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2.
Pituitary ; 27(1): 61-69, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37976013

RESUMEN

BACKGROUND: A proportion of patients with adrenal insufficiency (AI) require increases in their maintenance glucocorticoids following the Covid-19 vaccine as a result of vaccine-related symptoms or development of incipient or frank adrenal crisis. In a large cohort of AI patients, we aim to characterise symptoms, changes in glucocorticoid dosage, occurrence of adrenal crises and whether there are differences between the mRNA and adenovirus vector vaccines. PATIENTS AND METHODS: Patients with AI of any aetiology were invited to complete a short, structured questionnaire of their experience of the Covid-19 vaccination. RESULTS: 279 of the 290 patients enrolled to this study fully completed the questionnaires. 176, 100 and 3 received the Astra Zeneca (AZ), Pfizer-BioNTech (PB) and Moderna (MD) as initial vaccine respectively; and for the second vaccine, 170, 99 and 10 received AZ, PB and MD respectively. Moderate to severe symptoms occurred in 44.8 and 39.7% after the first and second vaccines respectively, were of early onset (6.0 h, IQR 2-12 &. 6.0 h, IQR 2-24 h) and short duration (24 h, IQR 12-72 h & 26 h, IQR 12-72 h). 34.4 and 29.7% increased their maintenance glucocorticoid dose. DISCUSSION: The Covid-19 vaccines appear well-tolerated in patients with AI, with similar frequency of symptoms to that reported in the background population. The AZ vaccine leads to slightly greater post-vaccination symptom burden and need to increase glucocorticoid dosage, but this does not translate to greater adverse outcomes.


Asunto(s)
Insuficiencia Suprarrenal , COVID-19 , Humanos , Vacunas contra la COVID-19/efectos adversos , Glucocorticoides/uso terapéutico , COVID-19/prevención & control , Esteroides
3.
J Clin Endocrinol Metab ; 107(7): 2026-2035, 2022 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-35275196

RESUMEN

CONTEXT: The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. OBJECTIVE: We hypothesized that local 11ß-HSD1 might mediate an age-related decrease in bone formation and that selective 11ß-HSD1 inhibition may enhance bone formation. METHODS: A dual-center, phase II, randomized, double-blind, placebo-controlled trial of 90 days' treatment with AZD4017 (a selective 11ß-HSD1 inhibitor) was conducted in 55 postmenopausal women with osteopenia. Participants received 400 mg oral AZD4017 twice daily vs matched placebo over 90 days. The primary outcome measure was the impact on the bone formation marker osteocalcin. Secondary objectives included correlation with 11ß-HSD1 activity. RESULTS: At 90 days, osteocalcin levels did not differ between treatment groups: active (mean 22.3 [SD 8.6] ng/mL, n = 22) and placebo (21.7 [SD 9.2] ng/mL, n = 24), with a baseline-adjusted treatment effect of 0.95 (95% CI: -2.69, 4.60). The results from the urinary [THF + alloTHF]/THE ratio (index of 11ß-HSD1 activity) and the urinary cortisol/cortisone ratio (index of 11ß-HSD2 activity) confirmed a > 90% inhibition of 11ß-HSD1 but no change in activity of 11ß-HSD2. CONCLUSION: This trial demonstrates that AZD4017 selectively inhibits 11ß-HSD1 activity in vivo in a safe and reversible manner. Following 90 days of treatment, there is no effect on bone formation, indicating that the relative impairment of bone mineral density in postmenopausal women is not mediated by local intracellular production of cortisol under normal physiological concentrations.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Enfermedades Óseas Metabólicas , Niacinamida , Piperidinas , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Remodelación Ósea , Femenino , Glucocorticoides , Humanos , Hidrocortisona , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Osteocalcina , Piperidinas/uso terapéutico , Posmenopausia
5.
Clin Endocrinol (Oxf) ; 94(3): 361-370, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33370485

RESUMEN

OBJECTIVE: Patients with rheumatic diseases are often treated with prolonged, high-dose systemic glucocorticoids which can cause hypothalamic-pituitary-adrenal (HPA) axis suppression and development of tertiary adrenal insufficiency. Adrenal insufficiency carries the risk of serious, potentially life-threatening adrenal crisis. Our study evaluated the prevalence, characteristics and recovery of patients with underlying rheumatology conditions who had received prolonged glucocorticoid treatment. DESIGN AND PATIENTS: Retrospective, cross-sectional study. We evaluated 238 patients seen in outpatient rheumatology clinic, managed in accordance with current nationally and internationally accepted clinical guidelines. MEASUREMENTS: Data collected included patient demographics, historical steroid data, 09.00 h cortisol/short synacthen test (SST) results and follow-up data on those with repeat assessments. RESULTS: Overall, 65% of our cohort had a 09.00 h cortisol <350 nmol/L. On SST, 43% of patients demonstrated evidence of possible tertiary adrenal insufficiency. Prednisolone equivalent dose at time of SST was significantly higher in the group who failed SST vs. those who passed; mean of 5.57 mg vs. 3.59mg (p = .005). 09.00 h cortisol result correlated with 30-min cortisol on SST (R2  = .20, p = .002). 0-min cortisol on SST correlated more strongly with 30-min cortisol than 09.00 h cortisol (R2  = .59, p-value < .001). Patients with 0-min cortisol >350 nmol/L, all passed their SST. Patients who remained on prednisolone were more likely to recover (71%) vs. those switched to hydrocortisone (27%), P = .02. Peak steroid dose was predictive of recovery; significantly lower in those who recovered (mean of 22.3 mg vs. 33.8 mg, P = .03). Steroid duration was not found to be a predictor of recovery [recovery (64.2 months) vs. non-recovery (55.6 months), P = .58]. There was no correlation found to outcome on SST with age, sex, peak steroid dose, steroid duration, underlying rheumatological condition, additional exogenous steroid use or serum sodium. CONCLUSIONS: Forty three percent of our patients demonstrated sub-optimal adrenal function on SST. Steroid dose at the time of SST was the only significant predictive risk factor for tertiary adrenal insufficiency. 09.00 h cortisol demonstrated good correlation with outcome on SST and could represent a valid screening test to reduce need for SST if 09.00 h >350 nmol/L. Further prospective data are required to further characterize risk factors, predictive features of recovery and establish optimal management strategy of steroids (prednisolone vs hydrocortisone) to encourage adrenal recovery.


Asunto(s)
Insuficiencia Suprarrenal , Enfermedades Reumáticas , Insuficiencia Suprarrenal/inducido químicamente , Estudios Transversales , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Hidrocortisona , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Estudios Retrospectivos , Enfermedades Reumáticas/tratamiento farmacológico
6.
Endocr Rev ; 41(6)2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32266384

RESUMEN

An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup, and clinical symptoms and signs are required in every case. Adrenocortical carcinoma remains a real concern but is restricted to <2% of all cases. Functional adrenal incidentaloma lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of autonomous cortisol secretion. Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Glándulas Suprarrenales , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/terapia , Glándulas Suprarrenales/anatomía & histología , Glándulas Suprarrenales/fisiología , Humanos
8.
Oncologist ; 21(3): 301-7, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26921289

RESUMEN

Remarkable progress has been made over the past decade in cancer medicine. Personalized medicine, driven by biomarker predictive factors, novel biotherapy, novel imaging, and molecular targeted therapeutics, has improved outcomes. Cancer is becoming a chronic disease rather than a fatal disease for many patients. However, despite this progress, there is much work to do if patients are to receive continuous high-quality care in the appropriate place, at the appropriate time, and with the right specialized expert oversight. Unfortunately, the rapid expansion of therapeutic options has also generated an ever-increasing burden of emergency care and encroaches into end-of-life palliative care. Emergency presentation is a common consequence of cancer and of cancer treatment complications. It represents an important proportion of new presentations of previously undiagnosed malignancy. In the U.K. alone, 20%-25% of new cancer diagnoses are made following an initial presentation to the hospital emergency department, with a greater proportion in patients older than 70 years. This late presentation accounts for poor survival outcomes and is often associated with poor patient experience and poorly coordinated care. The recent development of acute oncology services in the U.K. aims to improve patient safety, quality of care, and the coordination of care for all patients with cancer who require emergency access to care, irrespective of the place of care and admission route. Furthermore, prompt management coordinated by expert teams and access to protocol-driven pathways have the potential to improve patient experience and drive efficiency when services are fully established. The challenge to leaders of acute oncology services is to develop bespoke models of care, appropriate to local services, but with an opportunity for acute oncology teams to engage cancer care strategies and influence cancer care and delivery in the future. This will aid the integration of highly specialized cancer treatment with high-quality care close to home and help avoid hospital admission.


Asunto(s)
Servicios Médicos de Urgencia , Neoplasias/mortalidad , Neoplasias/terapia , Servicio de Oncología en Hospital , Medicina de Precisión , Humanos , Pronóstico , Reino Unido
9.
BMJ Open Diabetes Res Care ; 3(1): e000094, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26157583

RESUMEN

OBJECTIVES: Characterize patients with diabetes with severe hypoglycemia requiring emergency services intervention at home and investigate 12-month mortality. RESEARCH DESIGN AND METHODS: Emergency services call-outs for hypoglycemia were recorded between 2005 and 2013 in an area covering 34 000 patients with diabetes. Patient characteristics were documented together with capillary blood glucose (CBG), glycated hemoglobin (HbA1c), and treatment for hypoglycemia; 12-month mortality and variables influencing survival were analyzed. RESULTS: In 1835 episodes among 1156 patients, 45% had type 1 diabetes (68.2% males) and 44% had type 2 diabetes (49.4% males), with a minority unclassified. CBG at presentation (mean±SD) was 1.76±0.72 mmol/L in patients with type 1 diabetes and 1.96±0.68 mmol/L in patients with type 2 diabetes (p<0.0001), with a higher HbA1c in the former group (8.3±1.52% (67.5±16.4 mmol/mol) and 7.8±1.74% (61.6±19.0 mmol/mol), respectively; p<0.0001). A third of patients with type 2 diabetes were not on insulin therapy and displayed lower HbA1c compared with insulin users. Glucagon was used in 37% of patients with type 1 diabetes and 28% of patients with type 2 diabetes (p<0.0001). One-year mortality was 4.45% in type 1 diabetes and 22.1% in type 2 diabetes. Age and type of diabetes were predictive of mortality in multivariable analysis, whereas CBG levels/frequency of hypoglycemia had no effect. CONCLUSIONS: Severe hypoglycemia in the community is common with a male predominance in type 1 diabetes. Severe hypoglycemia in non-insulin treated patients with type 2 diabetes is associated with lower HbA1c compared with insulin users. Severe hypoglycemia appears to be associated with increased mortality at 12 months, particularly in type 2 diabetes.

10.
Diabetes ; 61(9): 2359-68, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22733797

RESUMEN

We recently demonstrated that reducing IGF-1 receptor (IGF-1R) numbers in the endothelium enhances nitric oxide (NO) bioavailability and endothelial cell insulin sensitivity. In the present report, we aimed to examine the effect of increasing IGF-1R on endothelial cell function and repair. To examine the effect of increasing IGF-1R in the endothelium, we generated mice overexpressing human IGF-1R in the endothelium (human IGF-1R endothelium-overexpressing mice [hIGFREO]) under direction of the Tie2 promoter enhancer. hIGFREO aorta had reduced basal NO bioavailability (percent constriction to N(G)-monomethyl-l-arginine [mean (SEM) wild type 106% (30%); hIGFREO 48% (10%)]; P < 0.05). Endothelial cells from hIGFREO had reduced insulin-stimulated endothelial NO synthase activation (mean [SEM] wild type 170% [25%], hIGFREO 58% [3%]; P = 0.04) and insulin-stimulated NO release (mean [SEM] wild type 4,500 AU [1,000], hIGFREO 1,500 AU [700]; P < 0.05). hIGFREO mice had enhanced endothelium regeneration after denuding arterial injury (mean [SEM] percent recovered area, wild type 57% [2%], hIGFREO 47% [5%]; P < 0.05) and enhanced endothelial cell migration in vitro. The IGF-1R, although reducing NO bioavailability, enhances in situ endothelium regeneration. Manipulating IGF-1R in the endothelium may be a useful strategy to treat disorders of vascular growth and repair.


Asunto(s)
Células Endoteliales/metabolismo , Endotelio Vascular/fisiología , Receptor IGF Tipo 1/fisiología , Animales , Aorta/fisiología , Glucemia/metabolismo , Presión Sanguínea , Femenino , Homeostasis , Humanos , Masculino , Ratones , Ratones Transgénicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Receptor IGF Tipo 1/deficiencia , Receptor IGF Tipo 1/genética , Vasoconstricción/efectos de los fármacos
11.
Diabetes ; 61(4): 915-24, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22357965

RESUMEN

Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR(+/-)), and ApoE(-/-) mice. Direct effects of human (h)IGFBP1 on nitric oxide (NO) generation and cellular signaling were studied in isolated vessels and in human endothelial cells. IGFBP1 circulating levels were markedly suppressed in dietary-induced obese mice. Overexpression of hIGFBP1 in obese mice reduced blood pressure, improved insulin sensitivity, and increased insulin-stimulated NO generation. In nonobese IR(+/-) mice, overexpression of hIGFBP1 reduced blood pressure and improved insulin-stimulated NO generation. hIGFBP1 induced vasodilatation independently of IGF and increased endothelial NO synthase (eNOS) activity in arterial segments ex vivo, while in endothelial cells, hIGFBP1 increased eNOS Ser(1177) phosphorylation via phosphatidylinositol 3-kinase signaling. Finally, in ApoE(-/-) mice, overexpression of hIGFBP1 reduced atherosclerosis. These favorable effects of hIGFBP1 on insulin sensitivity, blood pressure, NO production, and atherosclerosis suggest that increasing IGFBP1 concentration may be a novel approach to prevent cardiovascular disease in the setting of insulin resistance and diabetes.


Asunto(s)
Aterosclerosis/prevención & control , Presión Sanguínea/fisiología , Diabetes Mellitus/metabolismo , Resistencia a la Insulina/fisiología , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Óxido Nítrico/biosíntesis , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Células Cultivadas , Células Endoteliales , Eliminación de Gen , Humanos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Ratones , Ratones Transgénicos , Obesidad/metabolismo , Receptor de Insulina/genética
12.
Diabetes ; 60(8): 2169-78, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21677284

RESUMEN

OBJECTIVE: In mice, haploinsufficiency of the IGF-1 receptor (IGF-1R(+/-)), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1Rαß and one insulin receptor (IR), IRαß complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO). RESEARCH DESIGN AND METHODS: Using a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability. RESULTS: IGF-1R(+/-) mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity. CONCLUSIONS: These data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium.


Asunto(s)
Células Endoteliales/metabolismo , Óxido Nítrico/metabolismo , Receptor IGF Tipo 1/fisiología , Receptor de Insulina/fisiología , Animales , Aorta/efectos de los fármacos , Disponibilidad Biológica , Regulación hacia Abajo , Glucosa/metabolismo , Intolerancia a la Glucosa/genética , Humanos , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenilefrina/farmacología , Receptor IGF Tipo 1/deficiencia , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Transducción de Señal , Venas Umbilicales/citología , Vasoconstricción/efectos de los fármacos
13.
Diabetes ; 60(4): 1295-303, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21317296

RESUMEN

OBJECTIVE: Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration. RESEARCH DESIGN AND METHODS: We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion. RESULTS: IRKO mice, although glucose tolerant, had fewer circulating Sca-1(+)/Flk-1(+) APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor-stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit(+) bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit(+) cells from IRKO mice was less effective at improving endothelial repair. CONCLUSIONS: Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals.


Asunto(s)
Resistencia a la Insulina/fisiología , Neovascularización Fisiológica/fisiología , Células Madre/metabolismo , Animales , Western Blotting , Adhesión Celular/genética , Adhesión Celular/fisiología , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/metabolismo , Citometría de Flujo , Genotipo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Noqueados , Neovascularización Fisiológica/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Células Madre/citología
14.
Arterioscler Thromb Vasc Biol ; 30(4): 878-84, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20110574

RESUMEN

OBJECTIVE: Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. METHODS AND RESULTS: In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor L-NMMA, and norepinephrine. Flow-mediated vasodilatation (5.8%+/-0.4% vs 7.9%+/-0.5%; P=0.002) and CPC mobilization (CD34(+)/KDR(+) 53.2% vs 85.4%; P=0.001; CD133(+)/CD34(+)/KDR(+) 48.4% vs 73.9%; P=0.05; and CD34(+)/CD45(-) 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34(+)/KDR(+) -3.3% vs 68.4%; CD133(+)/CD34(+)/KDR(+) 0.7% vs 71.4%; and CD34(+)/CD45(-) -30.5% vs 77.8%; all P<0.001). CONCLUSIONS: In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.


Asunto(s)
Pueblo Asiatico , Movimiento Celular , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Ejercicio Físico , Óxido Nítrico/metabolismo , Células Madre/metabolismo , Población Blanca , Antígeno AC133 , Adulto , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Arteria Braquial/fisiopatología , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/administración & dosificación , Glicoproteínas/metabolismo , Humanos , Hiperemia/fisiopatología , Infusiones Intravenosas , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Norepinefrina/administración & dosificación , Péptidos/metabolismo , Células Madre/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Vasodilatación , omega-N-Metilarginina/administración & dosificación
15.
Biochim Biophys Acta ; 1801(3): 320-6, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19818873

RESUMEN

The number of people with the insulin-resistant conditions of type 2 diabetes mellitus (T2DM) and obesity has reached epidemic proportions worldwide. Eighty percent of people with T2DM will die from the complications of cardiovascular atherosclerosis. Insulin resistance is characterised by endothelial dysfunction, which is a pivotal step in the initiation/progression of atherosclerosis. A hallmark of endothelial dysfunction is an unfavourable imbalance between the bioavailability of the antiatherosclerotic signalling molecule nitric oxide (NO) and proatherosclerotic reactive oxygen species. In this review we discuss the mechanisms linking insulin resistance to endothelial dysfunction, with a particular emphasis on a potential role for a toxic effect of free fatty acids on endothelial cell homeostasis.


Asunto(s)
Endotelio Vascular/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Resistencia a la Insulina , Enfermedades Vasculares/metabolismo , Animales , Dislipidemias/metabolismo , Humanos , NADPH Oxidasas/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo
16.
Endocrinology ; 150(10): 4575-82, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19608653

RESUMEN

Obesity and type 2 diabetes mellitus are characterized by insulin resistance, reduced bioavailability of the antiatherosclerotic signaling molecule nitric oxide (NO), and accelerated atherosclerosis. IGF-I, the principal growth-stimulating peptide, which shares many of the effects of insulin, may, like insulin, also be involved in metabolic and vascular homeostasis. We examined the effects of IGF-I on NO bioavailability and the effect of obesity/type 2 diabetes mellitus on IGF-I actions at a whole-body level and in the vasculature. In aortic rings IGF-I blunted phenylephrine-mediated vasoconstriction and relaxed rings preconstricted with phenylephrine, an effect blocked by N(G)-monomethyl L-arginine. IGF-I increased NO synthase activity to an extent similar to that seen with insulin and in-vivo IGF-I led to serine phosphorylation of endothelial NO synthase (eNOS). Mice rendered obese using a high-fat diet were less sensitive to the glucose-lowering effects of insulin and IGF-I. IGF-I increased aortic phospho-eNOS levels in lean mice, an effect that was blunted in obese mice. eNOS activity in aortae of lean mice increased 1.6-fold in response to IGF-I compared with obese mice. IGF-I-mediated vasorelaxation was blunted in obese mice. These data demonstrate that IGF-I increases eNOS phosphorylation in-vivo, increases eNOS activity, and leads to NO-dependent relaxation of conduit vessels. Obesity is associated with resistance to IGF-I at a whole-body level and in the endothelium. Vascular IGF-I resistance may represent a novel therapeutic target to prevent or slow the accelerated vasculopathy seen in humans with obesity or type 2 diabetes mellitus.


Asunto(s)
Grasas de la Dieta/efectos adversos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Óxido Nítrico/metabolismo , Obesidad/metabolismo , Vasodilatación , Animales , Aorta/fisiología , Endotelio Vascular/metabolismo , Activación Enzimática , Humanos , Técnicas In Vitro , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/metabolismo , Obesidad/etiología , Obesidad/fisiopatología , Fosforilación , Receptor de Insulina/metabolismo , Serina/metabolismo
17.
PLoS One ; 3(10): e3483, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18941531

RESUMEN

BACKGROUND: Diabetes Mellitus (DM) is associated with adverse cardiovascular prognosis. However, the risk associated with DM may vary between individuals according to their overall cardiovascular risk burden. Therefore, we aimed to determine whether DM is associated with poor outcome in patients presenting with Acute Coronary Syndrome (ACS) according to the index episode being a first or recurrent cardiovascular event. METHODS AND FINDINGS: We conducted a retrospective analysis of a prospective cohort study involving 2499 consecutively admitted patients with confirmed ACS in 11 UK hospitals during 2003. Usual care was provided for all participants. Demographic factors, co-morbidity and treatment (during admission and at discharge) factors were recorded. The primary outcome was all cause mortality (median 2 year follow up), compared for cohorts with and without DM according to their prior cardiovascular disease (CVD) disease status. Adjusted analyses were performed with Cox proportional hazards regression analysis. Within the entire cohort, DM was associated with an unadjusted 45% increase in mortality. However, in patients free of a history of CVD, mortality of those with and without DM was similar (18.8% and 19.7% respectively; p = 0.74). In the group with CVD, mortality of patients with DM was significantly higher than those without DM (46.7% and 33.2% respectively; p<0.001). The age and sex adjusted interaction between DM and CVD in predicting mortality was highly significant (p = 0.002) and persisted after accounting for comorbidities and treatment factors (p = 0.006). Of patients free of CVD, DM was associated with smaller elevation of Troponin I (p<0.001). However in patients with pre-existing CVD Troponin I was similar (p = 0.992). CONCLUSIONS: DM is only associated with worse outcome after ACS in patients with a pre-existing history of CVD. Differences in the severity of myocyte necrosis may account for this. Further investigation is required, though our findings suggest that aggressive primary prevention of CVD in patients with DM may have beneficially modified their first presentation with (and mortality after) ACS.


Asunto(s)
Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/mortalidad , Diabetes Mellitus/mortalidad , Síndrome Coronario Agudo/epidemiología , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Diabetes Mellitus/epidemiología , Femenino , Humanos , Masculino , Mortalidad , Estudios Retrospectivos , Troponina I/sangre , Reino Unido
18.
Expert Rev Cardiovasc Ther ; 6(8): 1135-49, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18793116

RESUMEN

IGF-1 is a peptide hormone that is expressed in most tissues. It shares significant structural and functional similarities with insulin, and is implicated in the pathogenesis of insulin resistance and cardiovascular disease. Recombinant human IGF-1 has been used in Type 2 diabetes to improve insulin sensitivity and aid glycemic control. There is evidence supporting IGF-1 as a vascular protective factor and it may also be beneficial in the treatment of chronic heart failure. Further understanding of the effects of IGF-1 signaling in health and disease may lead to novel approaches to the prevention and treatment of diabetes and cardiovascular disease.


Asunto(s)
Glucemia/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/fisiopatología , Angiopatías Diabéticas/fisiopatología , Factor I del Crecimiento Similar a la Insulina/fisiología , Animales , Apoptosis/fisiología , Aterosclerosis/fisiopatología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/prevención & control , Endotelio Vascular/fisiopatología , Hormona del Crecimiento/fisiología , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Resistencia a la Insulina/fisiología , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Músculo Liso Vascular/fisiología , Miocitos Cardíacos/fisiología , Páncreas/fisiopatología , Fosfatidilinositol 3-Quinasas/fisiología , Receptor IGF Tipo 1/fisiología , Células Madre/fisiología
19.
Diabetes Care ; 31(2): 363-5, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17959865

RESUMEN

OBJECTIVE: We sought to compare mortality reduction associated with secondary prevention in patients with and without diabetes after acute coronary syndrome (ACS). RESEARCH DESIGN AND METHODS: We conducted a cohort study involving 2,499 patients with ACS recruited from 11 U.K. hospitals. Multivariable analysis comparing all-cause mortality risk reduction associated with pharmacologic agents in patients with and without diabetes. RESULTS: Aspirin was not associated with significant mortality benefit in diabetes sufferers (95% CI 0.50-1.08); nondiabetic patients derived a 48% mortality reduction (P < 0.001). The interaction between diabetes and aspirin use was statistically significant (P = 0.037), indicating that patients with diabetes experience less effective mortality reduction from aspirin use. CONCLUSIONS: Aspirin, but not other secondary prevention agents, is associated with less effective mortality reduction in patients with diabetes and unstable coronary artery disease.


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Aspirina/uso terapéutico , Angiopatías Diabéticas/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Síndrome Coronario Agudo/mortalidad , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estudios de Cohortes , Angiopatías Diabéticas/mortalidad , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/mortalidad , Masculino , Análisis Multivariante , Reproducibilidad de los Resultados , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Reino Unido/epidemiología
20.
Eur J Cardiovasc Prev Rehabil ; 14(5): 666-71, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17925626

RESUMEN

AIMS: Both diabetes mellitus (DM) and hyperglycaemia are known to predict outcome after acute coronary syndrome (ACS). Recent work has suggested women with DM have greater baseline cardiovascular risk and poorer outcome after ACS. The interaction between sex and abnormal glucose homoeostasis in patients without diabetes is unexplored; we aimed to assess this relationship. METHODS AND RESULTS: Retrospective analysis of data from a prospective cohort study of 1575 patients with a confirmed ACS and no previous diagnosis of DM in 11 UK hospitals. Multivariable analysis was performed to assess the value of clinical variables, including hyperglycaemia and sex, in predicting 2 year all-cause mortality. Sex and hyperglycaemia interacted in predicting mortality. In men, mortality risk increased more steeply with incremental levels of glycaemia than in women (glucose > or =11.1 mmol/l, hazard ratio, 2.19; 95% confidence interval, 1.2-4.0). In both sex groups increasing glycaemia predicted mortality at levels currently not recommended for acute therapeutic intervention (7.8-11.0 mmol/l). CONCLUSIONS: In patients not known to have diabetes, hyperglycaemia is a concentration-dependent predictor of long-term mortality after ACS; this predictive value is stronger in men than women.


Asunto(s)
Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/mortalidad , Hiperglucemia/complicaciones , Caracteres Sexuales , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
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