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1.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360563

RESUMO

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the "modern" Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin-GH-IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin-GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/patologia , Hiperinsulinismo/complicações , Resistência à Insulina , Neoplasias/patologia , Obesidade/patologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Neoplasias/etiologia
2.
Cells ; 10(2)2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673340

RESUMO

Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves' disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves' disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.

3.
J Clin Endocrinol Metab ; 105(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32869850

RESUMO

CONTEXT: Patients with craniopharyngioma suffer from obesity and impaired bone health. Little is known about longitudinal changes in body composition and bone mineral density (BMD). OBJECTIVE: To describe body composition and BMD (change). DESIGN: Retrospective longitudinal study. SETTING: Two Dutch/Swedish referral centers. PATIENTS: Patients with craniopharyngioma (n = 112) with a dual X-ray absorptiometry (DXA) scan available (2 DXA scans, n = 86; median Δtime 10.0 years; range 0.4-23.3) at age ≥ 18 years (58 [52%] male, 50 [45%] childhood onset). MAIN OUTCOME MEASURES: Longitudinal changes of body composition and BMD, and associated factors of ΔZ-score (sex and age standardized). RESULTS: BMI (from 28.8 ±â€…4.9 to 31.2 ±â€…5.1 kg/m2, P < .001), fat mass index (FMI) (from 10.5 ±â€…3.6 to 11.9 ±â€…3.8 kg/m2, P = .001), and fat free mass index (FFMI) (from 18.3 ±â€…3.2 to 19.1 ±â€…3.2 kg/m2, P < .001) were high at baseline and increased. Fat percentage and Z-scores of body composition did not increase, except for FFMI Z-scores (from 0.26 ±â€…1.62 to 1.06 ±â€…2.22, P < .001). Z-scores of total body, L2-L4, femur neck increased (mean difference 0.61 ± 1.12, P < .001; 0.74 ± 1.73, P < .001; 0.51 ±â€…1.85, P = .02). Linear regression models for ΔZ-score were positively associated with growth hormone replacement therapy (GHRT) (femur neck: beta 1.45 [95% CI 0.51-2.39]); and negatively with radiotherapy (femur neck: beta -0.79 [-1.49 to -0.09]), glucocorticoid dose (total body: beta -0.06 [-0.09 to -0.02]), and medication to improve BMD (L2-L4: beta -1.06 [-1.84 to -0.28]). CONCLUSIONS: Z-scores of BMI, fat percentage, and FMI remained stable in patients with craniopharyngioma over time, while Z-scores of FFMI and BMD increased. Higher glucocorticoid dose and radiotherapy were associated with BMD loss and GHRT with increase.


Assuntos
Composição Corporal , Densidade Óssea , Craniofaringioma/epidemiologia , Neoplasias Hipofisárias/epidemiologia , Absorciometria de Fóton , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Craniofaringioma/diagnóstico por imagem , Craniofaringioma/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/fisiopatologia , Estudos Retrospectivos , Suécia/epidemiologia , Fatores de Tempo , Adulto Jovem
4.
Cells ; 9(4)2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252327

RESUMO

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) play a crucial factor in the growth, differentiation and survival of cells in health and disease. IGF-I and IGF-II primarily activate the IGF-I receptor (IGF-IR), which is present on the cell surface. Activation of the IGF-IR stimulates multiple pathways which finally results in multiple biological effects in a variety of tissues and cells. In addition, activation of the IGF-IR has been found to be essential for the growth of cancers. The conventional view in the past was that the IGF-IR was exclusively a tyrosine kinase receptor and that phosphorylation of tyrosine residues, after binding of IGF-I to the IGF-IR, started a cascade of post-receptor events. Recent research has shown that this view was too simplistic. It has been found that the IGF-IR also has kinase-independent functions and may even emit signals in the unoccupied state through some yet-to-be-defined non-canonical pathways. The IGF-IR may further form hybrids with the insulin receptors but also with receptor tyrosine kinases (RTKs) outside the insulin-IGF system. In addition, the IGF-IR has extensive cross-talk with many other receptor tyrosine kinases and their downstream effectors. Moreover, there is now emerging evidence that the IGF-IR utilizes parts of the G-protein coupled receptor (GPCR) pathways: the IGF-IR can be considered as a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics. Like the classical GPCRs the IGF-IR can also show homologous and heterologous desensitization. Recently, it has been found that after activation by a ligand, the IGF-IR may be translocated into the nucleus and function as a transcriptional cofactor. Thus, in recent years, it has become clear that the IGF-IR signaling pathways are much more complex than first thought. Therefore a big challenge for the (near) future will be how all the new knowledge about IGF-IR signaling can be translated into the clinical practice and improve diagnosis and treatment of diseases.


Assuntos
Receptor IGF Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Fosforilação , Transdução de Sinais
5.
Growth Horm IGF Res ; 52: 101319, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32339897

RESUMO

Acromegaly is a disease characterized by overproduction of growth hormone (GH). As a consequence of excessive GH secretion, circulating insulin-like growth factor-I (IGF-I) is elevated in active (untreated) acromegaly. IGF-I is often used as a marker of disease activity and growth hormone status in acromegaly. Although IGF-I can directly improve insulin sensitivity and glucose uptake in muscles, the excessive GH secretion in active acromegaly frequently leads to insulin resistance, glucose intolerance and even diabetes. In this review evidence will be discussed that in active acromegaly chronically elevated IGF-I, insulin and soluble Klotho (S-Klotho) levels play a pathophysiological role in the development of IGF-I receptor (IGF-IR) resistance. It is postulated that as soon as circulating IGF-I, insulin and S-Klotho rise above a certain level the IGF-IR becomes relatively resistant to actions of IGF-I. The development of a degree of IGF-IR resistance for metabolic actions may help to explain why in active acromegaly diabetogenic effects of GH predominate and are not completely counteracted and neutralized by elevated circulating levels of IGF-I. Further studies are necessary in order to support this hypothesis.

6.
J Clin Endocrinol Metab ; 105(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145029

RESUMO

CONTEXT: Pituitary hormonal deficiencies in patients with craniopharyngioma may impair their bone health. OBJECTIVE: To investigate bone health in patients with craniopharyngioma. DESIGN: Retrospective cross-sectional study. SETTING: Dutch and Swedish referral centers. PATIENTS: Patients with craniopharyngioma (n = 177) with available data on bone health after a median follow-up of 16 years (range, 1-62) were included (106 [60%] Dutch, 93 [53%] male, 84 [48%] childhood-onset disease). MAIN OUTCOME MEASURES: Fractures, dual X-ray absorptiometry-derived bone mineral density (BMD), and final height were evaluated. Low BMD was defined as T- or Z-score ≤-1 and very low BMD as ≤-2.5 or ≤-2.0, respectively. RESULTS: Fractures occurred in 31 patients (18%) and were more frequent in men than in women (26% vs. 8%, P = .002). Mean BMD was normal (Z-score total body 0.1 [range, -4.1 to 3.5]) but T- or Z-score ≤-1 occurred in 47 (50%) patients and T-score ≤-2.5 or Z-score ≤-2.0 in 22 (24%) patients. Men received less often treatment for low BMD than women (7% vs. 18%, P = .02). Female sex (OR 0.3, P = .004) and surgery (odds ratio [OR], 0.2; P = .01) were both independent protective factors for fractures, whereas antiepileptic medication was a risk factor (OR, 3.6; P = .03), whereas T-score ≤-2.5 or Z-score ≤-2.0 was not (OR, 2.1; P = .21). Mean final height was normal and did not differ between men and women, or adulthood and childhood-onset patients. CONCLUSIONS: Men with craniopharyngioma are at higher risk than women for fractures. In patients with craniopharyngioma, a very low BMD (T-score ≤-2.5 or Z-score ≤-2.0) seems not to be a good predictor for fracture risk.


Assuntos
Estatura , Doenças Ósseas Metabólicas/epidemiologia , Craniofaringioma/fisiopatologia , Fraturas Ósseas/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Ósseas Metabólicas/patologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Fraturas Ósseas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Suécia/epidemiologia , Adulto Jovem
7.
Growth Horm IGF Res ; 48-49: 16-28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31493625

RESUMO

Determination of true IGF-I bioactivity in serum and other biological fluids is still a substantial challenge. The IGF-IR Kinase Receptor Activation assay (IGF-IR KIRA assay) is a novel tool to asses IGF-IR stimulating activity (IRSA) and has opened a new era in studying the IGF system. In this paper we discuss many studies showing that measuring IRSA by the IGF-IR KIRA assay often provides fundamentally different information about the IGF system than the commonly used total IGF-I immunoassays. With the IGF-IR KIRA assay phosphorylation of tyrosine residues of the IGF-IR is used as read out to quantify IRSA in unknown (serum) samples. The IGF-IR KIRA assay gives information about net overall effects of circulating IGF-I, IGF-II, IGFBPs and IGFBP-proteases on IGF-IR activation and seems especially superior to immunoreactive total IGF-I in monitoring therapeutic interventions. Although the IRSA as measured by the IGF-IR KIRA assay probably more closely reflects true bioactive IGF-I than measurements of total IGF-I in serum, the IGF-IR KIRA assay in its current form does not give information about all the post-receptor intracellular events mediated by the IGF-IR. Interestingly, in several conditions in health and disease IRSA measured by the IGF-IR KIRA assay is considerably higher in interstitial fluid and ascites than in serum. This suggests that both the paracrine (local) and endocrine (circulating) IRSA should be measured to get a complete picture about the role of the IGF system in health and disease.


Assuntos
Doença/etiologia , Fator de Crescimento Insulin-Like I/metabolismo , Receptor IGF Tipo 1/metabolismo , Humanos , Transdução de Sinais
8.
Eur J Endocrinol ; 181(2): 173-183, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31167166

RESUMO

Objective: Craniopharyngioma patients often have poor metabolic profiles due to hypothalamic-pituitary damage. Previously, using BMI as obesity marker, the occurrence of the metabolic syndrome in these patients was estimated at 46%. Our aim was to determine if dual X-ray absorptiometry (DXA) scan in evaluation of obesity and metabolic syndrome would be superior. Design: Retrospective study of craniopharyngioma patients for whom DXA scan results were available. Methods: BMI, fat percentage and fat mass index were used to evaluate obesity and as components for obesity in metabolic syndrome. Results: Ninety-five craniopharyngioma patients were included (51% female, 49% childhood-onset disease). Metabolic syndrome occurred in 34-53 (45-51%) subjects (depending on the definition of obesity, although all definitions occurred in higher frequency than in the general population). Metabolic syndrome frequency was higher if obesity was defined by fat percentage (52 vs 42%) or fat mass index (51 vs 43%) compared to BMI. Misclassification appeared in 9% (fat percentage vs BMI) and 7% (fat mass index vs BMI) for metabolic syndrome and 29 and 13% for obesity itself, respectively. For metabolic syndrome, almost perfect agreement was found for BMI compared with fat percentage or fat mass index. For obesity, agreement was fair to moderate (BMI vs fat percentage). Conclusion: Using BMI to evaluate obesity underestimates the true prevalence of metabolic syndrome in patients with craniopharyngioma. Furthermore, fat percentage contributes to a better evaluation of obesity than BMI. The contribution of DXA scan might be limited for identification of the metabolic syndrome.


Assuntos
Adenoma/diagnóstico por imagem , Composição Corporal/fisiologia , Índice de Massa Corporal , Craniofaringioma/diagnóstico por imagem , Síndrome Metabólica/diagnóstico por imagem , Neoplasias Hipofisárias/diagnóstico por imagem , Adenoma/epidemiologia , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Craniofaringioma/epidemiologia , Craniofaringioma/metabolismo , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/metabolismo , Estudos Retrospectivos , Adulto Jovem
9.
Endocrine ; 64(3): 673-684, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30838516

RESUMO

PURPOSE: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. METHODS: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. RESULTS: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. CONCLUSIONS: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Imidazóis/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
10.
Front Aging Neurosci ; 11: 20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809143

RESUMO

Background: Alterations in insulin-like growth factor I (IGF-I) signaling have been associated with dementia and Alzheimer's disease (AD). Studies on the association between IGF-I levels and dementia risk have been inconclusive. We reported earlier that higher levels of IGF-I receptor stimulating activity are associated with a higher prevalence and incidence of dementia. Objective: In the present study, we test the robustness of the association between IGF-I receptor stimulating activity and dementia by extending the follow-up period to 16 years and investigate possible effect modification by apolipoprotein E (ApoE). Methods: At baseline, circulating IGF-I receptor stimulating activity was determined by the IGF-I kinase receptor activation (KIRA) assay in 1,014 elderly from the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up in January 2015. Associations of IGF-I receptor stimulating activity and incident dementia were assessed with Cox proportional hazards models. Results: During 10,752 person-years of follow-up, 174 people developed dementia. In the extended follow-up we no longer observed a dose-response relationship between IGF-I receptor stimulating activity and risk of dementia [adjusted odds ratio 1.11; 95% confidence interval (CI) 0.97-1.28]. Interestingly, we found evidence of an interaction between ApoE-ε4 and tertiles of IGF-I receptor stimulating activity. IGF-I receptor stimulating activity in the median and top tertiles was related to increased dementia incidence in hetero- and homozygotes of the ApoE-ε4 allele, but did not show any association with dementia risk in people without the ApoE-ε4 allele (adjusted odds ratio medium vs. low IGF-I receptor stimulating activity in ApoE-ε4 carriers: 1.45; 95% CI 1.00-2.12). These findings suggest a threshold effect in ApoE-ε4 carriers. In line with the hypothesis that downregulation of IGF-I signaling is associated with increased dementia risk, ApoE-ε4 homozygotes without prevalent dementia displayed lower levels of IGF-I receptor stimulating activity than heterozygotes and non-carriers. Conclusion: The findings shed new light on the association between IGF-I signaling and the neuropathology of dementia and ask for replication in other cohorts, using measures of IGF-I receptor stimulating activity rather than total serum levels as putative markers of dementia risk.

11.
J Clin Endocrinol Metab ; 104(6): 1978-1988, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608534

RESUMO

CONTEXT: Pasireotide long-acting release (LAR) is a somatostatin multireceptor ligand, and in the current consensus criteria pasireotide LAR is considered the second-line medical treatment for acromegaly. We present in this article our recommendations to define the position of pasireotide LAR in the treatment of acromegaly and provide recommendations for the management of pasireotide-induced hyperglycemia. EVIDENCE ACQUISITION: Our recommendations are based on our experiences with the pasireotide LAR and pegvisomant (PEGV) combination study and the available basic or clinical articles published in peer-reviewed international journals on pasireotide LAR and acromegaly. EVIDENCE SYNTHESIS: In accordance with the current consensus criteria, we recommend pasireotide LAR monotherapy as a second-line therapy in young patients who show tumor growth during first-generation somatostatin receptor ligand (SRL) therapy and in patients who show tumor growth during PEGV therapy. In addition, we recommend pasireotide LAR monotherapy in patients with headache not responsive to first-generation SRL therapy and in patients who experience side effects or are intolerant to PEGV monotherapy. In contrast to the current consensus criteria, we recommend considering combination therapy with pasireotide LAR and PEGV as third-line treatment in patients without diabetes at low PEGV dosages (≤80 mg/week) and in patients with tumor growth or symptoms of active acromegaly during first-generation SRL and PEGV combination therapy. With respect to pasireotide-induced hyperglycemia, we recommend a more liberal strategy of blood glucose monitoring during pasireotide treatment. CONCLUSIONS: In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.


Assuntos
Acromegalia/tratamento farmacológico , Medicina Baseada em Evidências/métodos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Hiperglicemia/diagnóstico , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/etiologia , Glicemia/análise , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Consenso , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Medicina Baseada em Evidências/normas , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/análogos & derivados , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Resultado do Tratamento
12.
J Clin Endocrinol Metab ; 104(3): 915-924, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30346538

RESUMO

Background: The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression. Aim: To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment. Methods: We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS). Results: The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9). Conclusions: In a cohort of patients partially responsive to SRLs, the IGF-I-lowering effects of PAS-LAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.


Assuntos
Acromegalia/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Antagonistas de Hormônios/farmacologia , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/patologia , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do Tratamento
13.
Endocr Rev ; 40(1): 236-267, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30215690

RESUMO

Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.


Assuntos
Anticorpos Monoclonais/farmacologia , Oftalmopatia de Graves , Receptor IGF Tipo 1 , Receptores da Tireotropina , Animais , Anticorpos Monoclonais Humanizados , Oftalmopatia de Graves/tratamento farmacológico , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/metabolismo , Humanos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/imunologia , Receptor IGF Tipo 1/metabolismo , Receptores da Tireotropina/metabolismo
14.
Eur J Endocrinol ; 179(5): 269-277, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30076159

RESUMO

OBJECTIVE: to assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia. DESIGN: The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks. METHODS: 59 out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤ 1.2 x the Upper Limit of Normal (ULN)) at 48-weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT). RESULTS: At the end of the study median IGF-I was 0.98 x ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and 9 patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = -0.37, P < 0.005). CONCLUSIONS: PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a fifty percent pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.


Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Fator de Crescimento Insulin-Like I/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Substituição de Medicamentos , Seguimentos , Teste de Tolerância a Glucose , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Insulina/sangue , Octreotida/uso terapêutico , Estudos Prospectivos , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Resultado do Tratamento
15.
Eur J Endocrinol ; 178(2): 153-161, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29208737

RESUMO

OBJECTIVE: IGF-I may be a marker of later metabolic and cardiovascular disease. The interactions between IGF-I and glucose metabolism are multifactorial, and there is potential confounding from several secondary effects. In this study, we examined the interaction between IGF-I and glucose metabolism in a large cohort of clinically well-characterized elderly twins. DESIGN: A total of 303 twin pairs of the same gender (606 twins) were included in the study; 125 monozygotic and 178 dizygotic twin pairs. METHODS: A clinical examination including a standard oral glucose tolerance test (OGTT) and anthropometric measurements was performed. RESULTS: The heritability estimates were high for IGF-I and IGFBP-3 (h2: 0.65 (95% CI: 0.55-0.74) and 0.71 (0.48-0.94), respectively) and for insulin secretion (h2 = 0.56, P < 0.0001), whereas the heritability estimates for insulin sensitivity were low (h2 = 0.14, P = 0.11). In a multiple regression analysis (adjusting for age, gender and twin status), there was a negative association between IGF-I and insulin sensitivity (B: -0.13, SE 0.03, P < 0.0001) and IGF-I and disposition index (B: -0.05, SE 0.02, P < 0.001) in the entire cohort of 606 twins. The associations between IGF-I and both DI and HOMA-S did not differ between the DZ and MZ twins. Forty-five twin pairs were discordant for T2D, but the discordant twins had similar concentrations of IGF-I or IGFBP-3. CONCLUSIONS: There was a high heritability for IGF-I and IGFBP-3, but a low heritability for insulin secretion and insulin sensitivity in a group of elderly twins. In addition, we found a strong negative relationship between IGF-I and insulin sensitivity, which did not seem to be strongly genetically determined.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Idoso , Antropometria , Estudos de Coortes , Dinamarca , Diabetes Mellitus Tipo 2/metabolismo , Doenças em Gêmeos/genética , Doenças em Gêmeos/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Gêmeos Dizigóticos , Gêmeos Monozigóticos
16.
Eur J Endocrinol ; 178(1): 93-102, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29046325

RESUMO

OBJECTIVE: Most studies in patients with craniopharyngioma did not investigate morbidity and mortality relative to the general population nor evaluated risk factors for excess morbidity and mortality. Therefore, the objective of this study was to examine excess morbidity and mortality, as well as their determinants in patients with craniopharyngioma. DESIGN: Hospital-based retrospective cohort study conducted between 1987 and 2014. METHODS: We included 144 Dutch and 80 Swedish patients with craniopharyngioma identified by a computer-based search in the medical records (105 females (47%), 112 patients with childhood-onset craniopharyngioma (50%), 3153 person-years of follow-up). Excess morbidity and mortality were analysed using standardized incidence and mortality ratios (SIRs and SMRs). Risk factors were evaluated univariably by comparing SIRs and SMRs between non-overlapping subgroups. RESULTS: Patients with craniopharyngioma experienced excess morbidity due to type 2 diabetes mellitus (T2DM) (SIR: 4.4, 95% confidence interval (CI): 2.8-6.8) and cerebral infarction (SIR: 4.9, 95% CI: 3.1-8.0) compared to the general population. Risks for malignant neoplasms, myocardial infarctions and fractures were not increased. Patients with craniopharyngioma also had excessive total mortality (SMR: 2.7, 95% CI: 2.0-3.8), and mortality due to circulatory (SMR: 2.3, 95% CI: 1.1-4.5) and respiratory (SMR: 6.0, 95% CI: 2.5-14.5) diseases. Female sex, childhood-onset craniopharyngioma, hydrocephalus and tumour recurrence were identified as risk factors for excess T2DM, cerebral infarction and total mortality. CONCLUSIONS: Patients with craniopharyngioma are at an increased risk for T2DM, cerebral infarction, total mortality and mortality due to circulatory and respiratory diseases. Female sex, childhood-onset craniopharyngioma, hydrocephalus and tumour recurrence are important risk factors.


Assuntos
Craniofaringioma/epidemiologia , Craniofaringioma/mortalidade , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/mortalidade , Adolescente , Adulto , Idade de Início , Infarto Cerebral/complicações , Infarto Cerebral/epidemiologia , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Mortalidade Hospitalar , Humanos , Hidrocefalia/complicações , Hidrocefalia/epidemiologia , Hidrocefalia/mortalidade , Incidência , Masculino , Pessoa de Meia-Idade , Morbidade , Países Baixos/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Suécia/epidemiologia , Adulto Jovem
17.
Eur J Endocrinol ; 178(1): 11-22, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28882980

RESUMO

OBJECTIVE: Patients with craniopharyngioma are at an increased risk for cardio- and cerebrovascular mortality. The metabolic syndrome (MetS) is an important cardiometabolic risk factor, but barely studied in patients with craniopharyngioma. We aimed to investigate the prevalence of and risk factors for the MetS and its components in patients with craniopharyngioma. DESIGN: Cross-sectional study with retrospective data. METHODS: We studied the prevalence of and risk factors for the MetS and its components in 110 Dutch (median age 47 years, range 18-92) and 68 Swedish (median age 50 years, range 20-81) patients with craniopharyngioma with ≥3 years of follow-up (90 females (51%); 83 patients with childhood-onset craniopharyngioma (47%); median follow-up after craniopharyngioma diagnosis 16 years (range 3-62)). In Dutch patients aged 30-70 years and Swedish patients aged 45-69 years, we examined the prevalence of the MetS and its components relative to the general population. RESULTS: Sixty-nine (46%) of 149 patients with complete data demonstrated the MetS. Prevalence of the MetS was significantly higher in patients with craniopharyngioma compared with the general population (40% vs 26% (P < 0.05) for Dutch patients; 52% vs 15% (P < 0.05) for Swedish patients). Multivariable logistic regression analysis identified visual impairment as a borderline significant predictor of the MetS (OR 2.54, 95% CI 0.95-6.81; P = 0.06) after adjustment for glucocorticoid replacement therapy and follow-up duration. Age, female sex, tumor location, radiological hypothalamic damage, 90Yttrium brachytherapy, glucocorticoid replacement therapy and follow-up duration significantly predicted components of the MetS. CONCLUSIONS: Patients with craniopharyngioma are at an increased risk for the MetS, especially patients with visual impairment.


Assuntos
Craniofaringioma/diagnóstico por imagem , Craniofaringioma/epidemiologia , Síndrome Metabólica/diagnóstico por imagem , Síndrome Metabólica/epidemiologia , Transtornos da Visão/diagnóstico por imagem , Transtornos da Visão/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Craniofaringioma/terapia , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Transtornos da Visão/terapia , Adulto Jovem
18.
J Clin Endocrinol Metab ; 103(2): 586-595, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155991

RESUMO

Aim: To assess the efficacy and safety of pasireotide long-acting release (PAS-LAR) alone or in combination with pegvisomant by switching patients with acromegaly who were well controlled with long-acting somatostatin analogues (LA-SSAs) and pegvisomant to PAS-LAR with or without pegvisomant. Methods: Sixty-one patients with acromegaly were enrolled in a prospective open-label study. We included patients with an insulin-like growth factor I (IGF-I) ≤1.2 × upper limit of normal (ULN) during treatment with LA-SSAs and pegvisomant. At baseline, the pegvisomant dose was reduced by 50% up to 12 weeks. When IGF-I remained ≤1.2 × ULN after 12 weeks, patients were switched to PAS-LAR 60 mg monotherapy. When IGF-I was >1.2 × ULN, patients were switched to PAS-LAR 60 mg, and they continued with the 50% reduced pegvisomant dose. Results: At baseline, mean IGF-I was 0.97 × ULN, and the median pegvisomant dose was 80 mg/wk. At 12 weeks, mean IGF-I increased to 1.59 × ULN, and IGF-I levels ≤1.2 ULN were observed in 24.6% of participants. At 24 weeks, IGF-I levels were reduced into the reference range in 73.8% of patients. Between baseline and 24 weeks, the pegvisomant dose was reduced by 66.1%. PAS-LAR was well tolerated, but hyperglycemia was the most frequent adverse event. The frequency of diabetes increased from 32.8% at baseline to 68.9% at 24 weeks. Conclusions: Switching to PAS-LAR, either as monotherapy or combination with pegvisomant, can control IGF-I levels in most patients. PAS-LAR demonstrated a pegvisomant-sparing effect of 66% compared with the combination with LA-SSAs. Hyperglycemia was the most important safety issue.


Assuntos
Acromegalia/tratamento farmacológico , Substituição de Medicamentos , Hormônio do Crescimento Humano/análogos & derivados , Octreotida/administração & dosagem , Somatostatina/análogos & derivados , Acromegalia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Medicamentos/efeitos adversos , Quimioterapia Combinada , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Somatostatina/uso terapêutico , Resultado do Tratamento
19.
J Clin Endocrinol Metab ; 102(10): 3814-3821, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938465

RESUMO

Context: Insulin resistance could increase insulin requirements in type 1 diabetes (T1D). Current insulin immunoassays do not detect insulin analogs. Kinase insulin receptor (IR) activation (KIRA) bioassays specific for human IR isoforms A (IR-A) and B (IR-B) permit assessment of all circulating insulin bioactivity. We studied whether IR-A and IR-B KIRA assays are related to direct measures of insulin sensitivity or insulin doses in T1D. Design: We evaluated 31 adult patients with T1D (age 45.7 ± 1.6 years, body mass index 28.8 ± 0.7 kg/m2). Serum IR-A and IR-B bioactivities were measured by KIRA bioassays. Insulin sensitivity of glucose production (Ra) was measured by the euglycemic hyperinsulinemic clamp technique in which a low insulin dose (0.4 mU/kg/min for 240 minutes) was combined with D-[3-3H] glucose infusion to measure rates of Ra and utilization and insulin action on antilipolysis from suppression of serum free fatty acids. Results: Baseline circulating IR-A bioactivity was 53 ± 7 pmol/L, and IR-B bioactivity was 81 ± 11 pmol/L. Compared with baseline, insulin infusion significantly increased IR-A (P < 0.001) and IR-B (P < 0.001) bioactivities. Fasting IR-A and IR-B bioactivities were positively related to endogenous Ra (r = 0.44, P = 0.01 and r = 0.38, P < 0.05). Fasting IR-A (r = 0.43, P = 0.02) and IR-B (r = 0.47, P = 0.01) bioactivities were significantly correlated with insulin requirements and glycosylated hemoglobin (IR-A: r = 0.52, P = 0.002; IR-B: r = 0.48, P = 0.006). Conclusions: Circulating IR-A and IR-B bioactivities are associated with insulin resistance, high insulin requirements, and poor glycemic control in T1D. Measurement of IR bioactivity by KIRA assays provides a tool to assess the amount of biologically active insulin in groups of T1D patients treated with insulin analogs.


Assuntos
Bioensaio/métodos , Análise Química do Sangue/métodos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Insulina/administração & dosagem , Insulina/sangue , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Cálculos da Dosagem de Medicamento , Feminino , Técnica Clamp de Glucose , Hemoglobina A Glicada/análise , Humanos , Insulina/análise , Lipólise/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade
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