Pressão arterial, respostas metabólicas e autonômicas à insulina e infusão de intralipid® em pacientes chagásicos

FUNDAMENTO: Infusão de intralipid e heparina resulta em aumento da pressão arterial e também em anormalidades autonômicas em indivíduos normais e hipertensos. OBJETIVO: Avaliar a sensibilidade a insulina e o impacto da infusão de intralipid e de heparina (ILH) sobre a resposta hemodinâmica, metabólica e autonômica em pacientes com a forma indeterminada da doença de Chagas. MÉTODOS: Doze pacientes com a forma indeterminada da doença de Chagas e 12 voluntários saudáveis foram avaliados. RESULTADOS: A pressão arterial basal e a frequência cardíaca foram semelhantes nos dois grupos. Os níveis plasmáticos de noradrenalina encontravam-se ligeiramente aumentados no grupo de pacientes chagásicos. Após o Teste de Tolerância a Insulina (TTI), houve um declínio significativo na glicose dos dois grupos. A Infusão de ILH resultou em aumento da pressão arterial em ambos os grupos, mas não houve nenhuma mudança significativa na noradrenalina plasmática. O componente de Baixa Frequência (BF) mostrou-se semelhante e aumentou de forma semelhante em ambos os grupos. O componente de Alta Frequência (AF) apresentou-se menor no grupo chagásico. CONCLUSÃO: Pacientes com forma indeterminada da doença de Chagas apresentaram aumento da atividade simpática no momento basal e uma resposta inadequada à insulina. Eles também tiveram um menor componente de alta frequência e sensibilidade barorreflexa prejudicada no momento basal e durante a infusão de intralipid e heparina.

Ingestão de glutamina e maltodextrina duas horas no pré-operatório imediato melhora a sensibilidade à insulina pós-operatória: estudo aleatório, duplo-cego e controlado

OBJETIVO: investigar se a abreviação do jejum pré-operatório com uma bebida contendo glutamina e dextrinomaltose melhora a resposta orgânica ao trauma cirúrgico. MÉTODOS: trinta e seis pacientes adultas, (18-62 anos) candidatas à colecistectomia videolaparoscópica eletiva foram aleatoriamente divididas em três grupos: grupo jejum convencional (grupo Jejum), ou em dois grupos para receber duas dietas diferentes, oito horas (400ml) e duas horas antes da indução anestésica (200ml): grupo carboidrato (12,5% de dextrinomaltose) e glutamina (12,5% de dextrinomaltose e, respectivamente, 40 e 10g de glutamina). As amostras de sangue foram coletadas no período pré e pós-operatório. RESULTADOS: vinte e oito pacientes completaram o estudo. Nenhuma complicação pulmonar ocorreu durante o estudo. O volume residual gástrico foi similar entre os grupos (p=0,95). No pós-operatório, todas as pacientes do grupo jejum apresentaram glicemia anormal (>110mg/dl), sendo essa anormalidade 50% para o grupo CHO (p=0,14) e, apenas, 22,2% para o grupo GLN (p=0,01). No pós-operatório, todas as pacientes que abreviaram o jejum (grupo CHO + GLN) apresentaram insulinemia normal, contrastando com 66,7% no grupo jejum (p=0,02). A sensibilidade anormal à insulina subiu no pós-operatório de 32,1% para 46,4% dos casos (p=0,24). A sensibilidade anormal à insulina, no pós-operatório, ocorreu em apenas 11,1% das pacientes do grupo GLN comparado com 55,5% do grupo jejum (p=0,02). CONCLUSÃO: a abreviação do jejum pré-operatório para duas horas com glutamina e dextrinomaltose melhora a sensibilidade à insulina de pacientes submetidas à colecistectomia videolaparoscópica eletiva.

Prescription patterns for diabetes mellitus and therapeutic implications: a population-based analysis

Objective: To analyze drug prescriptions for insulin and oral antidiabetic drugs in type 1 and type 2 diabetes mellitus patients seen in the Brazilian Public Healthcare System (Unified Health System - SUS) in Ribeirao Preto, SP, Brazil. Subjects and methods: All the patients with diabetes seen in the SUS in the western district of Ribeirao Preto, SP, Brazil between March/2006 and February/2007 were included in the study. Results: A total of 3,982 patients were identified. Mean age of the patients was 60.6 years, and 61.0% were females. Sixty percent of the patients were treated with monotherapy. Doses of oral antidiabetic drugs were lower in monotherapy than in polytherapy. Ten patients received doses of glibenclamide or metformin above the recommended maximum doses, and in elderly patients there was no reduction in drug doses. Conclusion: Monotherapy with oral antidiabetic drugs was the predominant procedure, and the doses were not individualized according to age. Arq Bras Endocrinol Metab. 2012;56(2):120-7

Proposal of non-invasive experimental model to induce scoliosis in rats

Background: In the literature, there are several experimental models that induce scoliosis in rats; however, they make use of drugs or invasive interventions to generate a scoliotic curve. Objectives: To design and apply a non-invasive immobilization model to induce scoliosis in rats. Methods: Four-week old male Wistar rats (85 +/- 3.3 g) were divided into two groups: control (CG) and scoliosis (SG). The animals in the SG were immobilized by two vests (scapular and pelvic) made from polyvinyl chloride (PVC) and externally attached to each other by a retainer that regulated the scoliosis angle for twelve weeks with left convexity. After immobilization, the abdominal, intercostal, paravertebral, and pectoral muscles were collected for chemical and metabolic analyses. Radiographic reports were performed every 30 days over a 16-week period. Results: The model was effective in the induction of scoliosis, even 30 days after immobilization, with a stable angle of 28 +/- 5 degrees. The chemical and metabolic analyses showed a decrease (p<0.05) in the glycogenic reserves and in the relationship between DNA and total protein reserves of all the muscles analyzed in the scoliosis group, being lower (p<0.05) in the convex side. The values for the Homeostatic Model Assessment of Insulin Resistance indicated a resistance condition to insulin (p<0.05) in the scoliosis group (0.66 +/- 0.03), when compared to the control group (0.81 +/- 0.02). Conclusions: The scoliosis curvature remained stable 30 days after immobilization. The chemical and metabolic analyses suggest changes in muscular homeostasis during the induced scoliosis process.

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 beta-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); beta-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 beta-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24

Insulin analogues in the treatment of diabetes in pregnancy

Pregnancy affects both maternal and fetal metabolism, and even in non-diabetic women, it exerts a diabetogenic effect. Among pregnant women, 2% to 14% develop gestational diabetes. Pregnancy can also occur in women with preexisting diabetes, which may predispose the fetus to many alterations in organogenesis, restrict growth, and the mother, to some diabetes-related complications, such as retinopathy and nephropathy, or to acceleration of the course of these complications, if they are already present. Women with gestational diabetes generally start their treatment with diet and lifestyle changes; when these changes are not enough for optimal glycemic control, insulin therapy must then be considered. Women with type 2 diabetes using oral hypoglycemic agents are advised to change to insulin therapy. Those with preexisting type 1 diabetes should start intensive glycemic control. As basal insulin analogues have frequently been used off-label in pregnant women, there is a need to evaluate their safety and efficacy. The aim of this review is to report the use of both short- and long-acting insulin analogues during pregnancy and to enable clinicians, obstetricians, and endocrinologists to choose the best insulin treatment for their patients.

Hipoglicemia hiperinsulinêmica da infância: Análise de dados clínicos de uma amostra brasileira

OBJETIVO: Rever a apresentação dos casos de hipoglicemia hiperinsulinêmica da infância (HHI), tratamento e histologia nos serviços de endocrinologia pediátrica no Brasil. MATERIAIS E MÉTODO: Os serviços receberam protocolo para resgatar dados de nascimento, resultados laboratoriais, tipo de tratamento instituído, necessidade de pancreatectomia e histologia. RESULTADOS: Vinte e cinco casos de HHI de seis centros foram resgatados, 15 do sexo masculino, 3/25 nascidos de parto normal. A mediana de idade do diagnóstico foi 10,3 dias. As dosagens de glicose e insulina na amostra sérica crítica apresentaram mediana de 24,7 mg/dL e 26,3 UI/dL. A velocidade de infusão de glicose endovenosa foi superior a 10 mg/kg/min em todos os casos (M:19,1). Diazóxido foi utilizado em 15/25, octreotide em 10, corticoide em 8, hormônio de crescimento em 3, nifedipina em 2 e glucagon em 1. Quarenta por cento (10/25) foram pancreatectomizados, nos quais a análise histológica revelou a forma difusa da patologia. CONCLUSÃO: Primeira análise crítica de uma amostra brasileira de portadores de HHI congênita. Arq Bras Endocrinol Metab. 2012;56(9):666-71

Análise de força muscular e composição corporal de mulheres com Síndrome dos Ovários Policísticos

OBJETIVOS: Comparar os parâmetros metabólicos, a composição corporal e a força muscular de mulheres com Síndrome dos Ovários Policísticos (SOP) em relação a mulheres com ciclos menstruais ovulatórios. MÉTODOS: Estudo caso-controle com 27 mulheres com SOP e 28 mulheres controles com ciclos ovulatórios, com idade entre 18 e 37 anos, índice de massa corpórea entre 18 e 39,9 kg/m², que não praticassem atividade física regular. Níveis séricos de testosterona, androstenediona, prolactina, globulina carreadora dos hormônios sexuais (SHBG), insulina e glicemia foram avaliados. Índice de andrógeno livre (FAI) e resistência insulina (por HOMA) foram calculados. As voluntárias submetidas avaliação de composição corporal por dobras cutâneas e absorciometria de raio X de dupla energia (DEXA) e testes de força muscular máxima de 1-RM em três exercícios após procedimento de familiarização e de força isométrica de preensão manual. RESULTADOS: Os níveis de testosterona foram mais elevados no grupo SOP em relação ao CO (68,0±20,2 versus 58,2±12,8 ng/dL; p=0,02), assim como o FAI (282,5±223,8 versus 127,0±77,2; p=0,01), a insulina (8,4±7,0 versus 4,0±2,7 uIU/mL; p=0,01), e o HOMA (2,3±2,3 versus1,0±0,8; p=0,01). O SBHG foi inferior no grupo SOP comparado ao controle (52,5±43,3 versus 65,1±27,4 nmol/L; p=0,04). Não foram observadas diferenças significativas na composição corporal com os métodos propostos entre os grupos. O grupo SOP apresentou maior força muscular no teste de 1-RM nos exercícios supino reto (31,2±4,75 versus 27,8±3,6 kg; p=0,04) e cadeira extensora (27,9±6,2 versus 23,4±4,2 kg; p=0,01), assim como nos testes de força isométrica de preensão manual (5079,6±1035,7 versus 4477,3±69,6 kgf/m²; p=0,04). Ser portadora de SOP foi um preditor independente de aumento de força muscular nos exercícios supino reto (estimativa (E)=2,7) (p=0,04) e cadeira extensora (E=3,5) (p=0,04). Assim como o IMC no exercício de força isométrica de preensão manual do membro dominante (E=72,2) (p<0,01), supino reto (E=0,2) (p=0,02) e rosca direta (E=0,3) (p<0,01). Nenhuma associação foi encontrada entre HOMA-IR e força muscular. CONCLUSÕES: Mulheres com SOP apresentam maior força muscular, sem diferença na composição corporal. A RI não esteve associada ao desempenho da força muscular. Possivelmente, a força muscular pode estar relacionada aos níveis elevados de androgênios nessas mulheres.

Nursing intervention in insulin administration: telephone follow-up

OBJECTIVE: To analyze the competency of people with diabetes mellitus to perform the insulin administration process, before and after telephone monitoring. METHODS: A quantitative, observational, longitudinal, comparative study. Participants were 26 people enrolled in the at-home capillary glycemia self-monitoring program. Data collection occurred in three phases, in January and February of 2010, for a period of 30 days for each person, by means of interview guided by a data collection instrument and an intervention manual. RESULTS: Of the 38 (100%) questions referring to the insulin administration process, telephone monitoring was demonstrated to be efficient in 30 (78.9%), but in 19 (50%) the intervention was statistically significant (p<0.05), in 11 (28.9%) there were no errors in responses to the final competency evaluation, and seven (18.4%) were not amenable to intervention. CONCLUSION: Telephone mornitoring was effective, as a nursing intervention strategy for the insulin administration process in the home.

Association of acanthosis nigricans and skin tags with insulin resistance

Insulin resistance is a metabolic disorder in which target cells fail to respond to normal levels of circulating insulin. Insulin resistance has been associated with presence of acanthosis nigricans and acrochordons. It is known that early diagnosis and early initial treatment are of paramount importance to prevent a series of future complications. These dermatoses may represent an easily identifiable sign of insulin resistance and non-insulin-dependent diabetes.

SLC2A4 gene: a promising target for pharmacogenomics of insulin resistance

FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo)

Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation.

Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signalling in isolated rat pancreatic islets

LLong-chain fatty acids are capable of inducing alterations in the homoeostasis of glucose-stimulated insulin secretion (GSIS), but the effect of medium-chain fatty acids (MCFA) is poorly elucidated. In the present study, we fed a normoenergetic MCFA diet to male rats from the age of 1 month to the age of 4 months in order to analyse the effect of MCFA on body growth, insulin sensitivity and GSIS. The 45% MCFA substitution of whole fatty acids in the normoenergetic diet impaired whole body growth and resulted in increased body adiposity and hyperinsulinaemia, and reduced insulin-mediated glucose uptake in skeletal muscle. In addition, the isolated pancreatic islets from the MCFA-fed rats showed impaired GSIS and reduced protein kinase Ba (AKT1) protein expression and extracellular signal-related kinase isoforms 1 and 2 (ERK(1/2)) phosphorylation, which were accompanied by increased cellular death. Furthermore, there was a mildly increased cholinergic sensitivity to GSIS. We discuss these findings in further detail, and advocate that they might have a role in the mechanistic pathway leading to the compensatory hyperinsulinaemic status found in this animal model.

Loss of the anorexic response to systemic 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside administration despite reducing hypothalamic AMP-activated protein kinase phosphorylation in insulin-deficient rats

This study tested whether chronic systemic administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) could attenuate hyperphagia, reduce lean and fat mass losses, and improve whole-body energy homeostasis in insulin-deficient rats. Male Wistar rats were first rendered diabetic through streptozotocin (STZ) administration and then intraperitoneally injected with AICAR for 7 consecutive days. Food and water intake, ambulatory activity, and energy expenditure were assessed at the end of the AICAR-treatment period. Blood was collected for circulating leptin measurement and the hypothalami were extracted for the determination of suppressor of cytokine signaling 3 (SOCS3) content, as well as the content and phosphorylation of AMP-kinase (AMPK), acetyl-CoA carboxylase (ACC), and the signal transducer and activator of transcription 3 (STAT3). Rats were thoroughly dissected for adiposity and lean body mass (LBM) determinations. In non-diabetic rats, despite reducing adiposity, AICAR increased (∼1.7-fold) circulating leptin and reduced hypothalamic SOCS3 content and food intake by 67% and 25%, respectively. The anorexic effect of AICAR was lost in diabetic rats, even though hypothalamic AMPK and ACC phosphorylation markedly decreased in these animals. Importantly, hypothalamic SOCS3 and STAT3 levels remained elevated and reduced, respectively, after treatment of insulin-deficient rats with AICAR. Diabetic rats were lethargic and displayed marked losses of fat and LBM. AICAR treatment increased ambulatory activity and whole-body energy expenditure while also attenuating diabetes-induced fat and LBM losses. In conclusion, AICAR did not reverse hyperphagia, but it promoted anti-catabolic effects on skeletal muscle and fat, enhanced spontaneous physical activity, and improved the ability of rats to cope with the diabetes-induced dysfunctional alterations in glucose metabolism and whole-body energy homeostasis.

Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet-induced obesity in mice

A positive relationship between obesity and asthma has been well documented. The AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. The cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. In obese mice, greater levels of eotaxin, TNF-α and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. In addition, metformin nearly abrogated the binding of NF-κB subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. In separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-α mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. In conclusion, metformin inhibits the TNF-α-induced inflammatory signaling and NF-κB-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.