NK cell-activating receptor NKp46 does not participate in the development of obesity-induced inflammation and insulin resistance.

Recent evidence establishes a pivotal role for obesity-induced inflammation in precipitating insulin resistance and type-2 diabetes. Central to this process is the proinflammatory M1 adipose-tissue macrophages (ATMs) in epididymal white adipose tissue (eWAT). Notably, natural killer (NK) cells are a crucial regulator of ATMs since their cytokines induce ATM recruitment and M1 polarization. The importance of NK cells is shown by the strong increase in NK-cell numbers in eWAT, and by studies showing that removing and expanding NK cells respectively improve and worsen obesity-induced insulin resistance. It has been suggested that NK cells are activated by unknown ligands on obesity-stressed adipocytes that bind to NKp46 (encoded by Ncr1), which is an activating NK-cell receptor. This was supported by a study showing that NKp46-knockout mice have improved obesity-induced inflammation/insulin resistance. We therefore planned to use the NKp46-knockout mice to further elucidate the molecular mechanism by which NKp46 mediates eWAT NK-cell activation in obesity. We confirmed that obesity increased eWAT NKp46+ NK-cell numbers and NKp46 expression in wild-type mice and that NKp46-knockout ablated these responses. Unexpectedly, however, NKp46-knockout mice demonstrated insulin resistance similar to wild-type mice, as shown by fasting blood glucose/insulin levels and glucose/insulin tolerance tests. Obesity-induced increases in eWAT ATM numbers and proinflammatory gene expression were also similar. Thus, contrary to previously published results, NKp46 does not regulate obesity-induced insulin resistance. It is therefore unclear whether NKp46 participates in the development of obesity-induced inflammation and insulin resistance. This should be considered when elucidating the obesity-mediated molecular mechanisms that activate NK cells.

Unusual Suspects in the Development of Obesity-Induced Inflammation and Insulin Resistance: NK cells, iNKT cells, and ILCs.

The notion that obesity-induced inflammation mediates the development of insulin resistance in animal models and humans has been gaining strong support. It has also been shown that immune cells in local tissues, in particular in visceral adipose tissue, play a major role in the regulation of obesity-induced inflammation. Specifically, obesity increases the numbers and activation of proinflammatory immune cells, including M1 macrophages, neutrophils, Th1 CD4 T cells, and CD8 T cells, while simultaneously suppressing anti-inflammatory cells such as M2 macrophages, CD4 regulatory T cells, regulatory B cells, and eosinophils. Recently, however, new cell types have been shown to participate in the development of obesity-induced inflammation and insulin resistance. Some of these cell types also appear to regulate obesity. These cells are natural killer (NK) cells and innate lymphoid cells (ILCs), which are closely related, and invariant natural killer T (iNKT) cells. It should be noted that, although iNKT cells resemble NK cells in name, they are actually a completely different cell type in terms of their development and functions in immunity and metabolism. In this review, we will focus on the roles that these relatively new players in the metabolism field play in obesity-induced insulin resistance and the regulation of obesity.

Hyperglycemia effect on coronary disease in patients with metabolic syndrome evaluated by intracoronary ultrasonography.

INTRODUCTION: Metabolic syndrome (MS) is characterized by dyslipidemia, central obesity, hypertension and hyperglycemia. However, type 2 diabetes mellitus (T2DM) may or may not be present in metabolic syndrome. MS and T2DM are considered important cardiovascular risk factors, but the role of hyperglycemia in coronary disease is still contested in the literature. Therefore, we decided to evaluate the effect of hyperglycemia on the severity of coronary disease in MS patients, with or without T2DM, submitted to coronary angiography (CA) and intravascular ultrasonography (IVUS). MATERIALS AND METHODS: This is a cross sectional, observational study with 100 MS patients (50% with T2DM), 60% male. All of the patients had been referred for CA procedures. The obstruction was considered severe when stenosis was greater than 70% and moderate if it was between 50-69%. Patients detected with a moderate obstruction by CA were indicated to IVUS. A minimal luminal area of less than 4mm2 detected by IVUS was also considered severe. IDF criteria were used to define Metabolic Syndrome and T2DM diagnosis was defined according to the American Diabetes Association criteria. Student's t-test and Pearson Chi-square were used for statistical analysis, considering p < 0.05 statistically significant. RESULTS AND DISCUSSION: The majority of T2DM patients presented severe arterial lesions (74% vs 22%, p<0.001). Using CA procedure, 12% of T2DM had moderate obstructions, compared to 38% of the non-diabetic group (p< 0.05). 8% of patients with moderate lesions by CA were diagnosed with a luminal area less than 4mm2 using IVUS. This luminal area was significantly smaller in the T2DM group than in the control group (3.8mm2 ± 2.42. vs 4.6mm2 ± 2.58, p = 0.03). CONCLUSION: Patients with MS and T2DM submitted to angiography and IVUS, had more severe coronary lesions compared to MS patients without diabetes. This finding suggests that beyond insulin resistance that is present in MS, hyperglycemia may also play a role in the development of atherosclerotic disease. IVUS was useful for diagnosing 8% of severe cases initially considered to be moderate obstructions when using just CA in this scenario.

Aplicabilidade clínica da hemoglobina glicada na evolução do paciente com hiperglicemia hospitalar / Clinical applicability of glycated hemoglobin in the evolution of patients with hospital hyperglycemia

INTRODUÇÃO: O Diabetes Mellitus (DM) consiste em uma doença crônica ocasionada pela hiperglicemia. Sabe-se que essa patologia esta presente em aproximadamente 10% das internações hospitalares, e que uma porcentagem significativa dos pacientes com Diabetes Mellitus apresenta-se sem diagnóstico prévio no momento da internação. A hiperglicemia pode provocar efeitos deletérios no organismo como processo inflamatório. OBJETIVO: Avaliar a HbA1c como ferramenta diagnóstica e preditiva da evolução clínica de pacientes com e sem diagnóstico de Diabetes Mellitus, avaliada durante período de internação hospitalar e sua relação com as complicações hospitalares. MÉTODOS: Foram avaliados 100 pacientes no período de um ano e verificado através do protocolo Institucional NUMAD (Núcleo de assistência ao Paciente Diabético) os valores de hemoglobina glicada HbA1c em pacientes com hiperglicemia. RESULTADOS: Os pacientes sem diagnóstico prévio de Diabetes Mellitus apresentaram HbA1c entre 5,8% e 7,5%, com a mediana do tempo de internação de 9 dias, sem complicações. Os pacientes com Diabetes Mellitus que evoluíram com complicações, apresentaram HbA1c entre 7,3% e 12,4% e correspondiam a 20% do estudo, com tempo de internação de 34,5 dias. DISCUSSÃO: Estudos descrevem a prevalência de hiperglicemia relacionada a mortalidade e período de internação hospitalar, e principalmente em relação a hemoglobina glicada como marcador de gravidade independente da patologia. Nosso estudo demonstrou a importância dessa ferramenta como um aliado ao tratamento hospitalar. CONCLUSÃO: A HbA1c demonstrou em nosso estudo ser um marcador prognóstico e preditivo importante em pacientes com hiperglicemia hospitalar.

INTRODUCTION: Diabetes Mellitus (DM) is a chronic disease caused by hyperglycemia. It is known that this disease is present in approximately 10% of hospital admissions, and there is a significant percentage of patients with Diabetes Mellitus presents with no previous diagnosis at admission. Hyperglycemia can cause deleterious effects in the body as an inflammatory process. OBJECTIVE: To evaluate the HbA1c as a diagnostic and predictive tool outcome of patients with and without diagnosis of Diabetes Mellitus, performed during hospital stay and its relation with the hospital complications. METHODS: A total of 100 patients in the period of a year and verified by the Institutional NUMAD protocol (service core to Diabetic Patients) the glycated hemoglobin HbA1c in patients with hyperglycemia. RESULTS: Patients with no previous diagnosis of Diabetes Mellitus had HbA1c between 5.8% and 7.5%, with the median length of stay of nine days without complications. Patients with Diabetes Mellitus who developed complications, had HbA1c between 7.3% and 12.4% and accounted for 20% of the study, with hospital stay of 34.5 days. DISCUSSION: Studies describe the prevalence of hyperglycemia related mortality and hospital stay, and especially in relation to glycated hemoglobin as a marker of severity regardless of pathology. Our study demonstrated the importance of this tool as an ally to the hospital treatment. CONCLUSION: HbA1c demonstrated in our study to be a prognostic and predictive marker important in patients with hospital hyperglycemia.