included. Short-acting insulin analogues were associated with a decrease in total hypoglycemic episodes (risk rate 0.93, 95% CI 0.87-0.99; 6235 patients; I2 = 81%), nocturnal hypoglycemia (risk rate 0.55, 95% CI 0.40-0.76, 1995 patients, I2 = 84%), and severe hypoglycemia (risk rate 0.68, 95% CI 0.60-0.77; 5945 patients, I2 = 0%); and with lower postprandial glucose levels (mean difference/MD - 19.44 mg/dL; 95% CI - 21.49 to - 17.39; 5031 patients, I2 = 69%) and lower HbA1c (MD - 0,13%; IC 95% - 0.16 to - 0.10; 5204 patients; I2 = 73%) levels. CONCLUSIONS: Short-acting insulin analogues are superior to regular human insulin in T1DM patients for the following outcomes: total hypoglycemic episodes, nocturnal hypoglycemia, severe hypoglycemia, postprandial glucose, and HbA1c.

Continuous glucose monitoring system: dawn period calibration does not change accuracy of the method.

INTRODUCTION: Continuous glucose monitoring system is a valuable instrument to measure glycemic control, which uses a retrospective calibration based upon 3 to 4 capillary glucose meter values inserted by the patient each day. OBJECTIVE: We evaluated the interference of calibration during the dawn period in the system accuracy. METHODS: The monitoring data were retrospectively divided into two groups: with (Group A) or without (Group B) the dawn period calibration (between 1:00 and 5:00 AM). Accuracy of the method was expressed by relative absolute difference. RESULTS: Thirty-four continuous glucose monitoring data were evaluated comprising a total of 112 nights. A total of 289 paired readings were analyzed - 195 in Group A and 94 in Group B. We did not find a difference in relative absolute difference (RAD%) in any analyzed period of day by adding dawn calibration. CONCLUSIONS: These data suggest that dawn calibration does not alter accuracy of method.

Continuous glucose monitoring system: dawn period calibration does not change accuracy of the method / Sistema de monitorização contínua de glicose: calibração da madrugada não interfere na acurácia do método

INTRODUCTION: Continuous glucose monitoring system is a valuable instrument to measure glycemic control, which uses a retrospective calibration based upon 3 to 4 capillary glucose meter values inserted by the patient each day. OBJECTIVE: We evaluated the interference of calibration during the dawn period in the system accuracy. METHODS: The monitoring data were retrospectively divided into two groups: with (Group A) or without (Group B) the dawn period calibration (between 1:00 and 5:00 AM). Accuracy of the method was expressed by relative absolute difference. RESULTS: Thirty-four continuous glucose monitoring data were evaluated comprising a total of 112 nights. A total of 289 paired readings were analyzed - 195 in Group A and 94 in Group B. We did not find a difference in relative absolute difference (RAD%) in any analyzed period of day by adding dawn calibration. CONCLUSIONS: These data suggest that dawn calibration does not alter accuracy of method.

INTRODUÇÃO: O CGMS (sigla do inglês continuous glucose monitoring system) é um instrumento valioso no controle glicêmico e utiliza uma calibração por meio de 3 ou 4 medidas de glicemia capilar inseridas pelo paciente em cada dia do exame. OBJETIVO: Avaliar a interferência da calibração durante a madrugada na acurácia do sistema. MÉTODOS: Os dados das monitorizações foram divididos retrospectivamente em dois grupos: com (Grupo A) ou sem (Grupo B) a calibração da madrugada (entre 1:00 e 5:00 AM). A acurácia do método foi mostrada pela diferença relativa absoluta (DRA por cento). RESULTADOS: Trinta e quarto dados de monitorização foram avaliados em um total de 112 noites. Um total de 289 leituras pareadas foi analisado - 195 no Grupo A e 94 no Grupo B. Não foi encontrada diferença em DRA% em nenhum período do dia quando adicionada a calibração durante a madrugada. CONCLUSÕES: Esses dados sugerem que a calibração da madrugada não altera a acurácia do método.

The degree of external genitalia virilization in girls with 21-hydroxylase deficiency appears to be influenced by the CAG repeats in the androgen receptor gene.

BACKGROUND: Women with 21-hydroxylase deficiency present much variability in external genitalia virilization, even among those with similar impairments of 21-hydroxylase (21OH) activity. OBJECTIVE: To evaluate if the number of CAG (nCAG) repeats of the androgen receptor gene influences the degree of external genitalia virilization in women with CYP21A2 mutations, grouped according to impairment of 21OH activity. PATIENTS: The nCAG was determined in 106 congenital adrenal hyperplasia (CAH) patients and in 302 controls. The patients were divided, according to their CYP21A2 genotypes, into Groups A and B, which confer total and severe impairment of 21OH activity, respectively. METHODS: The inactivation pattern of the X-chromosome was studied through genomic DNA digestion with Hpa II. The CAG repeat region was amplified by polymerase chain reaction (PCR) and analysed by GeneScan. RESULTS: The nCAG and the frequency of severe skewed X-inactivation did not differ between normal women and patients. The nCAG median in genotype A was 20.7 (IQR 2.3) for Prader I + II, 22.5 (3.6) for Prader III and 21 (2.9) for Prader IV + V (P < 0.05 for Prader III and Prader IV + V). The nCAG median in genotype B was 21.3 (1.1) for Prader I + II, 20.5 (2.9) for Prader III and 22 (2.8) for Prader IV + V (P > 0.05). A significant difference was found regarding the nCAG median in patients presenting Prader III from genotypes A and B. CONCLUSIONS: We observed great variability in the degree of external genitalia virilization in both CYP21A2 genotypes, and we showed that the CAG repeats of the androgen receptor gene influences this phenotypic variability.

Efeitos fisiológicos do treinamento físico em pacientes portadores de diabetes tipo 1 / Physiological effects of exercise training in patients with type 1 diabetes / Physiological effects of exercise training in patients with type 1 diabetes

Insulinoterapia, atividade física regular e planejamento alimentar, em conjunto, consistem na abordagem mais completa no tratamento de portadores de diabetes mellitus tipo 1 (DM1). Estudos clínicos e experimentais têm evidenciado os benefícios do treinamento físico em indivíduos com DM1, tais como melhora na sensibilidade à insulina, redução das doses de insulina e atenuação das disfunções autonômicas e cardiovasculares. Essa revisão aborda as adaptações fisiológicas ao treinamento físico no indivíduo com DM1 e discute as recomendações e prescrição de atividade física para esta população.

Insulin therapy, regular physical activity and an individualized dietary plan are considered to be the ideal approach for the treatment plan of type 1 diabetes mellitus (T1DM) patients. Clinical and experimental studies have shown the benefits of exercise training in T1DM, as demonstrated by insulin sensitivity improvement, reduction in insulin requirement and an attenuation of autonomic and cardiovascular dysfunction. This review explores the physiological adaptations to exercise training in T1DM, and discuss the guidelines for physical activity recommendations and prescription in this setting.

[Physiological effects of exercise training in patients with type 1 diabetes]. / Efeitos fisiológicos do treinamento físico em pacientes portadores de diabetes tipo 1.

Insulin therapy, regular physical activity and an individualized dietary plan are considered to be the ideal approach for the treatment plan of type 1 diabetes mellitus (T1DM) patients. Clinical and experimental studies have shown the benefits of exercise training in T1DM, as demonstrated by insulin sensitivity improvement, reduction in insulin requirement and an attenuation of autonomic and cardiovascular dysfunction. This review explores the physiological adaptations to exercise training in T1DM, and discuss the guidelines for physical activity recommendations and prescription in this setting.

Síndrome de insensibilidade aos andrógenos: análise clínica, hormonal e molecular de 33 casos / Androgen insensitivity syndrome: clinical, hormonal and molecular analysis of 33 cases

A síndrome de insensibilidade aos andrógenos (AIS) é uma doença com herança ligada ao cromossomo X que afeta pacientes com cariótipo 46,XY, nos quais há prejuízo total (forma completa, CAIS) ou parcial (PAIS) do processo de virilização intra-útero devido à alteração funcional do receptor de andrógenos (AR). Apresentamos uma revisão da AIS e do AR com os dados clínicos, hormonais e moleculares de 33 casos. Analisamos a região codificadora do gene do AR em 33 pacientes de 21 famílias, com quadro clínico e hormonal sugestivo de AIS. Onze pacientes (9 famílias) com diagnóstico de CAIS e 22 pacientes (12 famílias) com diagnóstico de PAIS. Identificamos mutações no gene do receptor androgênico e a etiologia da síndrome de insensibilidade aos andrógenos em 86 por cento das 21 famílias estudadas: 100 por cento das famílias com insensibilidade completa aos andrógenos e 75 por cento das famílias com insensibilidade parcial aos andrógenos. Identificamos 9 mutações no AR descritas anteriormente na literatura (N705S, W741C, M742V, R752X, Y763C, R779W, M807V, R855C e R855H) e 7 mutações foram descritas pela primeira vez nesta casuística (S119X, T602P, L768V, R840S, I898F, P904R e IVS3 - 60 G>A).

Insensibilidade completa aos andrógenos em pacientes brasileiras causada pela mutação P766A no gene do receptor androgênico / Complete form of androgen insensitivity syndrome in brazilian patients due to P766A mutation in the androgen receptor

A síndrome de insensibilidade aos andrógenos é uma doença rara ligada ao X, causada por mutações no gene do receptor androgênico (AR), associada a uma variedade de fenótipos em indivíduos 46,XY. Avaliamos duas irmãs gêmeas de 23 anos com sexo social feminino encaminhadas por amenorréia primária, e que apresentavam gônadas palpáveis na região inguinal e cariótipo 46,XY. A ultra-sonografia pélvica não evidenciou útero. As dosagens basais revelaram concentrações elevadas de LH (35 e 42U/L), normais de FSH (7,9 e 7,8U/L) e altas de testosterona (1330 e 1660ng/dl). O estudo molecular identificou uma rara mutação missense no exon 5 do gene do AR com a troca de uma prolina por uma alanina na posição 766 da proteína. O aminoácido prolina 766 do AR é altamente conservado entre as espécies e situa-se em região correspondente ao domínio de ligação ao andrógeno.

[Complete form of androgen insensitivity syndrome in Brazilian patients due to P766A mutation in the androgen receptor]. / Insensibilidade completa aos andrógenos em pacientes brasileiras causada pela mutação P766A no gene do receptor androgênico.

Androgen insensitivity syndrome (AIS) is a rare X-linked disorder, caused by mutations in the androgen receptor gene (AR), associated with a variety of phenotypes in 46,XY individuals. We studied two 23 year-old twin-sisters with female social sex referred due to primary amenorrhea, who exhibited bilateral palpable gonads in the inguinal region and a 46,XY karyotype. The uterus was absent in pelvic sonograms. Basal LH levels were elevated (35 and 42 U/L), with normal FSH (7.9 and 7.8 U/L) and high testosterone levels (1330 and 1660 ng/dl). The molecular analysis identified a missense mutation in exon 5 of AR gene that changed a proline to an alanine at position 766 of the protein. Proline 766 is a highly conserved amino acid in the AR of several species and is located in the androgen binding domain.

[Androgen insensitivity syndrome: clinical, hormonal and molecular analysis of 33 cases]. / Síndrome de insensibilidade aos andrógenos: análise clínica, hormonal e molecular de 33 casos.

Androgen insensitivity syndrome (AIS) is a rare X-linked recessive condition in which patients with 46,XY karyotype have a complete (CAIS) or partial (PAIS) impairment of pre- and postnatal virilization due to mutations in the androgen receptor (AR). We present a concise revision of AIS and the AR and report the clinical, hormonal and molecular study of 33 subjects with AIS. The coding region of the AR was analyzed in 33 subjects with clinical and hormonal characteristics that suggested AIS. Eleven patients (9 families) had CAIS and 22 patients (12 families) had PAIS. Mutations in the AR were identified and the molecular diagnosis of AIS established in 100% of families with CAIS and 75% with PAIS. Nine mutations had been previously described (N705S, W741C, M742V, R752X, Y763C, R779W, M807V, R855C e R855H) and 7 mutations were first described in these cohort of patients (S119X, T602P, L768V, R840S, I898F, P904R e IVS3 - 60 G>A).

Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene.

Androgen insensitivity syndrome (AIS) is caused by mutations in the androgen receptor gene and is associated with a variety of phenotypes in 46,XY individuals, ranging from phenotypic women [complete form (CAIS)] to men with minor degrees of undervirilization or infertility [partial form (PAIS)]. We studied 32 subjects with male pseudohermaphroditism from 20 families (9 CAIS, 11 PAIS) with the following criteria for AIS: 46,XY karyotype, normal male basal and human chorionic gonadotropin-stimulated levels of serum testosterone and steroid precursors, gynecomastia at puberty, and, in prepubertal patients, a family history suggestive of X-linked inheritance. The entire coding region of the androgen receptor gene was analyzed, and mutations were found in all families with CAIS and in eight of 11 families with PAIS. Fifteen different mutations were identified, including five (S119X, T602P, L768V, I898F, and P904V) that have not been described previously. Detailed clinical and hormonal features were compared with genotype in 25 subjects with AIS and confirmed by mutational analysis. LH hormone levels and the LH x testosterone product were high in all postpubertal subjects with AIS. All subjects with PAIS maintained at postpubertal age the gender identity and social sex that was assigned to them in infancy, in contrast to other forms of pseudohermaphroditism.

An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis.

The Wilms' tumor gene (WT1) encodes a zinc-finger transcription factor involved in the development of the kidneys and gonads and their subsequent normal function. Mutations in the WT1 gene were identified in patients with WAGR (Wilms' tumor, aniridria, genitourinary abnormalities, and mental retardation), Denys-Drash syndrome, and Frasier syndrome (FS). Constitutional heterozygous mutations of the WT1 gene, almost all located at intron 9, are found in patients with FS. This syndrome is characterized by female external genitalia in 46,XY patients, late renal failure, streak gonads, and high risk of gonadoblastoma development. We report a male with FS with an unusual phenotype characterized by normal penis size with perineal hypospadias, end-stage renal failure at the age of 19 yr, normal adult male serum T levels, extremely elevated gonadotropin levels, para-testicular leiomyoma, unilateral testicular germ cell tumor, bilateral gonadoblastoma, and absence of gonadal dysgenesis. Automatic sequencing identified the IVS9 +4C>T mutation in the WT1 gene, which predicts a change in splice site utilization. WT1 transcript analysis showed reversal of the normal positive/negative KTS (lysine, threonine, and serine) isoform ratio, confirming the diagnosis of FS. This patient with FS presents an external genitalia of Denys-Drash syndrome, suggesting that these two syndromes are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in WT1 gene. This case expands the spectrum of phenotypes associated with WT1 mutations, by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, extremely high gonadotropin levels, and delayed adrenarche, and presence of a para-testicular leiomyoma, bilateral gonadoblastoma, and germ cell neoplasia.