RESUMO
Advanced glycation end products (AGEs) prime macrophages for lipopolysaccharide (LPS)-induced inflammation. We investigated the persistence of cellular AGE-sensitization to LPS, considering the nuclear content of p50 and p65 nuclear factor kappa B (NFKB) subunits and the expression of inflammatory genes. Macrophages treated with control (C) or AGE-albumin were rested for varying intervals in medium alone before being incubated with LPS. Comparisons were made using one-way ANOVA or Student t-test (n = 6). AGE-albumin primed macrophages for increased responsiveness to LPS, resulting in elevated levels of TNF, IL-6, and IL-1beta (1.5%, 9.4%, and 5.6%, respectively), compared to C-albumin. TNF, IL-6, and IL-1 beta secretion persisted for up to 24 h even after the removal of AGE-albumin (area under the curve greater by 1.6, 16, and 5.2 times, respectively). The expressions of Il6 and RelA were higher 8 h after albumin removal, and Il6 and Abca1 were higher 24 h after albumin removal. The nuclear content of p50 remained similar, but p65 showed a sustained increase (2.9 times) for up to 24 h in AGE-albumin-treated cells. The prolonged activation of the p65 subunit of NFKB contributes to the persistent effect of AGEs on macrophage inflammatory priming, which could be targeted for therapies to prevent complications based on the AGE-RAGE-NFKB axis.
Assuntos
Interleucina-6 , NF-kappa B , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Albuminas/metabolismoRESUMO
Aim: The pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A (MTNR1A). Methods: Eight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated. Results: The group of individuals with a renal function decline ≥ 5 mL min-1 1.73 m-2 year-1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20-2.82; p = 0.0046). No other significant associations were found. Conclusions: This is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting.
Assuntos
Diabetes Mellitus Tipo 1 , Melatonina , Humanos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Antioxidantes , Receptores de Melatonina , Estudos Transversais , Estudos Longitudinais , RimRESUMO
The best-known etiologies of hyperinsulinemic hypoglycemia are insulinoma, non-insulinoma pancreatogenous hypoglycemic syndrome, autoimmune processes, and factitious hypoglycemia. In 2009, a disease not associated with classic genetic syndromes and characterized by the presence of multiple pancreatic lesions was described and named insulinomatosis. We present the clinical and pathologic features of four patients with the diagnosis of insulinomatosis, aggregated new clinical data, reviewed extensively the literature, and illustrated the nature and evolution of this recently recognized disease. One of our patients had isolated (without fasting hypoglycemia) postprandial hypoglycemia, an occurrence not previously reported in the literature. Furthermore, we reported the second case presenting malignant disease. All of them had persistent/recurrent hypoglycemia after the first surgery even with pathology confirming the presence of a positive insulin neuroendocrine tumor. In the literature review, 27 sporadic insulinomatosis cases were compiled. All of them had episodes of fasting hypoglycemia except one of our patients. Only two patients had malignant disease, and one of them was from our series. The suspicion of insulinomatosis can be raised before surgery in patients without genetic syndromes, with multiple tumors in the topographic investigation and in those who had persistent or recurrent hypoglycemia after surgical removal of one or more tumors. The definitive diagnosis is established by histology and immunohistochemistry and requires examination of the "macroscopically normal pancreas." Our case series reinforces the marked predominance in women, the high frequency of recurrent hypoglycemia, and consequently, a definitive poor response to the usual surgical treatment.
Assuntos
Hiperinsulinismo , Hipoglicemia , Tumores Neuroendócrinos , Humanos , Feminino , Afeto , HipoglicemiantesRESUMO
ABSTRACT Objective: The aim of this study was to investigate the factors associated with hypoglycemia and severe hypoglycemia (SH) in individuals with type 1 diabetes mellitus (T1D) in Brazil. Materials and methods: This multicenter, cross-sectional study was conducted between August 2011 and August 2014 across 10 Brazilian cities. The data were obtained from 1,760 individuals with T1D. Sociodemographic and clinical characteristics related to hypoglycemic events in the previous 4 weeks were evaluated. Results: Of 1,760 individuals evaluated, 1,319 (74.9%) reported at least one episode of hypoglycemia in the previous 4 weeks. The main factors associated with hypoglycemia were lower hemoglobin A1c (HbA1c) level, better adherence to self-monitoring of blood glucose (SMBG), and higher education level. Episodes of SH were reported by 251 (19%) individuals who, compared with subjects with nonsevere hypoglycemia, received lower doses of prandial insulin and higher doses of basal insulin, in addition to reporting less frequent use of long-acting basal insulin analogs. The percentage of SH episodes was evenly distributed across all ranges of HbA1c levels, and there were no correlations between the mean number of nonsevere or severe hypoglycemic events and HbA1c values. Higher alcohol consumption and more frequent hospitalizations were independently associated with SH. Conclusion: Although individuals presenting with hypoglycemia had lower HbA1c values than those not presenting hypoglycemia, there were no correlations between the number of nonsevere hypoglycemia or SH and HbA1c values. Also, the frequency of SH was evenly distributed across all ranges of HbA1c values. Better adherence to SMBG and higher education level were associated with hypoglycemia, while alcohol consumption, higher doses of basal insulin, and more frequent hospitalizations in the previous year were associated with SH.
RESUMO
A doença cardiovascular (DCV) de origem aterosclerótica é a principal causa da morbidade e mortalidade em pacientes com diabetes mellitus (DM). Tanto os fatores de risco cardiovascular associados à resistência à insulina (RI) no contexto da síndrome da adiposidade visceral (SAV) quanto a hiperglicemia crônica contribuem para o risco da DCV na DM. A hiperinsulinemia compensatória que se estabelece na RI estimula os fatores de transcrição SREBP1c e SREBP1 em que se ativam os genes lipogênicos, levando à grande produção hepática de triglicérides. A hipertrigliceridemia é o gatilho para as demais alterações lipídicas que contribuem para o perfil pró-aterogênico na RI, caracterizando-se pelo predomínio de LDL pequenas e densas e redução do colesterol HDL. A hiperinsulinemia, também, está intimamente ligada à hipertensão arterial, pois aumenta o tônus simpático e a reabsorção renal de sódio. A RI é considerada o melhor fator preditivo para a ocorrência de DM tipo 2 (DM2), sendo necessário um defeito concomitante na secreção de insulina para que a hiperglicemia se estabeleça. Os efeitos deletérios da hiperglicemia devem-se à ativação de vias bioquímicas que resultam em inflamação e estresse oxidativo celular. A dislipidemia e a hipertensão arterial secundárias à RI, assim como a hiperglicemia, são importantes moduladores do risco cardiovascular na SAV e na DM2 e devem ser intensiva e conjuntamente abordados no tratamento e prevenção da DCV.
Cardiovascular disease (CVD) of atherosclerotic origin is the main cause of morbidity and mortality in patients with diabetes mellitus (DM). Both the cardiovascular risk factors associated with insulin resistance (IR) in the context of visceral adiposity syndrome (VAS) and chronic hyperglycemia contribute to the risk of CVD in DM. Compensatory hyperinsulinemia established in IR stimulates the transcription factors SREBP1c and SREBP1a, which activate lipogenic genes, leading to high hepatic production of triglycerides. Hypertriglyceridemia triggers other lipid changes that contribute to the pro-atherogenic profile in IR, which is characterized by the predominance of small and dense LDL and reduction of HDL-cholesterol. Hyperinsulinemia is also closely linked to arterial hypertension, as it increases sympathetic tone and renal sodium reabsorption. IR is considered the best predictive factor for the occurrence of type 2 DM (DM2), and a concomitant defect in insulin secretion is required for hyperglycemia to be established. The harmful effects of hyperglycemia are due to activation of biochemical pathways that result in inflammation and cellular oxidative stress. Dyslipidemia and hypertension secondary to IR, as well as hyperglycemia, are important modulators of cardiovascular risk in VAS and DM2 and should be intensively and jointly addressed in the management and prevention of CVD.
Assuntos
Humanos , Doenças Cardiovasculares/patologia , Síndrome Metabólica/complicações , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/patologia , Aterosclerose/complicações , Resistência à Insulina , Fatores de Risco , Inflamação/dietoterapiaRESUMO
The purpose of this study was to evaluate the therapeutic options for diabetes treatment and their potential side effects, in addition to analyzing the risks and benefits of tight glycemic control in patients with diabetic kidney disease. For this review, a search was performed using several pre-defined keyword combinations and their equivalents: “diabetes kidney disease” and “renal failure” in combination with “diabetes treatment” and “oral antidiabetic drugs” or “oral hypoglycemic agents.” The search was performed in PubMed, Endocrine Abstracts and the Cochrane Library from January 1980 up to January 2015. Diabetes treatment in patients with diabetic kidney disease is challenging, in part because of progression of renal failure-related changes in insulin signaling, glucose transport and metabolism, favoring both hyperglycemic peaks and hypoglycemia. Additionally, the decline in renal function impairs the clearance and metabolism of antidiabetic agents and insulin, frequently requiring reassessment of prescriptions. The management of hyperglycemia in patients with diabetic kidney disease is even more difficult, requiring adjustment of antidiabetic agents and insulin doses. The health team responsible for the follow-up of these patients should be vigilant and prepared to make such changes; however, unfortunately, there are few guidelines addressing the nuances of the management of this specific population.
Assuntos
Humanos , Glicemia/efeitos dos fármacos , /tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Glicemia/metabolismo , Creatinina/metabolismo , Progressão da Doença , /complicações , /metabolismo , Nefropatias Diabéticas/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/metabolismo , Cooperação do Paciente , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismoRESUMO
Celiac crisis, an acute severe onset of celiac disease, is a rare and life-threatening manifestation. We report a 30-year-old woman with type 1 diabetes mellitus who arrived at our service with one-month history of severe acute watery diarrhea associated with nausea, vomiting, abdominal pain, and weight loss of 9 kg. The diagnostic hypothesis of celiac crisis was reached based on profuse diarrhea leading to dehydration, severe metabolic and electrolyte abnormalities, and subsequent improvement after introduction of a gluten-free diet.
A crise celíaca é uma manifestação rara e grave da doença celíaca. Relatamos um caso de uma paciente de 30 anos de idade, com antecedente de diabetes melito tipo 1 e história de um mês de diarreia aquosa aguda, associada a náuseas, vômitos, dor abdominal e perda de peso de 9 kg. A hipótese diagnóstica de crise celíaca foi realizada, baseada no quadro de diarreia profusa, desidratação e distúrbios hidroeletrolíticos e ácido-básicos que melhorou após a introdução de dieta enteral sem glúten.
Assuntos
Adulto , Feminino , Humanos , Doença Celíaca/complicações , Diabetes Mellitus Tipo 1/complicações , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Diarreia/etiologiaRESUMO
The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease manifested by hypoglycemic symptoms triggered by fasting or high-protein meals, and by elevated serum ammonia. HI/HA is the second most common cause of hyperinsulinemic hypoglycemia of infancy, and it is caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Biochemical evaluation, as well as direct sequencing of exons and exon-intron boundary regions of the GLUD1 gene, were performed in a 6-year old female patient presenting fasting hypoglycemia and hyperammonemia. The patient was found to be heterozygous for one de novo missense mutation (c.1491A>G; p.Il497Met) previously reported in a Japanese patient. Treatment with diazoxide 100 mg/day promoted complete resolution of the hypoglycemic episodes. Arq Bras Endocrinol Metab. 2012;56(8):485-9.
A síndrome de hiperinsulinemia/hiperamonemia (HI/HA) é uma condição rara, de herança autossômica dominante, que se manifesta por sintomas de hipoglicemia desencadeada por jejum ou refeições de alto conteúdo proteico, juntamente com elevação da concentração de amônia sérica. HI/HA é a segunda causa de hipoglicemia hiperinsulinêmica da infância e é causada por mutações ativadoras no GLUD1, o gene que codifica a enzima mitocondrial glutamato desidrogenase (GDH). A avaliação bioquímica, bem como o sequenciamento direto dos éxons e junções éxon-íntron do gene GLUD1, foi realizada em uma paciente de 6 anos de idade com hipoglicemia de jejum e hiperamonemia. A paciente apresentava uma mutação de novo missense (c.1491A>G; p.Il497Met) em heterozigose, que havia sido previamente relatada em um paciente japonês. O tratamento com diazóxido 100 mg/dia promoveu resolução completa dos episódios hipoglicêmicos. Arq Bras Endocrinol Metab. 2012;56(8):485-9.
Assuntos
Criança , Feminino , Humanos , Glutamato Desidrogenase/genética , Hiperinsulinismo/genética , Hipoglicemia/genética , Mutação de Sentido Incorreto/genéticaRESUMO
Acredita-se que o controle glicêmico e a duração do diabetes sejam os fatores de risco mais importantes para o desenvolvimento das microangiopatias diabéticas, contudo, as velocidades de progressão da nefropatia, da retinoaptia e da polineuropatia variam consideravelmente entre os pacientes. Além da presença de fatores de risco, como a hipertensão arterial, a dislipidemia e o fumo, existem evidências sugerindo que uma predisposição genética desempenha um papel na susceptibilidade para as complicações microvasculares. Com base na patogênese dessas complicações crônicas do diabetes, polimorfismos de vários genes candidatos que atuam em diferentes vias desse processo têm sido investigados, como os genes relacionados aos mecanismos dos danos induzidos pela hiperglicemia (os produtos finais de glicação avançada, o aumento na formação de espécies reativas de oxigênio e a atividade aumentada da via da aldose-redutase), os genes relacionados ao sistema renina-angiotensina; os genes que codificam a síntese das citoquinas, dos fatores de crescimento e dos seus receptores e dos transportadores de glicose entre muitos outros. Este artigo discute alguns estudos que corroboram com a importância da predisposição genética no desenvolvimento da microangiopatia diabética.
Glycemic control and diabetes duration are believed to be the most important risk factors for the development of diabetic microangiopathy; however, the rate of progression of nephropathy, retinopathy and polyneuropathy varies considerably among patients. Besides the presence of risk factors such as hypertension, dyslipidaemia and smoking, there is evidence suggesting that genetic predisposition plays a role in the susceptibility to microvascular complications. Based on underlying pathogenesis, polymorphisms of several candidate genes belonging to multiple pathways have been investigated, like the genes related to mechanisms of hyperglycaemia-induced damage (such as advanced glycation end-products and reactive oxygen species increased formation, augmented activity of the aldose reductase pathway); genes related to the renin-angiotensin system; genes coding for cytokines, growth factors and its receptors, glucose transporter; among many others. This article reviews some studies that corroborate the importance of the genetic background in the development of diabetic microangiopathy.
Assuntos
Humanos , Diabetes Mellitus Tipo 1/genética , Angiopatias Diabéticas/genética , Predisposição Genética para Doença/genética , Albuminúria/metabolismo , Sequência de Bases , Glicemia/análise , Doença Crônica , Angiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/genética , Neuropatias Diabéticas/genética , Retinopatia Diabética/genética , /biossíntese , Hiperglicemia/complicações , Hiperglicemia/prevenção & controle , Estresse Oxidativo/fisiologia , Polimorfismo Genético , Fatores de RiscoRESUMO
Combination therapy with pegylated interferon and ribavirin is considered the new standard therapy for naïve patients with chronic hepatitis C. We evaluated the efficacy and safety of treatment with weight-based peginterferon alpha-2b (1.5 mg/kg per week) plus ribavirin (800-1,200 mg/day) for 48 weeks in naïve, relapser and non-responder (to previous treatment with interferon plus ribavirin) patients with chronic hepatitis C. Sixty-seven naïve, 26 relapser and 40 non-responder patients were enrolled. The overall sustained virological response (SVR) for the intention-to-treat population was 54 percent for naïve, 62 percent for relapser and 38 percent for non-responder patients. In the naïve subgroup, SVR was significantly higher in patients with the non-1 genotype (67 percent) compared to those with genotype 1 (45 percent). In relapsers and non-responders, SVR was, respectively, 69 percent and 24 percent in patients with genotype 1 and 43 percent and 73 percent in those with genotype non-1. There were no significant differences in SVR rates among the three body weight ranges (< 65 kg, 65-85 kg and > 85 kg) in any of the subgroups. Early virological response (EVR) was reached by 78 percent, 81 percent and 58 percent of naïve, relapser and non-responder patients, respectively, and among those with EVR, 63 percent, 67 percent and 61 percent, respectively, subsequently achieved SVR. All of the non-responder patients who did not have EVR reached SVR. Treatment was discontinued in 13 percent of the patients, due to loss to follow-up, hematological abnormalities or depression.