RESUMEN
BACKGROUND: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene. METHODS AND RESULTS: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele. CONCLUSIONS: Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.
Asunto(s)
Caveolina 1/genética , Glucosa/metabolismo , Resistencia a la Insulina/genética , Metabolismo de los Lípidos/genética , Tejido Adiposo/metabolismo , Adolescente , Adulto , Anciano , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Aldosterona/metabolismo , Animales , Glucemia/efectos de los fármacos , Colesterol/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Eplerenona , Femenino , Frecuencia de los Genes , Homeostasis , Humanos , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Insulina/metabolismo , Lipoproteínas HDL/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/farmacología , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Receptores de Mineralocorticoides/metabolismo , Resistina/genética , Resistina/metabolismo , Proteínas Plasmáticas de Unión al Retinol/genética , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Espironolactona/análogos & derivados , Espironolactona/farmacología , Triglicéridos/metabolismo , Adulto JovenRESUMEN
Studies have shown associations between exposure to hypoglycemia and increased mortality, raising the possibility that hypoglycemia has adverse cardiovascular effects. In this study, we determined the acute effects of hypoglycemia on cardiovascular autonomic control. Seventeen healthy volunteers were exposed to experimental hypoglycemia (2.8 mmol/L) for 120 min. Cardiac vagal baroreflex function was assessed using the modified Oxford method before the initiation of the hypoglycemic-hyperinsulinemic clamp protocol and during the last 30 min of hypoglycemia. During hypoglycemia, compared with baseline euglycemic conditions, 1) baroreflex sensitivity decreases significantly (19.2 ± 7.5 vs. 32.9 ± 16.6 ms/mmHg, P < 0.005), 2) the systolic blood pressure threshold for baroreflex activation increases significantly (the baroreflex function shifts to the right; 120 ± 14 vs. 112 ± 12 mmHg, P < 0.005), and 3) the maximum R-R interval response (1,088 ± 132 vs. 1,496 ± 194 ms, P < 0.001) and maximal range of the R-R interval response (414 ± 128 vs. 817 ± 183 ms, P < 0.001) decrease significantly. These findings indicate reduced vagal control and impaired cardiovascular homeostasis during hypoglycemia.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Barorreflejo , Presión Sanguínea/fisiología , Sistema Cardiovascular/fisiopatología , Frecuencia Cardíaca/fisiología , Hipoglucemia/fisiopatología , Nervio Vago/fisiopatología , Adulto , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Masculino , Reflejo Anormal , Adulto JovenRESUMEN
CONTEXT AND OBJECTIVE: We examined whether a prevalent caveolin-1 gene (CAV1) variant, previously related to insulin resistance, is associated with metabolic syndrome (MetS). PATIENTS AND METHODS: We included subjects genotyped for the CAV1 variant rs926198 from two cohorts: 735 Caucasians from the HyperPATH multicenter study, and 810 Hispanic participants from the HTN-IR cohort. RESULTS: Minor allele carriers from HyperPATH cohort (57% of subjects) had higher Framingham risk scores, higher odds of diabetes (10.7% vs 5.7%, p=0.016), insulin resistance (44.3% vs 35.1%, p=0.022), low HDL (49.3% vs 39.6%, p=0.018) and MetS (33% vs 20.5%, p<0.001) but similar BMI. Consistently, minor allele carriers exhibited higher odds of MetS, even when adjusted for confounders and relatedness (OR 2.83 (1.73-4.63), p<0.001). The association with MetS was replicated in the Hispanic cohort HTN-IR (OR 1.61, [1.06-2.44], p=0.025). Exploratory analyses suggest that MetS risk is modified by a CAV1 variant-BMI status interaction, whereby the minor allele carrier status strongly predicted MetS (OR 3.86 [2.05-7.27], p<0.001) and diabetes (OR 2.27 [1.07-4.78], p=0.03) in non-obese, but not in obese subjects. In addition, we observed a familial aggregation for MetS diagnosis in minor allele carriers. CONCLUSION: The prevalent CAV1 gene variant rs926198 is associated with MetS in separate Caucasian and Hispanic cohorts. These findings appear to be driven by an interaction between the genetic marker and obesity status, suggesting that the CAV1 variant may improve risk profiling in non-obese subjects. Additional studies are needed to confirm the clinical implications of our results.