Glucagon stimulation test to assess growth hormone status in Prader-Willi syndrome.

PURPOSE: Growth hormone deficiency (GHD) must be confirmed before starting treatment in adults with Prader-Willi syndrome (PWS). Most studies use the growth-hormone-releasing hormone plus arginine (GHRH-arginine) test. No data are available on the glucagon stimulation test (GST) in PWS. We compared the utility of fixed-dose (1 mg) GST versus GHRH-arginine test in diagnosing GHD. METHODS: Adults and late adolescents with PWS underwent both tests on separate days. In the GHRH-arginine test, GHD was defined according to body mass index. In the GST, two cutoffs were analyzed: peak GH concentration < 3 ng/mL and < 1 ng/mL. For analyses, patients were divided into two groups according to body weight (≤ 90 kg and > 90 kg). RESULTS: We analyzed 34 patients: 22 weighing ≤ 90 kg and 12 weighing > 90 kg. In patients weighing ≤ 90 kg, the two tests were concordant in 16 (72.72%) patients (k = 0.476, p = 0.009 with GST cutoff < 3 ng/mL, and k = 0.450, p = 0.035 with GST cutoff < 1 ng/mL). In patients weighing > 90 kg, the two tests were not concordant with GST cutoff < 3 ng/mL, but were concordant in 11 (91.6%) patients (k = 0.833, p = 0.003) with GST cutoff < 1 ng/mL. GH peaks on the two tests correlated (r = 0.725, p = 0.008). CONCLUSION: Fixed-dose (1 mg) GST using a peak GH cutoff of < 3 ng/mL or < 1 ng/mL promises to be useful for screening for GHD in adults and late adolescents with PWS. However, in those weighing > 90 kg, the < 1 ng/mL cutoff seems better. Larger studies are necessary to establish definitive glucagon doses and cutoffs, especially in extremely obese patients.

Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as programmed death-1 inhibitors (anti-PD1), have become a cornerstone for the treatment of different advanced cancers. These antibodies act as modulators of immune checkpoint proteins. However, ICI can lead to the breaking of immune self-tolerance, inducing autoimmune side effects (irAEs), including endocrinopathies. One of the most frequent endocrine irAE of anti-PD1 is thyroid dysfunction, but the exact mechanism of this disease still remains unknown. MATERIALS AND METHODS: We conducted a descriptive retrospective study, analyzing 11 patients who received at least one dose of anti-PD1 (nivolumab or pembrolizumab) and presented thyroid irAEs. Data were collected between September 2015 and May 2018 in our hospital. The aim was to analyze the clinically relevant features of thyroid irAEs and the frequency of antithyroid antibodies (ATA) positivity observed on them. RESULTS AND DISCUSSION: 8 of the 11 patients were treated with nivolumab and the other three patients received pembrolizumab. Six patients presented silent thyroiditis with a thyrotoxicosis phase; three patients developed directly primary/subclinical hypothyroidism and two patients showed primary hyperthyroidism. Thyroid autoantibodies (anti-Thyroglobulin and anti-Thyroid Peroxidase) were assessed in all the 11 patients, and only in two of them (18%) a positive titer was displayed. Anti-TSH receptor antibodies (TRAbs) were examined in five patients, three with painless thyroiditis at the time of thyrotoxicosis and two with primary hyperthyroidism, and they all had undetectable levels. CONCLUSIONS: In our sample of 11 Caucasian patients with thyroid dysfunction related with anti-PD1, we found low frequency of ATA positive titers, comparable to other recent reports in others ethnicities, which could suggest that silent thyroiditis due to pembrolizumab or nivolumab has a different pathogenesis from the classical autoimmune spontaneous thyroiditis. Further investigations are required to completely understand the immune mechanisms involved.

Controversias del tratamiento con hormona de crecimiento en pacientes con síndrome de Prader-Willi / Controversies in growth hormone treatment in patients with Prader-Willi syndrome

Introducción: El tratamiento con hormona de crecimiento (GH) en pacientes con síndrome de Prader-Willi (SPW) está aprobado en Europa desde 2001. A diferencia de otras indicaciones de la GH, su uso no solo está enfocado a incrementar la talla final, sino también a mejorar la composición corporal, la fuerza muscular y la capacidad cognitiva. Sin embargo, sigue habiendo dudas sobre los beneficios reales del tratamiento y sus potenciales efectos adversos. Este hecho limita en parte el uso de la GH, y dificulta que se beneficien de manera sistemática todos los pacientes susceptibles de ser tratados. Material y métodos: Se ha realizado una revisión de la literatura en Pubmed introduciendo "Prader-Willi" y "hormona de crecimiento" como palabras clave, en inglés y castellano, sin límite de fecha de publicación. Resultados: Se discuten los condicionantes que tradicionalmente han limitado el uso de la terapéutica con GH, y se actualizan ciertos aspectos controvertidos, como la edad de inicio del tratamiento y su prolongación en la edad de transición y la edad adulta. Conclusiones: El tratamiento con GH es seguro y eficaz en pacientes con SPW. La GH produce una mejora en el crecimiento, pero también aporta beneficios importantes en la composición corporal, el perfil metabólico y la función cognitiva. El inicio del tratamiento debería ser lo más precoz posible, preferiblemente antes del año de edad

Introduction: Treatment with growth hormone (GH) in patients with Prader Willi syndrome (PWS) has been approved in Europe since 2001. Unlike other GH indications, its use is not only focused on increasing final height, but also on improving body composition, muscular strength and cognitive capacity. However, there are still uncertainties regarding the real benefits of the treatment and its potential adverse effects. This partly limits the use of GH and prevents that every potential candidate systematically benefits from the treatment. Material and methods: A review of the literature was performed in Pubmed using «Prader Willi» and "growth hormone" as key words, in both English and Spanish, with no publication date limit. Results: Main conditioning factors that have traditionally limited the use of GH therapy are discussed and controversial aspects, such as age at treatment start and its continuation at the transition and adult age, are reviewed and updated. Conclusions: GH therapy is safe and effective in patients with PWS. GH not only improves linear growth but also provides significant benefits in body composition, metabolic profile and cognitive function. The onset of treatment should be as early as possible, preferably before one year of age

Fasting plasma peptide YY concentrations are increased in patients with major depression who associate weight loss.

BACKGROUND: Many patients with major depression refer a decreased appetite and weight loss among their symptoms. Peptide YY (PYY) and ghrelin belong to the family of peptides of the gut-brain axis implicated in the regulation of appetite and energy metabolism. PYY stimulates a powerful central satiety response and ghrelin increases food intake and weight gain. Brain-derived neurotrophic factor (BDNF) also contributes to the central control of food intake as an anorexigenic factor. AIM: To study fasting plasma total and acylated ghrelin, plasma PYY and serum BDNF levels in patients with major depression with weight loss as one of their symptoms and compare them with matched healthy controls. SUBJECTS AND METHODS: Fifteen adult patients, 9 male and 6 female, with recent diagnosis of major depression, and 16 healthy adult subjects, matched by age and anthropometric parameters were studied. All depressed patients referred weight loss and were not under antidepressant therapy. Fasting total PYY, total ghrelin and acylated ghrelin and BDNF were determined. RESULTS: Fasting total PYY was higher in patients than controls (2.01±0.09 vs 1.29±0.16 pmol/l). There were no differences in fasting total ghrelin, acylated ghrelin or BDNF levels. CONCLUSIONS: Major depressed patients, with weight loss at diagnosis, showed higher fasting plasma PYY levels that could contribute to their reduced appetite.

Insulin resistance, low-grade inflammation and type 1 diabetes mellitus.

To assess the relationships between insulin resistance and low-grade inflammation in subjects with type 1 diabetes mellitus (T1DM) who do not have clinical macrovascular complications. A total of 120 subjects diagnosed with T1DM 14 years before were evaluated for the following: (1) sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) microvascular complications; (3) plasma concentrations of soluble fractions of tumour necrosis factor-α receptors type 1 and 2, interleukin-6, adiponectin, leptin and high-sensitivity C-reactive protein (hs-CRP); and (4) insulin resistance (estimation of the glucose disposal rate-eGDR). Those subjects with an eGDR below the median of the same sex group were classified as insulin resistant and the others as insulin sensitive. Insulin-resistant men, compared to the insulin-sensitive, had higher WHR (0.89 ± 0.08 vs. 0.83 ± 0.05; P < 0.01), higher systolic [121 (118-125) vs. 114 (108-120) mmHg; P = 0.01] and diastolic [73 (66-80) vs. 67 (70-73) mmHg; P = 0.02] blood pressures, higher HbA1c values [8.7 (8.1-9.9) vs. 7.5 (7.2-8.0) %; P < 0.01] and higher hs-CRP concentrations [1.16 (0.61-3.20) vs. 0.49 (0.31-0.82) mg/dl; P = 0.01], but no other significant differences between groups were found. Insulin-resistant women had higher WHR and HbA1c values, compared to the insulin-sensitive, but they did not have any other differences. In men, hs-CRP correlated significantly with WHR and HbA1c (r = 0.363; P = 0.016 and r = 0.317; P = 0.036, respectively), after adjusting for age, alcohol intake, smoking and microvascular complications. Insulin-resistant men with T1DM have an increase in plasma concentrations of hs-CRP. Central obesity and HbA1c are its main determinants.

Plasma visfatin concentrations increase in both hyper and hypothyroid subjects after normalization of thyroid function and are not related to insulin resistance, anthropometric or inflammatory parameters.

OBJECTIVE: The objective of this study was to evaluate plasma visfatin levels in thyroid dysfunction and its relationship with inflammatory, anthropometric and insulin resistance parameters. DESIGN AND PATIENTS: Twenty-four hyperthyroid and 27 hypothyroid patients were studied before and after treatment. Forty-five euthyroid subjects were used as control group. MEASUREMENTS: Fasting plasma visfatin, IL-6, C reactive protein, adiponectin, thyroid hormones, waist-to-hip ratio, BMI, percentage of body fat and homeostasis model insulin resistance index (HOMA-IR) were measured. RESULTS: Hyperthyroid patients showed increased insulin resistance, IL-6 and visfatin levels compared with controls (3.21 +/- 3.0 vs. 1.67 +/- 0.75, P = 0.022; 3.35 +/- 0.41 vs. 2.10 +/- 0.25 pg/ml, P = 0.016; and 37.4 +/- 5.81 vs. 23.79 +/- 4.2 ng/ml, P = 0.061 respectively). After normalization of thyroid function, IL-6 levels and HOMA-IR decreased (2.35 +/- 0.37 vs. 2.10 +/- 0.25 pg/ml, P = 0.045 and 3.21 +/- 0.60 vs. 2.28 +/- 0.38, P = 0.032 respectively), while body weight, adiposity and visfatin levels increased (26.1 +/- 1.2 vs. 26.7 +/- 1.2 kg/m(2), P = 0.049; 30.9 +/- 1.6 vs. 32.2 +/- 1.6%, P = 0.007; and 37.4 +/- 5.81 vs. 63.13 +/- 8.72 ng/ml, P = 0.047 respectively). C reactive protein and adiponectin levels were similar to those of the control group. Hypothyroid patients showed high visfatin levels (40.59 +/- 3.07 vs. 29.34 +/- 4.9 ng/ml, P = 0.049) that increased after treatment (81.4 +/- 9.2 ng/ml, P = 0.001) without changes in anthropometric or insulin resistance parameters. C reactive protein, IL-6 and adiponectin levels were similar to those of the control group. No correlations between visfatin and any analysed parameter were found in either hyper- or hypothyroidism. CONCLUSION: Visfatin exhibits a marked increase after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that visfatin may play a role in the hormone stabilization process independent of anthropometric, inflammatory or insulin resistance variables.

Adult subjects with Prader-Willi syndrome show more low-grade systemic inflammation than matched obese subjects.

AIM: Adult subjects with Prader-Willi syndrome (PWS) may show several conditions that are associated with an activation of innate immunity such as obesity, deficient GH secretion or hypogonadism. Our aim was to study whether obese adult PWS subjects show an additional low-grade systemic inflammation (LGSI) in relation to obese adult non-PWS subjects and lean healthy control subjects before and after a standardized liquid meal. METHODS: Seven obese adult PWS subjects, 7 matched obese non-PWS subjects and 7 lean healthy control subjects were studied for 6 h from the administration of a standard liquid meal. RESULTS: Compared to non-PWS, PWS subjects showed higher plasma concentrations of C-reactive protein (CRP) (p=0.030), complement component C3 (p=0.018), interleukin(IL)-18 (p=0.048), and IL-6 (p=0.041) that persisted post-prandially elevated for CRP (p<0.0001), C3 (p=0.015), and IL-18 (p=0.003). Tumor necrosis factor(TNF)-alpha did not differ between the 3 groups. These results were independent from IGF-I levels, homeostasis model assessment index, and body mass index (BMI). In male subjects with PWS, testosterone levels correlated to IL-18 (r=-0,646, p=0.041). CONCLUSIONS: Compared to matched non-PWS subjects, the obese PWS subjects in this study showed an additional LGSI that persisted postprandially and was independent from BMI, insulin resistance, and deficient GH secretion. However, in PWS males, high IL-18 levels were related to low testosterone concentrations.

Lower heart rate variability is associated with higher plasma concentrations of IL-6 in type 1 diabetes.

OBJECTIVE: In type 1 diabetes, cardiovascular autonomic neuropathy (CAN) is associated with cardiovascular risk factors related to insulin resistance, which in turn are associated with low-grade systemic inflammation. Reduced heart rate variability (HRV) is considered one of the first indicators of CAN. Since the autonomic nervous system interacts with systemic inflammation, we evaluated CAN to study its possible association with low-grade systemic inflammation. DESIGN: Cross-sectional study of a group of 120 subjects diagnosed with type 1 diabetes mellitus 14 years before. METHODS: Information recorded: 1) clinical characteristics: sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure (BP), smoking, alcohol intake, insulin dose, HbA1c, and lipid profile; 2) plasma levels of soluble fractions of tumour necrosis factor alpha receptors 1 and 2, IL-6, and C-reactive protein; 3) insulin resistance by estimation of the glucose disposal rate (eGDR); and 4) tests for CAN: HRV in response to deep breathing (E/I ratio), HRV in response to the Valsalva maneuver, and changes in systolic BP responding to standing. RESULTS: A significant negative correlation was found between E/I ratio and plasma concentrations of IL-6 (r=-0.244, P=0.032), which remained significant after adjusting for potential confounding factors (age, sex, HbA1c, WHR, diastolic BP, triglycerides, HDL-cholesterol, retinopathy, nephropathy, peripheral neuropathy, insulin dose, and smoking; r=-0.231, P=0.039). No other significant associations were found between inflammation-related proteins, tests for CAN, and eGDR. CONCLUSIONS: These findings suggest a link between low-grade inflammation and early alterations of CAN in type 1 diabetes and may be of importance in the pathogenesis of CAN and/or its clinical implications.

The tumour necrosis factor (TNF)-alpha system is activated in accordance with pulse pressure in normotensive subjects with type 1 diabetes mellitus.

OBJECTIVE: Pulse pressure (PP) and inflammation are important predictors of cardiovascular disease (CVD), even in the normotensive. The age-related increase in PP can be diagnosed up to 20 years earlier in subjects with type 1 diabetes mellitus (T1DM) than in the general population. Some evidence suggests that PP can stimulate inflammation. Our aim was to study the relationship between PP and plasma inflammatory proteins in normotensive subjects with T1DM. DESIGN: This was a cross-sectional study of a group of normotensive (<140/80 mmHg) subjects diagnosed with T1DM 14 years before. None of them had clinically proven CVD or inflammatory conditions or were on antiplatelet, antihypertensive, anti-inflammatory or lipid-lowering treatment. METHODS: The following information was recorded: sex, age, body-mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), PP, mean blood pressure (MBP), smoking, alcohol intake, insulin dose, lipid profile, HbA1c, microvascular complications, and plasma concentrations of soluble receptor types 1 and 2 of tumour necrosis factor (TNF)-alpha (sTNFR1 and sTNFR2, respectively), interleukin-6, C-reactive protein, adiponectin and leptin. RESULTS: A total of 112 subjects were evaluated (aged 27.4+/-6.6 years, 52.7% women, BMI: 20.4+/-2.7 kg/m2, WHR: 0.82+/-0.09, SBP: 112+/-12 mmHg, DBP: 68+/-9 mmHg, PP: 45+/-9 mmHg, MBP: 82+/-9 mmHg, HbA1c: 8.2% (7.3-9.0%), 41.1% microvascular complications). After adjusting for potential confounders, only inflammatory markers of the TNF-alpha system correlated significantly with PP (Pearson correlation coefficient between sTNFR1 and PP: r = 0.215, P = 0.030; and between PP and sTNFR2: r = 0.238, P = 0.020). CONCLUSION: In normotensive subjects with T1DM after 14 years of diagnosis, the activation of the TNF-alpha system is positively associated with PP levels. This finding might suggest a pathogenic role of the TNF-alpha system in the development of cardiovascular disease in T1DM.

Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus.

OBJECTIVE: The development of diabetic neuropathy (DN) is predicted by cardiovascular risk factors associated with insulin resistance. As inflammation seems to be implicated in the pathogenesis of insulin resistance, we investigated whether subjects with type 1 diabetes mellitus (T1DM) and DN have an increase in plasma concentrations of inflammatory proteins involved in insulin resistance. DESIGN: Cross-sectional. Patients One hundred twenty subjects, all diagnosed with T1DM 14 years before. MEASUREMENTS: (1) Sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) DN (peripheral and cardiac autonomic), retinopathy and nephropathy; (3) plasma concentrations of soluble fractions of tumour necrosis factor alpha receptors 1 and 2 (sTNFR1 and sTNFR2), interleukin-6, high-sensitive C-reactive protein, adiponectin and leptin; and (4) insulin resistance (by way of a mathematical estimation of the glucose disposal rate - eGDR-). RESULTS: Thirty-six subjects had DN and 84 did not. Subjects with DN received higher insulin doses (57.6 +/- 16.7 vs. 49.2 +/- 15.0 IU/day; P = 0.008) and had higher WHR (0.85 +/- 0.07 vs. 0.81 +/- 0.10; P = 0.007) and HbA1c values (8.5 (7.6-9.6) vs. 7.7 (7.3-8.9)%; P = 0.049) than subjects without DN. They also had higher values of sTNFR1 (2.42 +/- 0.60 vs. 1.96 +/- 0.66 microg/l; P = 0.001) and sTNFR2 (4.73 +/- 1.33 vs. 4.14 +/- 1.09 microg/l; P = 0.015), and were more insulin resistant (eGDR values: 7.28 (5.83-8.03) vs. 8.30 (7.17-9.03) mg kg(-1) min(-1); P = 0.003). The relationship between DN and either sTNFR1 or sTNFR2 remained essentially unchanged after adjusting for several confounders, including glycaemic control, WHR, lipid profile, blood pressure and other microvascular complications (OR for sTNFR1: 2.592 (1.222-5.498), P = 0.013; OR for sTNFR2: 2.124 (1.258-3.587), P = 0.005). CONCLUSIONS: The activity of the TNF-alpha system is increased in subjects with type 1 diabetes mellitus and diabetic neuropathy, regardless of their glycaemic control and cardiovascular risk factors associated with insulin resistance. These results suggest that TNF-alpha may play a pathogenic role in the development of diabetic neuropathy.

Dissemination of 'patient-oriented evidence that matters' on the Internet: the case of Type 2 diabetes treatment.

AIMS: To evaluate the dissemination of patient-oriented evidence that matters (POEMs) derived from the UK Prospective Diabetes Study (UKPDS) through health information websites. METHODS: Google and Altavista search engines were used to generate a list of websites about Type 2 diabetes treatments. We evaluated a random sample of 50 websites from each list, plus the first 10 websites displayed on each search engine looking for the presence of POEMs about diabetes treatment derived from the UKPDS. Websites were also ranked using the DISCERN instrument. RESULTS: The final sample consisted of 66 websites. The most frequently stated item was that tight blood pressure decreased complications and/or mortality (55.5%). The effects of metformin on morbidity and/or mortality in overweight patients and the greater effect of control of blood pressure rather than blood glucose control on complications were stated in 18.2 and 16.7% of cases, whereas the lack of effect of tight blood glucose control on premature mortality and of insulin or sulphonylureas on aggregate micro- or macrovascular outcomes in overweight patients were stated in one case each (1.5%). The lack of effect of tight blood glucose control on quality of life was not stated in any website. POEMs were more frequently present in websites rated high with the DISCERN instrument, websites with the Health-on-the-Net seal and non-commercial websites. CONCLUSIONS: The dissemination of POEMs through the Internet is poor. If patients are to be involved in decision-making processes, efforts should be made to update the Internet contents to meet this challenge.