Enrichment of apolipoprotein A-IV and apolipoprotein D in the HDL proteome is associated with HDL functions in diabetic kidney disease without dialysis.

BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is associated with lipid derangements that worsen kidney function and enhance cardiovascular (CVD) risk. The management of dyslipidemia, hypertension and other traditional risk factors does not completely prevent CVD complications, bringing up the participation of nontraditional risk factors such as advanced glycation end products (AGEs), carbamoylation and changes in the HDL proteome and functionality. The HDL composition, proteome, chemical modification and functionality were analyzed in nondialysis subjects with DKD categorized according to the estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (AER). METHODS: Individuals with DKD were divided into eGFR> 60 mL/min/1.73 m2 plus AER stages A1 and A2 (n = 10) and eGFR< 60 plus A3 (n = 25) and matched by age with control subjects (eGFR> 60; n = 8). RESULTS: Targeted proteomic analyses quantified 28 proteins associated with HDL in all groups, although only 2 were more highly expressed in the eGFR< 60 + A3 group than in the controls: apolipoprotein D (apoD) and apoA-IV. HDL from the eGFR< 60 + A3 group presented higher levels of total AGEs (20%), pentosidine (6.3%) and carbamoylation (4.2 x) and a reduced ability to remove 14C-cholesterol from macrophages (33%) in comparison to HDL from controls. The antioxidant role of HDL (lag time for LDL oxidation) was similar among groups, but HDL from the eGFR< 60 + A3 group presented a greater ability to inhibit the secretion of IL-6 and TNF-alpha (95%) in LPS-elicited macrophages in comparison to the control group. CONCLUSION: The increase in apoD and apoA-IV could contribute to counteracting the HDL chemical modification by AGEs and carbamoylation, which contributes to HDL loss of function in well-established DKD.

Diet consistency modification improves postprandial glycemic and gastroparesis symptoms.

Abstract: Diabetic gastroparesis (DGP) is an autonomic neuropathy resulting from long-standing poorly controlled diabetes, and it is also linked to fluctuations in glycemic control due to variability on nutrient absorption. Objectives: Considering the scarcity of information, the aim of this study was to identify the impact of modifications on diet consistency on post-prandial glucose variability using a continuous glucose monitoring (CGM) and its effect on the perception and severity of gastrointestinal symptoms. Methods: This proof-of-concept study was carried out in a cross-sectional cohort of six individuals with type 1 diabetes mellitus with confirmed diagnosis of DGP. Two types of diet were used to evaluate glycemic control and DGP symptoms, general consistency standard meal (SD) and modified consistency test diet (MD), associated with an application of rapid acting insulin at the time of food intake. Glycemic control was evaluated by CGM, and the Gastroparesis Cardinal Symptom Index (GCSI) was applied after meals. Results: The CGM curve was different for MD + insulin and SD + insulin. There was a smaller increment of interstitial glucose with 2 h after MD + insulin, returning almost to the basal level 4 h later. Patients scored significantly lower GCSI after MD + insulin compared to the same index after they received SD + insulin. Moreover, there was a decrease in important clinical scores present in the index, like: "Not able to finish meal", "Loss of appetite" and "Stomach or belly feels larger". Conclusion: This study showed that a modified diet can improve postprandial glycemic excursion and the perception and severity of gastroparesis symptoms. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01117-w.

Short-term effects of intravitreal bevacizumab in contrast sensitivity of patients with diabetic macular edema and optimizing glycemic control.

AIMS: To analyze contrast sensitivity of intravitreal bevacizumab injections with optimizing glycemic control versus optimizing glycemic control (in combination with sham injections) in eyes with Diabetic Macular Edema (DME). DESIGN: Prospective, interventional, masked, randomized controlled trial. METHODS: Forty-one eyes of 34 patients with type 2 diabetes mellitus and DME with glycated hemoglobin (HbA1c) < 11% received either intravitreal bevacizumab injection (Group 1) or sham injection (Group 2) at 0 and 6 weeks along with optimizing glycemic control. Mean change in best-corrected visual acuity (BCVA), contrast sensitivity (CS), optical coherence tomography (OCT)-measured by central macular thickness (CMT) were compared and correlated at baseline, 2, 6 and 12 weeks. RESULTS: The study showed a mean CS improved in group 1 from 1.14 ±â€¯0.36 logCS to 1.32 ±â€¯0.24 logCS and also in group 2 from 1.11 ±â€¯0.29 logCS to 1.18 ±â€¯0.29 logCS at 12 weeks (P = 0.12). CS and CMT promptly decreased in group 1 compared to group 2 at 2 weeks (ΔCS = 0.15 ±â€¯0.25 vs. 0.03 ±â€¯0.15 logCS; P = 0.04; ΔCMT = 116 ±â€¯115 vs. 17 ±â€¯71 µm; P = 0.01). There was a mean reduction of approximately 0.5% in HbA1c levels in both groups at 12 weeks (P = 0.002). CONCLUSION: The use of bevacizumab in combination with optimizing glycemic control results in earlier improvement of contrast sensitivity in type 2 diabetes patients with DME. However, the optimizing glycemic control itself has shown also to be effective at 12 weeks. ClinicalTrials.gov Identifier: NCT02308644.

Micro-RNAs 518d-3p and 618 Are Upregulated in Individuals With Type 1 Diabetes With Multiple Microvascular Complications.

Objective: To compare the serum micro-RNAs (miRNAs) profile of individuals with type 1 diabetes without microvascular complications vs. those with multiple severe microvascular complications, in order to identify epigenetically modulated pathways in these two groups of individuals. Research Design and Methods: A total of 10 subjects were selected among individuals followed in the Diabetes Outpatient Clinic and sorted according to the absence or presence of all microvascular complications. Samples from these participants were used for evaluation of serum miRNA expression profile employing a qRT-PCR assay with hydrolysis probes based on the Taqman Low Density Arrays (TLDA) system. The top six most differentially expressed miRNAs between the aforementioned groups were validated by qRT-PCR in additional 47 type 1 diabetes individuals sorted according to the absence or presence of all microvascular complications and matched for age, sex, degree of metabolic control, diabetes duration, and age at diagnosis. Results: Twenty one out of three hundred and seventy seven miRNAs were upregulated in the group of individuals with all microvascular complications vs. the group without complications. The following miRs were validated: 518-3p, 34a-5p, 126-5p, 425-5p, 618, and 139-5p and logistic regression analyses showed that miRNA-518-3p and miRNA-618 were positively associated with multiple microvascular complications after adjustment for age, sex, diabetes duration, HbA1c and use of statin, angiotensin-converting enzyme inhibitors and amlodipine. Conclusions: In this cohort of type 1 diabetes individuals, serum miR-518d-3p and miR-618 were upregulated in those with diabetes kidney disease, diabetes retinopathy, peripheral neuropathy, and cardiovascular autonomic neuropathy in comparison to individuals with no microvascular complications.

Dietary advanced glycated end-products and medicines influence the expression of SIRT1 and DDOST in peripheral mononuclear cells from long-term type 1 diabetes patients.

Quantitative polymerase chain reaction was employed to quantify expression of two genes coding for advanced glycation end-product receptors [RAGE ( AGER) and AGER1 ( DDOST)] and of the gene coding the deacetylase SIRT1 ( SIRT1) in peripheral blood mononuclear cells from type 1 diabetes patients without [Group A, n = 35; 28.5 (24-39) years old; median (interquartile interval)] or with at least one microvascular complication [Group B, n = 117; 34.5 (30-42) years old]; 31 healthy controls were also included. In a subgroup of 48 patients, daily advanced glycation end-products intake before blood collection was assessed. Lower expression of DDOST was found in patients than in controls after adjustment for sex, age, use of statins, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Higher expressions of AGER, DDOST and SIRT1 were observed in Group A. Stratifying by complications, AGER and DDOST expressions were higher in those without retinopathy and without diabetic kidney disease, respectively, compared to patients with these complications. Patients using statins or angiotensin receptor blockers presented higher expression of DDOST. Expression of SIRT1 was higher in patients consuming ≥12,872 KU daily of advanced glycation end-products. Although AGER, DDOST and SIRT1 are differently expressed in peripheral blood mononuclear cells from type 1 diabetes patients with and without microvascular complications, they are also influenced by dietary advanced glycation end-products and by statins and angiotensin receptor blockers.

Assessment guidance of carbohydrate counting method in patients with type 2 diabetes mellitus.

AIMS: We evaluated the application of the method of carbohydrate counting performed by 21 patients with type 2 diabetes, 1 year later attending a guidance course. METHODS: Participants answered a questionnaire to assess patients' adhesion to carbohydrate counting as well as to identify habit changes and the method's applicability, and values of glycated hemoglobin were also analyzed. RESULTS: Most participants (76%) were females, and 25% of them had obesity degree III. There was a statistically significant decrease in glycated hemoglobin from 8.42±0.02% to 7.66±0.01% comparing values before and after counseling. We observed that although patients stated that the method was difficult they understood that carbohydrate counting could allow them make choices and have more freedom in their meals; we also verified if they understood accurately how to replace some foods used regularly in their diets and most patients correctly chose replacements for the groups of bread (76%), beans (67%) and noodles (67%). CONCLUSIONS: We concluded that participation in the course led to improved blood glucose control with a significant reduction of glycated hemoglobin, better understanding of food groups and the adoption of healthier eating habits.

Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects.

Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative ß-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); ß-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative ß-cell antibodies.

Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment.

Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life.The treatment in this age-group is non pharmacological and aims at promoting changes in lifestyle. However, pharmacological treatments are indicated in special situations.The major goals in dietary treatments are not only limited to weight loss, but also to an improvement in the quality of life. Modification of risk factors associated to comorbidities, personal satisfaction of the child or adolescent and trying to establish healthy life habits from an early age are also important. There is a continuous debate on the best possible exercise to do, for children or adolescents, in order to lose weight. The prescription of physical activity to children and adolescents requires extensive integrated work among multidisciplinary teams, patients and their families, in order to reach therapeutic success.The most important conclusion drawn from this symposium was that if the growing prevalence of overweight and obesity continues at this pace, the result will be a population of children and adolescents with metabolic syndrome. This would lead to high mortality rates in young adults, changing the current increasing trend of worldwide longevity. Government actions and a better understanding of the causes of this problem must be implemented worldwide, by aiming at the prevention of obesity in children and adolescents.

[Diabetes immersion training as teaching method to medical practitioners]. / Curso de imersão em diabetes como técnica educativa para profissionais médicos.

This study evaluated the effectiveness of theoretical and practical teaching method in diabetes and doctors' position about feasibility of intensive blood glucose control. Forty-eight internal medicine or endocrinology residents participated in a two-day diabetes immersion course. The participants received training on self-blood glucose monitoring, techniques of insulin administration and carbohydrate counting. They were also instructed to behave as patients with diabetes and to follow individual medical prescription. They were assessed through questionnaires. In knowledge assessment, a significant increase of 12% was observed between the beginning and the end of the course (61.2% and 73.2%, respectively, with p < 0.0001). Before the course, 70.8% and 89.6% of the participants believed there were complications in performing carbohydrate counting and blood glucose monitoring, respectively. After the experience, 82.9% of them had difficulties in carbohydrate counting and 80.8% in self-monitoring; 40.4% took all medications prescribed and 36.1% monitored blood glucose correctly. These results show that the methodology of this course is an effective way to disseminate knowledge and that it contributes to doctors becoming more sensitive to daily problems faced by patients with diabetes melito concerning the acceptance of medical recommendations.

[Type 1 diabetes and autoimmune polyendocrine syndromes]. / Diabetes melito tipo 1 no contexto das poliendocrinopatias auto-imunes.

Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.

Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects / Hiperglicemia incidental em crianças: duas famílias com MODY 2 identificadas em brasileiros

Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative β-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); β-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative β-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24.

O diabetes do tipo MODY (maturity-onset diabetes of the young) caracteriza-se por herança autossômica dominante, início precoce da hiperglicemia e defeitos na secreção de insulina. Os subtipos de MODY apresentam diferenças genéticas, metabólicas e clínicas. O MODY 2 é caracterizado por hiperglicemia leve assintomática e raramente requer tratamento farmacológico. O diagnóstico preciso de MODY é importante para se determinar o tratamento e o prognóstico. Relatamos duas mutações no gene GCK em heterozigose identificadas durante investigação de baixa estatura. Caso 1: paciente do sexo masculino, com 14 anos, pré-púbere, avaliado por atraso constitucional do crescimento e da puberdade. Durante o acompanhamento, apresentou glicemia de jejum alterada (113 mg/dL), aumento de HbA1c (6,6%) e anticorpos anticélulas β negativos. Seu pai e dois irmãos também apresentavam glicemia levemente elevada. A mãe tinha glicemia normal. Foi identificada no gene GCK uma mutação missense em heterozigose, p.Arg191Trp. Dezoito membros da família foram rastreados e 11 apresentavam essa mutação. Caso 2: paciente do sexo masculino, com 4 anos, em avaliação por baixa estatura. Não apresentou alterações laboratoriais, exceto por glicemia elevada (118 mg/dL). Anticorpos anticélulas β foram negativos. Seu pai, uma tia paterna e a avó paterna também apresentavam glicemia discretamente elevada, e a mãe, glicemia normal. A mutação missense em heterozigose, p.Glu221Lys, foi identificada no paciente-índice e em 4 membros da família. Todos os pacientes afetados apresentavam hiperglicemia leve. Essas mutações não foram identificadas nos indivíduos com glicemia normal. O rastreamento de mutações no gene GCK deve ser considerado em pacientes com hiperglicemia crônica leve e de início precoce, história familiar de glicemia elevada e anticorpos anticélulas β negativos. Arq Bras Endocrinol Metab. 2012;56(8):519-24.

Curso de imersão em diabetes como técnica educativa para profissionais médicos / Diabetes immersion training as teaching method to medical practitioners

Este estudo avaliou a eficácia do método de ensino teórico e prático sobre diabetes e a atitude de profissionais médicos quanto à realização de controle glicêmico intensivo. Participaram de um curso de imersão em diabetes, com dois dias de duração, 48 médicos-residentes de clínica médica ou endocrinologia. Os participantes receberam treinamento de monitorização de glicemia capilar, técnicas de aplicação de insulina e contagem de carboidratos, sendo orientados a se portarem como diabéticos e a seguir prescrição médica individual. Foram avaliados através de questionários. No questionário de conhecimentos, observou-se um aumento significante de 12 por cento no índice de acertos entre o início e o final do curso (61,2 por cento e 73,2 por cento, respectivamente, com p < 0,0001). Antes do curso, 70,8 por cento dos participantes diziam ter dificuldades na contagem de carboidratos e 89,6 por cento, na automonitorização glicêmica. Após a experiência prática, 82,9 por cento dos participantes encontraram dificuldades na realização de contagem de carboidratos e 80,8 por cento, na automonitorização; 40,4 por cento fizeram uso de todas as medicações prescritas e 36,1 por cento monitorizaram todas as glicemias. Os resultados deste estudo mostram que esse tipo de curso é eficaz para a aquisição de conhecimentos e contribui com a sensibilização do profissional médico quanto às dificuldades cotidianas enfrentadas pelo portador de diabetes melito na aderência às recomendações.

This study evaluated the effectiveness of theoretical and practical teaching method in diabetes and doctors' position about feasibility of intensive blood glucose control. Forty-eight internal medicine or endocrinology residents participated in a two-day diabetes immersion course. The participants received training on self-blood glucose monitoring, techniques of insulin administration and carbohydrate counting. They were also instructed to behave as patients with diabetes and to follow individual medical prescription. They were assessed through questionnaires. In knowledge assessment, a significant increase of 12 percent was observed between the beginning and the end of the course (61.2 percent and 73.2 percent, respectively, with p < 0.0001). Before the course, 70.8 percent and 89.6 percent of the participants believed there were complications in performing carbohydrate counting and blood glucose monitoring, respectively. After the experience, 82.9 percent of them had difficulties in carbohydrate counting and 80.8 percent in self-monitoring; 40.4 percent took all medications prescribed and 36.1 percent monitored blood glucose correctly. These results show that the methodology of this course is an effective way to disseminate knowledge and that it contributes to doctors becoming more sensitive to daily problems faced by patients with diabetes melito concerning the acceptance of medical recommendations.

Diabetes melito tipo 1 no contexto das poliendocrinopatias auto-imunes: [revisão] / Type 1 diabetes and autoimmune polyendocrine syndromes: [review]

Três entidades clínicas distintas, causadas por desarranjos genéticos, estão associadas a múltiplas desordens auto-imunes: síndrome linfoproliferativa auto-imune, poliendocrinopatias auto-imunes (APSs) e desregulação imune, poliendocrinopatia, enteropatia ligada ao X (IPEX). O diabetes melito auto-imune ou tipo 1 (DM1) pode estar presente nas APSs e na IPEX. A APS-1 caracteriza-se pela associação de candidíase crônica, hipoparatireoidismo e insuficiência adrenal auto-imune ou idiopática (doença de Addison), no entanto, o diabetes melito tipo 1 pode estar presente em até 12 por cento dos casos. A APS-2 inclui a doença de Addison (sempre presente), a doença tireoidiana auto-imune e o diabetes melito tipo 1, enquanto na APS-3 a doença tireoidiana se associa a outra doença imunológica, excluindo a insuficiência adrenal e o hipoparatireoidismo, e a APS-4 é composta por combinações diferentes das descritas anteriormente. Já a IPEX caracteriza-se por alteração rara da regulação auto-imune que resulta doenças auto-imunes de início precoce, envolvendo pâncreas, tireóide, intestino com diarréia secretora grave, eczema e anemia. O diagnóstico e o tratamento das doenças componentes das poliendocrinopatias e da IPEX são semelhantes ao da patologia na forma isolada.

Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.