Dietary approach for the treatment of arterial hypertension in patients with diabetes mellitus.

The association of hypertension and diabetes mellitus is extremely common, increasing the mortality risk of patients, mainly by cardiovascular causes. Regarding the blood pressure (BP) targets to be achieved, most guidelines suggest levels of 130 mmHg for SBP and of 80 mmHg for DBP. Dietary modifications are quite effective, and many studies suggest that decreasing sodium intake and increasing potassium ingestion are both valuable practices for reducing BP. This can be achieved by stimulating the ingestion of lacteous products, vegetables, and nuts. As for the ideal pharmacologic treatment for hypertension, either calcium channel blockers, diuretics or angiotensin-system blockers can be the first class of drug to be used. In this review, we summarize the evaluation of patients with diabetes mellitus and hypertension, and discuss the available therapeutic approaches, with emphasis on evidence-based dietary recommendations.

Patient-centered Management of Type 2 Diabetes Mellitus Based on Specific Clinical Scenarios: Systematic Review, Meta-analysis and Trial Sequential Analysis.

INTRODUCTION: New antihyperglycemic medications have been proven to have cardiovascular (CV) and renal benefits in type 2 diabetes mellitus (T2DM); however, an evidence-based decision tree in specific clinical scenarios is lacking. MATERIALS AND METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs), with trial sequential analysis (TSA). Randomized controlled trial inclusion criteria were patients with T2DM from 1 of these subgroups: elderly, obese, previous atherosclerotic CV disease (ASCVD), previous coronary heart disease (CHD), previous heart failure (HF), or previous chronic kidney disease (CKD). Randomized controlled trials describing those subgroups with at least 48 weeks of follow-up were included. Outcomes: 3-point major adverse cardiovascular events (MACE), CV death, hospitalization due to HF, and renal outcomes. We performed direct meta-analysis with the number of events in the intervention and control groups in each subset, and the relative risk of the events was calculated. RESULTS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) were the only antihyperglycemic agents related to a reduction in CV events in different populations. For obese and elderly populations, GLP-1 RA were associated with benefits in 3-point MACE; for patients with ASCVD, both SGLT2i and GLP-1 RA had benefits in 3-point MACE, while for patients with CHD, only SGLT2i were beneficial. CONCLUSIONS: SGLT2i and GLP-1 RA reduced CV events in selected populations: SGLT2i led to a reduction in events in patients with previous CHD, ASCVD, and HF. GLP-1 RA led to a reduction in CV events in patients with ASCVD, elderly patients, and patients with obesity. Trial sequential analysis shows that these findings are conclusive. This review opens a pathway towards evidence-based, personalized treatment of T2DM. REGISTRATION: PROSPERO CRD42019132807.

Targeted sequencing identifies novel variants in common and rare MODY genes.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). METHODS: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. RESULTS: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. CONCLUSION: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes.

Influence of maternal weight gain on birth weight: a gestational diabetes cohort.

Objective Our objective was to evaluate gestational weight gain (GWG) patterns and their relation to birth weight. Subjects and methods We prospectively enrolled 474 women with gestational diabetes mellitus (GDM) at a university hospital (Porto Alegre, Brazil, November 2009-May 2015). GWG was categorized according to the 2009 Institute of Medicine guidelines; birth weight was classified as large (LGA) or small (SGA) for gestational age. Adjusted relative risks (aRRs) and 95% confidence intervals (95% CIs) were determined. Results Adequate GWG occurred in 121 women [25.5%, 95% CI: 22, 30%]; excessive, in 180 [38.0%, 95% CI: 34, 43%]; and insufficient, in 173 [36.5%, 95% CI: 32, 41%]. In women with normal body mass index (BMI), the prevalence of SGA was higher in those with insufficient compared to adequate GWG (30% vs. 0%, p < 0.001). In women with BMI ≥ 25 kg/m2, excessive GWG increased the prevalence of LGA [aRR 2.58, 95% CI: 1.06, 6.29] and protected from SGA [aRR 0.25, 95% CI: 0.10, 0.64]. Insufficient vs. adequate GWG did not influence the prevalence of SGA [aRR 0.61, 95% CI: 0.31, 1.22]; insufficient vs. excessive GWG protected from LGA [aRR 0.46, 95% CI: 0.23, 0.91]. Conclusions One quarter of this cohort achieved adequate GWG, indicating that specific ranges have to be tailored for GDM. To prevent inadequate birth weight, excessive GWG in women with higher BMI and less than recommended GWG in normal BMI women should be avoided; less than recommended GWG may be suitable for overweight and obese women.

Influence of maternal weight gain on birth weight: a gestational diabetes cohort

ABSTRACT Objective Our objective was to evaluate gestational weight gain (GWG) patterns and their relation to birth weight. Subjects and methods We prospectively enrolled 474 women with gestational diabetes mellitus (GDM) at a university hospital (Porto Alegre, Brazil, November 2009-May 2015). GWG was categorized according to the 2009 Institute of Medicine guidelines; birth weight was classified as large (LGA) or small (SGA) for gestational age. Adjusted relative risks (aRRs) and 95% confidence intervals (95% CIs) were determined. Results Adequate GWG occurred in 121 women [25.5%, 95% CI: 22, 30%]; excessive, in 180 [38.0%, 95% CI: 34, 43%]; and insufficient, in 173 [36.5%, 95% CI: 32, 41%]. In women with normal body mass index (BMI), the prevalence of SGA was higher in those with insufficient compared to adequate GWG (30% vs. 0%, p < 0.001). In women with BMI ≥ 25 kg/m2, excessive GWG increased the prevalence of LGA [aRR 2.58, 95% CI: 1.06, 6.29] and protected from SGA [aRR 0.25, 95% CI: 0.10, 0.64]. Insufficient vs. adequate GWG did not influence the prevalence of SGA [aRR 0.61, 95% CI: 0.31, 1.22]; insufficient vs. excessive GWG protected from LGA [aRR 0.46, 95% CI: 0.23, 0.91]. Conclusions One quarter of this cohort achieved adequate GWG, indicating that specific ranges have to be tailored for GDM. To prevent inadequate birth weight, excessive GWG in women with higher BMI and less than recommended GWG in normal BMI women should be avoided; less than recommended GWG may be suitable for overweight and obese women.

Update in diagnosis and management of primary aldosteronism.

Primary aldosteronism (PA) is a group of disorders in which aldosterone is excessively produced. These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis. The prevalence of PA ranges from 5% to 12% around the globe, and the most common causes are adrenal adenoma and adrenal hyperplasia. The importance of PA recognition arises from the fact that it can have a remarkably adverse cardiovascular and renal impact, which can even result in death. The aldosterone-to-renin ratio (ARR) is the election test for screening PA, and one of the confirmatory tests, such as oral sodium loading (OSL) or saline infusion test (SIT), is in general necessary to confirm the diagnosis. The distinction between adrenal hyperplasia (AH) or aldosterone-producing adenoma (APA) is essential to select the appropriate treatment. Therefore, in order to identify the subtype of PA, imaging exams such as computed tomography or magnetic ressonance imaging, and/or invasive investigation such as adrenal catheterization must be performed. According to the subtype of PA, optimal treatment - surgical for APA or pharmacological for AH, with drugs like spironolactone and amiloride - must be offered.

Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data.

AIMS: Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic forms of diabetes caused by mutations in at least 14 genes, but mostly by mutations in Glucokinase (GCK) and hepatocyte nuclear factor-1 homeobox A (HNF1A). This study aims to establish a national registry of MODY cases in Brazilian patients, assessing published and unpublished data. METHODS: 311 patients with clinical characteristics of MODY were analyzed, with unpublished data on 298 individuals described in 12 previous publications and 13 newly described cases in this report. RESULTS: 72 individuals had GCK mutations, 9 described in Brazilian individuals for the first time. One previously unpublished novel GCK mutation, Gly178Ala, was found in one family. 31 individuals had HNF1A mutations, 2 described for the first time in Brazilian individuals. Comparisons of GCK probands vs HNF1A: age 16±11 vs 35±20years; age at diagnosis 11±8 vs 21±7years; BMI 19±6 vs 25±6kg/m2; sulfonylurea users 5 vs 83%; insulin users 5 vs 17%; presence of arterial hypertension 0 vs. 33%, all p<0.05. No differences were observed in lipids and C-peptide. CONCLUSIONS: Most MODY cases in Brazil are due to GCK mutations. In agreement with other studied populations, novel mutations are common. Only 14% of patients with familial diabetes carry a HNF1A mutation. Diagnosis of other rare forms of MODY is still a challenge in Brazilian population, as well as adequate strategies to screen individuals for molecular diagnosis.

Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations.

Thirty-two patients with diabetes negative for point mutations in GCK and HNF1A underwent further molecular screening of GCK, HNF1A, HNF4A, and HNF1B by MLPA analysis. We described the first Brazilian case of MODY5 due to a heterozygous whole-gene deletion in HNF1B, who developed rapidly progressive renal failure and death.

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory.

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM", who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre - Rio Grande do Sul, Brazil.

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with “brittle T1DM”, who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre – Rio Grande do Sul, Brazil.

Three unreported glucokinase (GCK) missense mutations detected in the screening of thirty-two Brazilian kindreds for GCK and HNF1A-MODY.

Thirty-two Brazilian families with MODY phenotype were screened for GCK and HNF1A mutations. GCK mutations were found in 8 families, all patients with mild asymptomatic hyperglycaemia; 3 of them are novel: p.Asp365Asn, p.Gly81Asp and p.Val253Leu. Previously described mutations in HNF1A were found in 2 families.

Performance of CKD-EPI equation to estimate glomerular filtration rate as compared to MDRD equation in South Brazilian individuals in each stage of renal function.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation seems to correct the overdiagnosis of chronic kidney disease (CKD) provided by Modification of Diet in Renal Disease (MDRD) equation. However, this point has not been tested in some ethnic groups. This study investigated the performance of MDRD and CKD-EPI equations in South Brazilian individuals. METHODS: This cross-sectional study included 354 individuals including healthy volunteers, diabetic and non-diabetic individuals with or without CKD. Glomerular filtration rate (GFR) was measured by the 51Cr-EDTA single-injection method (51Cr-GFR). Accuracy (P30), bias, and Bland-Altman agreement plots were evaluated. RESULTS: In the group as a whole, 51Cr-GFR was 87±37 (6-187), CKD-EPI eGFR, 82±30 (6-152), and MDRD eGFR, 77±28 (6-156) mL/min/1.73 m2 (p<0.001 for all comparisons). Analyzing the subset of individuals with 51Cr-GFR <60 mL/min/1.73 m2, P30 values were, respectively, 76% and 84% for MDRD and for CKD-EPI (p<0.001) while for 51Cr-GFR ≥60 mL/min/1.73 m2, P30 values were 57.5% for both equations (p=1.000). For MDRD and CKD-EPI, mean bias were negative for GFRs <60 (-11 vs. -12, p=0.221) and positive for values >60 (16 vs. 9, p<0.001). In multivariate analysis, absolute bias was unfavorably influenced by measured GFR >60 (for MDRD) and being diabetic or younger (for CKD-EPI). CONCLUSIONS: CKD-EPI reduces GFR underestimation in individuals with GFRs >60, but still presents a quite low accuracy at this GFR range. Moreover, it tends to overestimate GFR in subjects with GFRs <60 mL/min/1.73 m2. CKD stages 1 and 2, diabetes and young age had a negative influence on the performance of the equations.

Serum vitamin D insufficiency is related to blood pressure in diabetic pregnancy.

BACKGROUND: Vitamin D deficiency in pregnancy has been associated with an increased risk of preeclampsia. However, the association between serum vitamin D and blood pressure in pregnant women has been scarcely evaluated, particularly in women with a high risk of developing hypertensive disorders of pregnancy. We sought to evaluate the association between serum 25-hydroxyvitamin D and blood pressure in pregnant women with gestational diabetes mellitus (GDM). METHODS: A cohort of 184 pregnant women with GDM was followed during the third trimester of pregnancy and early puerperium. Blood pressure was recorded in all prenatal visits, and serum vitamin D was measured by chemiluminescence immunoassay. Pearson's coefficients and multiple linear regressions were used to study predictors of blood pressure levels. RESULTS: Women with vitamin D insufficiency (<30ng/mL; n = 159) had higher systolic and diastolic blood pressure than the remaining participants. In white women (n = 136), serum vitamin D levels presented a significant negative correlation with systolic blood pressure at the beginning (r = -0.268; P = 0.002) and at the end of the third trimester (r = -0.203; P = 0.02), and vitamin D significantly affected systolic blood pressure after adjusting for confounders. This was not observed in women of other ethnicities. CONCLUSIONS: In this cohort of pregnant women with GDM, vitamin D insufficiency was associated with higher blood pressure, and in white women, serum vitamin D was an independent predictor of systolic blood pressure during pregnancy.

Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation pronouncedly underestimates glomerular filtration rate in type 2 diabetes.

OBJECTIVE To evaluate the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate glomerular filtration rate (GFR) in type 2 diabetic patients with GFR >60 mL/min/1.73 m(2). RESEARCH DESIGN AND METHODS This was a cross-sectional study including 105 type 2 diabetic patients. GFR was measured by (51)Cr-EDTA method and estimated by the MDRD and CKD-EPI equations. Serum creatinine was measured by the traceable Jaffe method. Bland-Altman plots were used. Bias, accuracy (P30), and precision were evaluated. RESULTS The mean age of patients was 57 ± 8 years; 53 (50%) were men and 90 (86%) were white. Forty-six (44%) patients had microalbuminuria, and 14 (13%) had macroalbuminuria. (51)Cr-EDTA GFR was 103 ± 23, CKD-EPI GFR was 83 ± 15, and MDRD-GFR was 78 ± 17 mL/min/1.73 m² (P < 0.001). Accuracy (95% CI) was 67% (58-74) for CKD-EPI and 64% (56-75) for MDRD. Precision was 21 and 22, respectively. CONCLUSIONS The CKD-EPI and MDRD equations pronouncedly underestimated GFR in type 2 diabetic patients.

[Low-dose aspirin in patients with diabete melitus: risks and benefits regarding macro and microvascular complications]. / Aspirina em baixa dosagem em pacientes com diabete melito: riscos e benefícios em relação às complicações macro e microvasculares.

Aspirin is recommended as cardiovascular disease prevention in patients with diabetes mellitus. Due to the increased risk of bleeding and because of the hypothesis that there could be a worsening of microvascular complications related to aspirin, there has been observed an important underutilization of the drug. However, it is now known that aspirin is not associated with a deleterious effect on diabetic retinopathy and there is evidence indicating that it also does not affect renal function with usual doses (150 mg/d). On the other hand, higher doses may prove necessary, since recent data suggest that diabetic patients present the so called "aspirin resistance". The mechanisms of this resistance are not yet fully understood, being probably related to an abnormal intrinsic platelet activity. The employment of alternative antiplatelet strategies or the administration of higher aspirin doses (150-300 mg/d) should be better evaluated regarding effective cardiovascular disease prevention in diabetes as well as the possible effects on microvascular complications.

Aspirina em baixa dosagem em pacientes com diabete melito: riscos e benefícios em relação às complicações macro e microvasculares / Low-dose aspirin in patients with diabete melitus: risks and benefits regarding macro and microvascular complications

O uso de aspirina é recomendado como estratégia de prevenção cardiovascular em pacientes com diabete melito. Em decorrência do risco de eventos hemorrágicos e da hipótese de que poderia haver um agravamento das complicações microvasculares associado ao uso da aspirina, tem havido importante sub-utilização dessa terapia. Entretanto, está definido que o uso de aspirina não piora a retinopatia diabética e existem evidências de que também não afeta a função renal em doses usuais (150 mg/dia). Por outro lado, pacientes com diabete melito parecem necessitar de doses maiores do agente antiplaquetário, o que sugere que esses indivíduos apresentem a chamada "resistência à aspirina". Os mecanismos dessa resistência ainda não estão completamente esclarecidos, estando provavelmente relacionados à atividade plaquetária intrínseca anormal. Portanto, o emprego de terapêuticas antiplaquetárias alternativas ou a administração de doses maiores de aspirina (150-300 mg/dia) devem ser melhor avaliados em relação a um aumento da eficácia na prevenção da doença cardiovascular e também a possíveis efeitos nas complicações microvasculares no diabete melito.

Aspirin is recommended as cardiovascular disease prevention in patients with diabetes mellitus. Due to the increased risk of bleeding and because of the hypothesis that there could be a worsening of microvascular complications related to aspirin, there has been observed an important underutilization of the drug. However, it is now known that aspirin is not associated with a deleterious effect on diabetic retinopathy and there is evidence indicating that it also does not affect renal function with usual doses (150 mg/d). On the other hand, higher doses may prove necessary, since recent data suggest that diabetic patients present the so called "aspirin resistance". The mechanisms of this resistance are not yet fully understood, being probably related to an abnormal intrinsic platelet activity. The employment of alternative antiplatelet strategies or the administration of higher aspirin doses (150-300 mg/d) should be better evaluated regarding effective cardiovascular disease prevention in diabetes as well as the possible effects on microvascular complications.