RESUMEN
Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Enfermedad de Alzheimer/metabolismo , Adiponectina/uso terapéutico , Diabetes Mellitus Tipo 2/metabolismo , Encéfalo/metabolismoRESUMEN
Hypertension, one of the most common and severe comorbidities of obesity and overweight, is a worldwide epidemic affecting over 30% of the population. We induced overweight in young male rats (aged 58 days) by exposure to a hypercaloric high lipid (HL) diet in which 70% of the calories originated from fat. The HL diet also contained 33 or 57% higher Na+ than the control (CTR) diet. Over the following weeks the HL rats gradually became overweight (490 ± 12 g vs 427 ± 7 g in the CTR group after 15 weeks) with high visceral fat. They developed elevated systolic blood pressure (SBP) (141 ± 1.9 mmHg), which was fully restored to CTR values (128 ± 1.1 mmHg) by oral administration of Ang-(3-4) (Val-Tyr), the shortest renin-angiotensin-derived peptide. The overweight rats had lower plasma Na+ concentration that augmented to CTR values by Ang-(3-4) treatment. Na+ ingestion was depressed by 40% as result of the Ang-(3-4) treatment, whereas the urinary excretion of Na+ (UNaV) remained unmodified. The preservation of UNaV after Ang-(3-4) treatment - despite the sharp decrease in the dietary Na+ intake - can be ascribed to the normalization of renal type 1 angiotensin II receptors and Na+-transporting ATPases, both up-regulated in overweight rats. These renal effects complete a counterregulatory action on elevated renin-angiotensin activity that allows the high SBP to be normalized and body Na+ homeostasis to be restored concomitantly in overweight rats.
Asunto(s)
Angiotensinas/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Ingestión de Energía/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Sobrepeso/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Animales , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertensión/orina , Masculino , Sobrepeso/complicaciones , Sobrepeso/fisiopatología , Sobrepeso/orina , Ratas , Ratas Wistar , Sodio/metabolismo , Sodio/orinaRESUMEN
In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed "the adiponectin paradox". Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.
Asunto(s)
Adiponectina/metabolismo , Enfermedades Cardiovasculares/patología , Síndrome Metabólico/patología , Receptores de Adiponectina/metabolismo , Animales , Enfermedades Cardiovasculares/metabolismo , Humanos , Síndrome Metabólico/metabolismoRESUMEN
BACKGROUND: Obesity hypertension is an ongoing pandemic. The first-line medications to treat this condition are still subject to debate. We compared diuretics, calcium-channel blockers (CCB), beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) as an initial antihypertensive therapy for prevention of cardiovascular morbimortality of hypertensive individuals who are overweight or obese. METHODS: We conducted a search of the literature for randomized clinical trials in which at least 50% of the participants were overweight or obese. The primary outcomes were all-cause mortality, cardiovascular mortality, acute myocardial infarction (MI), heart failure (HF), stroke, or end-stage renal disease. RESULTS: Our search yielded 16 randomized studies. Comparisons of two classes of drugs with at least two studies indicated that (1) CCB and ACEI increased the risk of HF [relative risk (RR) = 2.26; 95% confidence interval (CI) 1.16-4.40] and stroke [hazard ratio (HR) = 1.13; 1.00-1.26]), respectively, compared to diuretics; and (2) CCB showed a reduction in stroke (HR = 0.77; 0.66-0.89) and total mortality (HR = 0.94; 0.87-1.01) compared to the BB atenolol. Comparisons of two classes of antihypertensive medications with only one study showed that the risk of MI was higher with ARB valsartan versus CCB (HR = 1.19; 95% CI 1.02-1.38, p = 0.02). In contrast, losartan lowered the risk of a composite cardiovascular outcome compared to atenolol (HR = 0.87; 95% CI 0.77-0.98, p = 0.02). CONCLUSIONS: In hypertensive subjects with excess weight, diuretics are more effective for preventing HF and stroke than CCB and ACEI, respectively. CCB are a good first-line choice for prevention of cardiovascular disease, except HF.
Asunto(s)
Antihipertensivos , Enfermedades Cardiovasculares , Hipertensión , Obesidad , Antihipertensivos/clasificación , Antihipertensivos/farmacología , Factores de Riesgo Cardiometabólico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Obesidad/diagnóstico , Obesidad/fisiopatología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be clinically useful in prognosing patient outcome.
Asunto(s)
Adiponectina/sangre , Biomarcadores/sangre , Resistencia a la Insulina , Síndrome Metabólico/sangre , Salud Urbana/estadística & datos numéricos , Adiponectina/química , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Brasil , HDL-Colesterol/sangre , Ayuno/sangre , Femenino , Humanos , Insulina/sangre , Modelos Logísticos , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/etnología , Persona de Mediana Edad , Peso Molecular , Análisis Multivariante , Obesidad/sangre , Obesidad/complicaciones , Pronóstico , Triglicéridos/sangre , Circunferencia de la Cintura , Adulto JovenRESUMEN
Obesity is associated with increased cardiovascular morbidity and mortality. We hypothesized that microvascular function may be impaired in obese subjects with metabolic syndrome (OB-MetSnd) compared to obese subjects without MetSnd (OB) and healthy subjects (HS). In this cross-sectional study, we evaluated skin capillary density (SCD) in OB-MetSnd (n=20, 12 women, BMI=36.5±1.1kg/m(2)), OB (n=25, 16 women, BMI=34.5±0.7kg/m(2)), and HS (n=30, 22 women, BMI=22.8±0.3kg/m(2)) groups. SCD was evaluated by intravital video-microscopy at rest and after post-occlusive reactive hyperemia (PORH) and venous congestion (VC). OB-MetSnd subjects exhibited significant differences in the values of MetSnd components and in leptin and HOMA-IR levels compared to OB and HS individuals. There were no differences in SCD among groups in resting conditions. The OB-MetSnd group failed to show a significant increase in the number of recruited capillaries during PORH and VC compared to the SCD evaluated at rest. A negative correlation of SCD with waist circumference, BMI, blood pressure, and HOMA-IR was observed after PORH and VC. When obese subjects were analyzed according to their HOMA-IR quartiles, a significant decrease in SCD was observed during POHR (P=0.02). Our findings showed that obese subjects have structural and functional alterations in skin microcirculation that are proportional to the increase in the degree of global and central obesity. In addition, in OB-MetSnd subjects, the cutaneous capillaries at rest are already maximally recruited, indicating an absence of functional capillary reserve. This may be related to the insulin resistance observed in OB-MetSnd individuals.
Asunto(s)
Capilares/fisiopatología , Síndrome Metabólico/fisiopatología , Microcirculación/fisiología , Obesidad/fisiopatología , Piel/irrigación sanguínea , Adulto , Presión Sanguínea/fisiología , Índice de Masa Corporal , Capilares/patología , Femenino , Humanos , Hiperemia/patología , Hiperemia/fisiopatología , Insulina/sangre , Resistencia a la Insulina/fisiología , Leptina/sangre , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/patología , Angioscopía Microscópica , Obesidad/complicaciones , Obesidad/patología , Circunferencia de la Cintura/fisiologíaRESUMEN
OBJECTIVE: Recent evidence has suggested obesity as an independent risk factor for chronic kidney disease. However, the temporal relation between body mass index (BMI) and early renal dysfunction is unknown. This study aimed at evaluating whether longitudinal variations in BMI would reflect on changes in estimated glomerular filtration rate (GFR) in hypertensive individuals with excess body weight. METHODS: This was a cross-sectional, longitudinal study. RESULTS: Of the 218 participants who attended the first examination, 150 were available for paired final analyses. At the end of follow-up, GFR decreased by 1.024 mL/min for each 1-kg/m(2) increment in BMI (P<0.03). When BMI was analyzed in quartiles, a positive graded relation with GFR changes was observed in quartiles 1 and 2 (individuals who maintained or lost weight), and a negative relation in quartiles 3 and 4 (individuals who gained weight, P=0.05). A significant difference was observed between the smallest and highest BMI quartiles (P=0.01). At the end of follow-up, the 76 participants (51%) who gained weight (+4.6+/-0.4 kg) showed a reduction in GFR (-2.99+/-1.99 mL/min) of borderline significance (P=0.06) and a significant increase in fasting plasma glucose and triacylglycerol levels. Conversely, the 74 participants who maintained or lost weight showed no significant change in GFR and in fasting plasma glucose and triacylglycerol levels, although their blood pressure decreased significantly. CONCLUSIONS: Our study showed a significant temporal association between changes in BMI and GFR in overweight and obese hypertensive patients.