RESUMO
Hyperglycemia and insulin resistance accelerate atherosclerosis by an unclear mechanism. The two factors down-regulate insulin receptor substrate-1 (IRS-1), an intermediary of the insulin/IGF-I signaling system. We previously reported that IRS-1 down-regulation leads to vascular smooth muscle cell (VSMC) dedifferentiation and that IRS-1 deletion from VSMCs in normoglycemic mice replicates this response. However, we did not determine IRS-1's role in mediating differentiation. Here, we sought to define the mechanism by which IRS-1 maintains VSMC differentiation. High glucose or IRS-1 knockdown decreased p53 levels by enhancing MDM2 proto-oncogene (MDM2)-mediated ubiquitination, resulting in decreased binding of p53 to Krüppel-like factor 4 (KLF4). Exposure to nutlin-3, which dissociates MDM2/p53, decreased p53 ubiquitination and enhanced the p53/KLF4 association and differentiation marker protein expression. IRS-1 overexpression in high glucose inhibited the MDM2/p53 association, leading to increased p53 and p53/KLF4 levels, thereby increasing differentiation. Nutlin-3 treatment of diabetic or Irs1-/- mice enhanced p53/KLF4 and the expression of p21, smooth muscle protein 22 (SM22), and myocardin and inhibited aortic VSMC proliferation. Injecting normoglycemic mice with a peptide disrupting the IRS-1/p53 association reduced p53, p53/KLF4, and differentiation. Analyzing atherosclerotic lesions in hypercholesterolemic, diabetic pigs, we found that p53, IRS-1, SM22, myocardin, and KLF4/p53 levels are significantly decreased compared with their expression in nondiabetic pigs. We conclude that IRS-1 is critical for maintaining VSMC differentiation. Hyperglycemia- or insulin resistance-induced IRS-1 down-regulation decreases the p53/KLF4 association and enhances dedifferentiation and proliferation. Our results suggest that enhancing IRS-1-dependent p53 stabilization could attenuate the progression of atherosclerotic lesions in hyperglycemia and insulin-resistance states.
Assuntos
Diferenciação Celular , Hiperglicemia/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Complexos Multiproteicos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Humanos , Hiperglicemia/genética , Hiperglicemia/patologia , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Estabilidade Proteica , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Suínos , Proteína Supressora de Tumor p53/genéticaRESUMO
The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
Assuntos
Acromegalia/terapia , Consenso , Agonistas de Dopamina/uso terapêutico , Procedimentos Neurocirúrgicos , Equipe de Assistência ao Paciente , Guias de Prática Clínica como Assunto , Radioterapia , Receptores da Somatotropina/antagonistas & inibidores , Somatostatina/análise , Acromegalia/diagnóstico , Humanos , Procedimentos Neurocirúrgicos/métodos , Procedimentos Neurocirúrgicos/normas , Radioterapia/métodos , Radioterapia/normasRESUMO
Objective: To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). Methods: This was a retrospective study in a tertiary center from 2010-2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. Results: A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; P = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 (P = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; P = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Conclusion: Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. Abbreviations: ASCO = American Society of Clinical Oncology; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; T4 = thyroxine; TSH = thyroid-stimulating hormone.
Assuntos
Melanoma , Humanos , Nivolumabe , Prognóstico , Estudos RetrospectivosRESUMO
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins-2 (IGFBP-2) function coordinately to stimulate osteoblast differentiation. Induction of AMP-activated protein kinase (AMPK) is required for differentiation and is stimulated by these two factors. These studies were undertaken to determine how these two peptides lead to activation of AMPK. Enzymatic inhibitors and small interfering RNA were utilized to attenuate calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) activity in osteoblasts, and both manipulations resulted in failure to activate AMPK, thereby resulting in inhibition of osteoblast differentiation. IGFBP-2 and IGF-I stimulated an increase in CaMKK2, and inhibition of IGFBP-2 binding its receptor resulted in failure to induce CaMKK2 and AMPK activation. Injection of a peptide that contained the IGFBP-2 receptor-binding domain into IGFBP-2-/- mice activated CaMKK2 and injection of a CaMKK2 inhibitor into normal mice inhibited both CamKK2 and AMPK activation in osteoblasts. We conclude that induction of CaMKK2 by IGFBP-2 and IGF-I in osteoblasts is an important signaling event that occurs early in differentiation and is responsible for activation of AMPK, which is required for optimal osteoblast differentiation.
Assuntos
Adenilato Quinase/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Diferenciação Celular/fisiologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Osteoblastos/metabolismo , Células 3T3 , Animais , Ativação Enzimática/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteogênese/fisiologiaRESUMO
Diabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulin-like growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is down-regulated, and cells become resistant to insulin. Under these conditions, the IGF-I receptor signals through an alternate scaffold protein, SHPS-1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS-1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS-1 expression in VSMCs in non-diabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF-I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up-regulated in IRS-1-/- mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild-type mice during hyperglycemia. These findings illuminate a new function of IRS-1: that of maintaining cells in their normal, differentiated state. Because IRS-1 is down-regulated in states of insulin resistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications.
Assuntos
Desdiferenciação Celular , Regulação para Baixo , Hiperglicemia/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Humanos , Hiperglicemia/genética , Hiperglicemia/patologia , Fator 4 Semelhante a Kruppel , Camundongos , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
PURPOSE: Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient's perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. METHODS: An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. RESULTS: From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. CONCLUSION: The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly.
Assuntos
Acromegalia/diagnóstico , Software , HumanosRESUMO
OBJECTIVE: The 5-year survival rate for childhood cancer has increased to 80%, resulting in a growing population of adult survivors of childhood cancer (ASOCC). Long-term endocrine dysfunction is as high as 63% when screened in research protocols. The purpose of this study was to evaluate the prevalence of endocrine testing, endocrine dysfunction, diabetes, obesity, and endocrinologist visits outside of a research screening protocol. METHODS: A retrospective chart review was performed for 176 ASOCC who were diagnosed with cancer before age 18, followed at least 10 years, were now at least 18, and had survived to the time of chart review. RESULTS: After a mean follow-up of 15.2 years (range 10-21 years), 33.5% of ASOCC had endocrine dysfunction, excluding obesity and diabetes. These outcomes were more common in those with any radiation (64.8%, P<.0001) or cranial radiation (73.1%, P<.0001). Many subjects had never had certain endocrine tests. Over half (54.6%) of subjects were either overweight or obese. Glycated hemoglobin A1C (A1C) testing was rare, but when performed, 38.1% were abnormal. 71% of subjects had never seen an endocrinologist. Even among subjects with cranial radiation, 65.4% had either never seen an endocrinologist or had not seen one in the past 5 years. CONCLUSION: This cohort of ASOCC showed high rates of endocrine dysfunction, overweight or obesity, and diabetes in those who had been tested, combined with low rates of testing and endocrinology evaluation. Endocrinologists need to be aware of the endocrine risks in ASOCC, the need for long-term monitoring, and increase their collaboration with oncology. ABBREVIATIONS: A1C = glycated hemoglobin A1C ASOCC = adult survivors of childhood cancer BMI = body mass index COG = Children's Oncology Group EMR = electronic medical record FSH = follicle-stimulating hormone IGF-1 = insulin-like growth factor 1 LH = luteinizing hormone TSH = thyroid-stimulating hormone.
Assuntos
Sobreviventes de Câncer , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/epidemiologia , Neoplasias/epidemiologia , Obesidade/diagnóstico , Obesidade/epidemiologia , Adolescente , Adulto , Idade de Início , Antineoplásicos/efeitos adversos , Sobreviventes de Câncer/estatística & dados numéricos , Criança , Pré-Escolar , Irradiação Craniana/efeitos adversos , Diabetes Mellitus/etiologia , Doenças do Sistema Endócrino/etiologia , Humanos , Lactente , Monitorização Fisiológica/métodos , Neoplasias/sangue , Neoplasias/complicações , Obesidade/etiologia , Prevalência , Radioterapia/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Insulin-like growth factor-binding protein-2 (IGFBP-2) functions coordinately with IGF-I to stimulate cellular proliferation and differentiation. IGFBP-2 binds to receptor tyrosine phosphatase ß (RPTPß), and this binding in conjunction with IGF-I receptor stimulation induces RPTPß polymerization leading to phosphatase and tensin homolog inactivation, AKT stimulation, and enhanced cell proliferation. To determine the mechanism by which RPTPß polymerization is regulated, we analyzed the protein(s) that associated with RPTPß in response to IGF-I and IGFBP-2 in vascular smooth muscle cells. Proteomic experiments revealed that IGF-I stimulated the intermediate filament protein vimentin to bind to RPTPß, and knockdown of vimentin resulted in failure of IGFBP-2 and IGF-I to stimulate RPTPß polymerization. Knockdown of IGFBP-2 or inhibition of IGF-IR tyrosine kinase disrupted vimentin/RPTPß association. Vimentin binding to RPTPß was mediated through vimentin serine phosphorylation. The serine threonine kinase PKCζ was recruited to vimentin in response to IGF-I and inhibition of PKCζ activation blocked these signaling events. A cell-permeable peptide that contained the vimentin phosphorylation site disrupted vimentin/RPTPß association, and IGF-I stimulated RPTPß polymerization and AKT activation. Integrin-linked kinase recruited PKCζ to SHPS-1-associated vimentin in response to IGF-I and inhibition of integrin-linked kinase/PKCζ association reduced vimentin serine phosphorylation. PKCζ stimulation of vimentin phosphorylation required high glucose and vimentin/RPTPß-association occurred only during hyperglycemia. Disruption of vimetin/RPTPß in diabetic mice inhibited RPTPß polymerization, vimentin serine phosphorylation, and AKT activation in response to IGF-I, whereas nondiabetic mice showed no difference. The induction of vimentin phosphorylation is important for IGFBP-2-mediated enhancement of IGF-I-stimulated proliferation during hyperglycemia, and it coordinates signaling between these two receptor-linked signaling systems.
Assuntos
Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Vimentina/metabolismo , Sequência de Aminoácidos , Animais , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Dados de Sequência Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/química , Transdução de Sinais/efeitos dos fármacos , Suínos , Vimentina/químicaRESUMO
BACKGROUND & AIMS: Budesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. METHODS: Two identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo. RESULTS: Remission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P = .0324; Study 2: 44.0% vs 22.4%; P < .0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P = .0022; Study 2: 50.0% vs 28.6%; P = .0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P = .0486; Study 2: 56.0% vs 36.7%; P = .0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency. CONCLUSIONS: Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.
Assuntos
Budesonida/administração & dosagem , Colo Sigmoide , Glucocorticoides/administração & dosagem , Proctocolite/tratamento farmacológico , Úlcera/tratamento farmacológico , Administração Retal , Administração Tópica , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proctite/tratamento farmacológico , Indução de Remissão/métodos , Resultado do TratamentoRESUMO
Hyperglycemia leads to vascular smooth muscle cell (VSMC) dedifferentiation and enhances responses to IGF-I. Prior studies showed that hyperglycemia stimulated NADPH oxidase 4 (Nox4) synthesis, and IGF-I facilitated its recruitment to a signaling complex where it oxidized src, leading to AKT and MAPK activation. To determine the mechanism that led to these changes, we analyzed the roles of p62 (sequestrosome1) and PKCζ. Hyperglycemia induced a 4.9 ± 1.0-fold increase in p62/PKCζ association, and disruption of PKCζ/p62 using a peptide inhibitor or p62 knockdown reduced PKCζ activation (78 ± 6%). 3-Phosphoinoside-dependent protein kinase 1 was also recruited to the p62 complex and directly phosphorylated PKCζ, leading to its activation (3.1 ± 0.4-fold). Subsequently, activated PKCζ phosphorylated p65 rel, which led to increased Nox4 synthesis. Studies in diabetic mice confirmed these findings (6.0 ± 0.4-fold increase in p62/PKCζ) and their disruption of attenuated Nox4 synthesis (76 ± 9% reduction). PKCζ/p62 activation stimulated inflammatory cytokine production and enhanced IGF-I-stimulated VSMC proliferation. These results define the molecular mechanism by which PKCζ is activated in response to hyperglycemia and suggest that this could be a mechanism by which other stimuli such as cytokines or metabolic stress function to stimulate NF-κB activation, thereby altering VSMC sensitivity to IGF-I.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Citocinas/metabolismo , Proteínas de Choque Térmico/metabolismo , Hiperglicemia/metabolismo , Mediadores da Inflamação/metabolismo , Músculo Liso Vascular/metabolismo , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Animais , Células Cultivadas , Ativação Enzimática , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , NADPH Oxidase 4 , Fosforilação , Proteína Sequestossoma-1 , SuínosRESUMO
Nox4-derived ROS is increased in response to hyperglycemia and is required for IGF-I-stimulated Src activation. This study was undertaken to determine the mechanism by which Nox4 mediates sustained Src activation. IGF-I stimulated sustained Src activation, which occurred primarily on the SHPS-1 scaffold protein. In vitro oxidation experiments indicated that Nox4-derived ROS was able to oxidize Src when they are in close proximity, and Src oxidation leads to its activation. Therefore we hypothesized that Nox4 recruitment to the plasma membrane scaffold SHPS-1 allowed localized ROS generation to mediate sustained Src oxidation and activation. To determine the mechanism of Nox4 recruitment, we analyzed the role of Grb2, a component of the SHPS-1 signaling complex. We determined that Nox4 Tyr-491 was phosphorylated after IGF-I stimulation and was responsible for Nox4 binding to the SH2 domain of Grb2. Overexpression of a Nox4 mutant, Y491F, prevented Nox4/Grb2 association. Importantly, it also prevented Nox4 recruitment to SHPS-1. The role of Grb2 was confirmed using a Pyk2 Y881F mutant, which blocked Grb2 recruitment to SHPS-1. Cells expressing this mutant had impaired Nox4 recruitment to SHPS-1. IGF-I-stimulated downstream signaling and biological actions were also significantly impaired in Nox4 Y491F-overexpressing cells. Disruption of Nox4 recruitment to SHPS-1 in aorta from diabetic mice inhibited IGF-I-stimulated Src oxidation and activation as well as cell proliferation. These findings provide insight into the mechanism by which localized Nox4-derived ROS regulates the sustained activity of a tyrosine kinase that is critical for mediating signal transduction and biological actions.
Assuntos
Estruturas da Membrana Celular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Quinases da Família src/metabolismo , Substituição de Aminoácidos , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Aorta/metabolismo , Aorta/patologia , Estruturas da Membrana Celular/genética , Estruturas da Membrana Celular/patologia , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Ativação Enzimática/genética , Proteína Adaptadora GRB2/genética , Proteína Adaptadora GRB2/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/genética , Camundongos , Mutação de Sentido Incorreto , NADPH Oxidase 4 , NADPH Oxidases/genética , Oxirredução , Ligação Proteica , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais/genética , Suínos , Domínios de Homologia de src , Quinases da Família src/genéticaRESUMO
Serum insulin-like growth factor (IGF-I) is the primary biochemical measure of disease activity in patients with acromegaly, and the 2014 Endocrine Society guidelines recommended normal age-adjusted serum IGF-I as the biochemical target of treatment. However, quantification and interpretation of IGF-I levels are subject to limitations that may affect therapeutic decisions. Techniques for measuring IGF-I have evolved greatly over the past 40 years and continue to do so. Results can vary substantially for different assays, procedures, and laboratories. For any assay, the interpretation of IGF-I values requires robust reference ranges. Using currently available large normative databases, the upper limit of normal (ULN) for IGF-I in middle-aged and elderly individuals is lower than historical reference ranges. Thus, the goal of achieving IGF-I < 1× ULN is more demanding than in the past, and some patients with acromegaly who were classified as "normal" (IGF-I < 1× ULN) in previous studies would be reclassified as above the ULN based on newer normative data. In addition, substantial intra-individual, week-to-week variation in serum IGF-I levels (unrelated to assay performance) has been observed. With changes over time in the measurement of IGF-I and the advent of updated reference ranges derived from large normative databases, it is difficult to justify rigid adherence to the goal of maintaining IGF-I below the ULN for all patients with acromegaly. Instead, symptoms, comorbidities, and quality of life should be considered, along with growth hormone and IGF-I levels, when evaluating the need for further treatment.
Assuntos
Acromegalia , Fator de Crescimento Insulin-Like I , Humanos , Acromegalia/sangue , Acromegalia/diagnóstico , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Valores de Referência , Hormônio do Crescimento Humano/sangue , Resultado do TratamentoRESUMO
Purpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level. Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on algorithmically determined likelihoods of AGHD. Likelihood groups were further stratified by age and sex. Trajectories of annual costs (USD) by likelihood level were also investigated. Results: The study cohort comprised 135 million US adults (aged ≥18 years). Individuals ranked as high-likelihood AGHD had a greater burden of comorbid illness, including cardiovascular disease and diabetes, than those ranked moderate- or low-likelihood. Those in the high-likelihood group had greater mean total direct medical monthly costs ($1844.51 [95% confidence interval (CI): 1841.24;1847.78]) than those in the moderate- ($945.65 [95% CI: 945.26;946.04]) and low-likelihood groups ($459.10 [95% CI: 458.95;459.25]). Outpatient visits accounted for the majority of costs overall, although cost per visit was substantially lower than for inpatient services. Costs tended to increase with age and peaked around the time that individuals were assigned a level of AGHD likelihood. Total direct medical costs in individuals with a high likelihood of AGHD exceeded those for individuals with moderate or low likelihood. Conclusion: Understanding the trajectory of healthcare costs in AGHD may help rationalize allocation of healthcare resources.
Growth hormone is an important substance found in the body. Adult growth hormone deficiency (AGHD) is the reduced production of growth hormone unrelated to the normal reduction seen with aging. Untreated AGHD can result in the development of other conditions, known as comorbidities, which can be expensive to manage. Previously, 135 million privately insured people in the US, aged 1864 years, were categorized into groups by their likelihood (high, medium, or low) of having AGHD. This study compared the estimated direct medical costs (eg hospital care and medication) across the different likelihood levels. People with a high likelihood of AGHD had more comorbidities than people with a medium/low likelihood, and an average total direct medical monthly cost of $1844.51, nearly twice as much as those with a medium likelihood ($945.65), and four times as much as those with a low likelihood ($459.10). These costs tended to increase with age, with the highest costs associated with people aged 5059 years and 6064 years. Outpatient costs (for treatments not requiring an overnight hospital stay) accounted for the greatest proportion of total medical costs, ahead of inpatient costs (for treatments requiring an overnight hospital stay) and medication costs. These findings suggest that diagnosing and treating AGHD earlier may help to reduce medical costs over time. Increased testing and treatment will cause an initial increase in the use of healthcare resources, but could improve overall cost effectiveness by reducing the long-term impact of the disease and avoiding unnecessary healthcare use.
RESUMO
OBJECTIVE: Children with growth hormone deficiency (GHD) face multiple challenges that can negatively impact the transition from pediatric to adult endocrinology care. For children with GHD resulting from brain cancer or its treatment, the involvement of oncology care providers and possible disease-related comorbidities add further complexity to this transition. DESIGN: An advisory board of pediatric and adult endocrinologists was convened to help better understand the unique challenges faced by childhood cancer survivors with GHD, and discuss recommendations to optimize continuity of care as these patients proceed to adulthood. Topics included the benefits and risks of growth hormone (GH) therapy in cancer survivors, the importance of initiating GH replacement therapy early in the patient's journey and continuing into adulthood, and the obstacles that can limit an effective transition to adult care for these patients. RESULTS/CONCLUSIONS: Some identified obstacles included the need to prioritize cancer treatment over treatment for GHD, a lack of patient and oncologist knowledge about the full range of benefits provided by long-term GH administration, concerns about tumor recurrence risk in cancer survivors receiving GH treatment, and suboptimal communication and coordination (e.g., referrals) between care providers, all of which could potentially result in treatment gaps or even complete loss of follow-up during the care transition. Advisors provided recommendations for increasing education for patients and care providers and improving coordination between treatment team members, both of which are intended to help improve continuity of care to maximize the health benefits of GH administration during the critical period when childhood cancer survivors transition into adulthood.
Assuntos
Neoplasias Encefálicas , Sobreviventes de Câncer , Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipopituitarismo , Adulto , Criança , Humanos , Encéfalo , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Hormônio do Crescimento/uso terapêutico , Hormônio do Crescimento Humano/deficiência , Transferência de PacientesRESUMO
CONTEXT: Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs). METHODS: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL. RESULTS: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs. CONCLUSION: Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.
RESUMO
IGFBP3 is a multi-functional protein that has IGF-dependent and IGF-independent actions in cultured cells. Here we show that the IGF binding domain (IBD), nuclear localization signal (NLS) and transactivation domain (TA) are conserved and functional in zebrafish Igfbp3. The in vivo roles of these domains were investigated by expression of Igfbp3 and its mutants in zebrafish embryos. Igfbp3, and its NLS and TA mutants had equally strong dorsalizing effects. Human IGFBP3 had similar dorsalizing effects in zebrafish embryos. The activities of IBD and IBD+NLS mutants were lower, but they still caused dorsalization. Thus, the IGF-independent action of Igfbp3 is not related to NLS or TA in this in vivo model. We next tested the hypothesis that Igfbp3 exerts its IGF-independent action by affecting Bmp signaling. Co-expression of Igfbp3 with Bmp2b abolished Bmp2b-induced gene expression and inhibited its ventralizing activity. Biochemical assays and in vitro experiments revealed that IGFBP3 bound BMP2 and inhibited BMP2-induced Smad signaling in cultured human cells. In vivo expression of Igfbp3 increased chordin expression in zebrafish embryos by alleviating the negative regulation of Bmp2. The elevated level of Chordin acted together with Igfbp3 to inhibit the actions of Bmp2. Knockdown of Igfbp3 enhanced the ventralized phenotype caused by chordin knockdown. These results suggest that Igfbp3 exerts its IGF-independent actions by antagonizing Bmp signaling and that this mechanism is conserved.
Assuntos
Proteína Morfogenética Óssea 2/antagonistas & inibidores , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Peixe-Zebra/embriologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Sequência Conservada , Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Dados de Sequência Molecular , Sinais de Localização Nuclear/metabolismo , Estrutura Terciária de Proteína , Transporte Proteico , Alinhamento de Sequência , Ativação Transcricional , Regulação para Cima , Peixe-Zebra/metabolismoRESUMO
Nocturnin (NOC) is a circadian-regulated protein related to the yeast family of transcription factors involved in the cellular response to nutrient status. In mammals, NOC functions as a deadenylase but lacks a transcriptional activation domain. It is highly expressed in bone-marrow stromal cells (BMSCs), hepatocytes, and adipocytes. In BMSCs exposed to the PPAR-gamma (peroxisome proliferator-activated receptor-gamma) agonist rosiglitazone, Noc expression was enhanced 30-fold. Previously, we reported that Noc(-/-) mice had low body temperature, were protected from diet-induced obesity, and most importantly exhibited absence of Pparg circadian rhythmicity on a high-fat diet. Consistent with its role in influencing BMSCs allocation, Noc(-/-) mice have reduced bone marrow adiposity and high bone mass. In that same vein, NOC overexpression enhances adipogenesis in 3T3-L1 cells but negatively regulates osteogenesis in MC3T3-E1 cells. NOC and a mutated form, which lacks deadenylase activity, bind to PPAR-gamma and markedly enhance PPAR-gamma transcriptional activity. Both WT and mutant NOC facilitate nuclear translocation of PPAR-gamma. Importantly, NOC-mediated nuclear translocation of PPAR-gamma is blocked by a short peptide fragment of NOC that inhibits its physical interaction with PPAR-gamma. The inhibitory effect of this NOC-peptide was partially reversed by rosiglitazone, suggesting that effect of NOC on PPAR-gamma nuclear translocation may be independent of ligand-mediated PPAR-gamma activation. In sum, Noc plays a unique role in the regulation of mesenchymal stem-cell lineage allocation by modulating PPAR-gamma activity through nuclear translocation. These data illustrate a unique mechanism whereby a nutrient-responsive gene influences BMSCs differentiation, adipogenesis, and ultimately body composition.
Assuntos
Adipogenia , Proteínas Nucleares/metabolismo , PPAR gama/metabolismo , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Composição Corporal , Linhagem Celular , Linhagem da Célula , Ritmo Circadiano , Humanos , Camundongos , Camundongos Knockout , Proteínas Nucleares/deficiência , Osteoblastos/citologia , Osteoblastos/metabolismo , Fatores de Transcrição/deficiênciaRESUMO
Standard treatment for acromegaly focuses on the achievement of target absolute levels of growth hormone (GH) and insulin-like growth factor (IGF-I). The appropriateness of these targets when measured using modern assay methods is not well defined. This paper reviews biochemical status assessed using methods available at the time and associated clinical outcomes. GH measurements were shown to provide an indication of changes in tumor size, and failure of GH suppression after glucose stimulation is associated with tumor recurrence. IGF-I levels were more closely associated with changes in symptoms and signs. Reduced GH and IGF-I concentrations were shown to be associated with increased longevity, although the degree of increase has only been analyzed for GH. Lowering of GH and IGF-I has consistently been associated with improved outcomes; however, absolute levels reported in previous studies were based on results from methods and reference ranges that are now obsolete. Applying previously described absolute thresholds as targets (e.g. "normal" IGF-I level) when using current methods is best applied to those with active acromegaly symptoms who could benefit from further lowering of biochemical markers. In asymptomatic individuals with mild IGF-I or GH elevations, targeting biochemical "normalization" would result in the need for combination pharmacotherapy in many patients without proven benefit. Measurement of both GH and IGF-I remains an essential component of diagnosis and monitoring the effectiveness of treatment in acromegaly; however, treatment goals based only on previously identified absolute thresholds are not appropriate without taking into account the assay and reference ranges being employed. Treatment goals should be individualized considering biochemical improvement from an untreated baseline, symptoms of disease, risks, burdens and costs of complex treatment regimens, comorbidities, and quality of life.
Assuntos
Acromegalia , Hormônio do Crescimento Humano , Humanos , Acromegalia/diagnóstico , Acromegalia/terapia , Hormônio do Crescimento , Fator de Crescimento Insulin-Like I/metabolismo , Valores de Referência , Qualidade de Vida , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/metabolismo , Resultado do TratamentoRESUMO
[This corrects the article DOI: 10.3389/fendo.2022.1040046.].