Growth hormone, ghrelin and peptide YY secretion after oral glucose administration in healthy and obese women

[Abstract] The mechanism of the altered GH secretion in obesity is unclear. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Ghrelin is a peptide that displays strong growth hormone-releasing activity. Its physiological importance on GH regulation is unclear. Our aim was to study fasting GH concentrations and their response to OG administration in relation with ghrelin secretion in obese and healthy women, in order to elucidate the hypothetical participation of ghrelin on post-oral glucose GH secretion. 36 women were included in the study. After an overnight fast, 75 g of oral glucose was administered; glucose, insulin, ghrelin, and PYY1–36 were obtained at baseline and during 300 min. The area under the curve between 0 and 300 min (AUC) of GH μ/l·min) was lower in obese patients than in controls; 262.5±57.5 vs. 534.9±95.6, p=0.01, for obese and controls respectively. GH peak (μg/l) was lower in obese patients than in controls; 3.7±0.7 vs. 7.1±1.0, p=0.012, for obese and controls, respectively. The AUC of total ghrelin (pg/ml·min) was lower in obese patients than in controls; 233 032±12 641 vs. 333 697±29 877, p=0.004, for the obese patients and controls respectively. PYY1–36 was similar in obese and healthy women after OG. There were significant correlations between the different indices of post-oral glucose GH and ghrelin secretion. These data suggest that ghrelin is a physiological regulator of GH in the post-oral glucose state, and the decreased ghrelin secretion could be one of the mechanisms responsible for the altered GH secretion in obesity.Instituto de Salud Carlos III; PI051024Instituto de Salud Carlos III; PI070413Instituto de Salud Carlos III; PI10 / 00088Xunta de Galicia; PS07 / 12Xunta de Galicia; 05PXIC91605PNXunta de Galicia; INCITE08ENA916110E

MiR-19 family impairs adipogenesis by the downregulation of the PPARγ transcriptional network

[Abstract] microRNAs (miRNAs) are a class of small endogenous RNA that play pivotal roles in both the differentiation and function of adipocytes during the development of obesity. Despite this, only a few miRNA families have been identified as key players in adipogenesis. Here, we show the relevance of the miR-19 family, miR-19a and miR-19b, in lipid accumulation and the expansion of the adipose tissue in obesity. We observed that miR-19s were upregulated in the abdominal subcutaneous adipose tissue (aSAT) of human patients with morbid obesity, whereas after bariatric surgery, their expression was reduced. In vitro experiments identified miR-19a and b as crucial actors in adipogenesis and lipid accumulation. Overall, our results suggest a novel role of the miR-19 family in the regulatory networks underlying adipogenesis and, therefore, adipose tissue dysfunction.Instituto de Salud Carlos III; PI16/0088

Sexual dimorphism on growth hormone secretion after oral glucose administration

[Abstract] Sexual dimorphism of GH secretion is unclear in humans. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Our aim was to study fasting GH concentrations and their response to OG administration in obese and healthy women and men, in order to elucidate the mechanism of sexual dimorphism of GH secretion and the possible contribution of ghrelin. We selected 33 women and 11 men as obese and healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, ghrelin, and PYY1-36 were obtained at baseline and during 300 min. Fasting GH (μg/l) was higher in women than men; 1.3 ± 0.3 vs. 0.2 ± 0.1, p=0.009, for women and men, respectively. The area under the curve between 0 and 150 min (AUC) of GH (μg/l · min) was higher in women than men; 98.2 ± 25.9 vs. 41.5 ± 28.6, p=0.002, for women and men, respectively. The AUC of total ghrelin (pg/ml · min, mean ± SEM) between 0 and 150 min was borderline and significantly higher in women than men; 128 562.3 ± 8 335.9 vs. 98 839.1 ± 7 668.6, p=0.069, for women and men, respectively. Several initial time points were higher in women than men. Glucose, insulin, and PYY1-36 were similar in women and men after OG. There were significant correlations between indices of post-oral glucose GH and ghrelin secretion. Fasting and initial GH secretion is higher in women than men, in contrast to peak and late GH secretion, which is similar in both cases. Sexual dimorphism in the regulation of GH secretion probably involves ghrelin.Instituto de Salud Carlos III; PI070413Instituto de Salud Carlos III; PI10/00088Xunta de Galicia; PS07/12Xunta de Galicia; INCITE08ENA916110ESXunta de Galicia; INCITE09E1R91634ESXunta de Galicia; IN845B-2010/187Xunta de Galicia; 10CSA916014P

Cost-effectiveness analysis of preoperative treatment of acromegaly with somatostatin analogue on surgical outcome

[Abstract] Context. There is no uniform standard of care for acromegaly. Due to the high costs involved, steps must be taken to ensure the cost-effective delivery of treatment. Objective. Taking the results of an earlier meta-analysis as a starting point, this study aims to determine whether treatment with long-acting somatostatin analogue (SSA) prior to surgery improves the cost-effectiveness of the treatment of acromegaly. Methods. The results are presented as an Incremental Cost Effectiveness Ratio (ICER) immediately after surgery, for the following year and over the next four decades. The cure rates percentage (95% CI) for the three randomized prospective controlled trials were 44.4% (34.2–54.7) and 18.2% (10.1–26.3) for preoperative treated and untreated patients respectively. The cost of pharmacological treatments was based on the number of units prescribed, dose and length of treatment. Results. The mean (95% CI) ICER immediately after surgery was €17,548 (12,007–33,250). In terms of the postoperative SSA treatment, the ICER changes from positive to negative before two years after surgery. One decade after surgery the ICER per patient/year was €− 9973 (− 18,798; − 6752) for postoperative SSA treatment and €− 31,733 (− 59,812; − 21,483) in the case of postoperative pegvisomant treatment. Conclusions. In centres without optimal surgical results, preoperative treatment of GH-secreting pituitary macroadenomas with SSA not only shows a significant improvement in the surgical results, but is also highly cost-effective, with an ICER per patient/year one decade after surgery, of between €− 9973 (− 18,798; − 6752) and €− 31,733 (− 59,812; − 21,483) for SSA and pegvisomant respectively.Instituto de Salud Carlos III; PI10/00088Instituto de Salud Carlos III; PI13/00322Xunta de Galicia; IN845B-2010/187Xunta de Galicia; 10CSA916014PRXunta de Galicia; CN2012/31

Oral glucose-stimulated growth hormone (GH) test in adult GH deficiency patients and controls: potential utility of a novel test

[Abstract] Context. The diagnosis of adult GH deficiency requires confirmation with a GH stimulation test. Oral glucose (OG) administration affects GH secretion, initially decreasing and subsequently stimulating GH secretion. Objective. The aim of this study was to investigate the diagnostic efficacy and safety of a long OG test (LOGT) as a stimulus of GH secretion for the diagnosis of adult GH deficiency (AGHD). Design. Prospective experimental cross-sectional study. Settings. The study was conducted at the Endocrinology department of the University Hospital of a Coruña, Spain. Participants and methods. We included 60 (40 women) AGHD patients (15) and controls (45) paired 1:3, of similar age, sex and BMI. The area under the curve (AUC) and peak were calculated for GH. The Mann-Whitney test was used to compare the different groups. ROC curve analyses were used. p-Values < 0.05 were considered as statistically significant. Interventions. The intervention consisted of orally administering 75 g oral glucose administration; GH was obtained every 30 min for a total of 300 min. Main outcome measurement. Peak GH area under receiver operating characteristic curve (ROC-AUC) following LOGT. Results. Peak GH (μg/L) levels were lower in the AGHD patients (0.26 ± 0.09) than in the controls (4.00 ± 0.45), p < 0.001. After LOGT, with the ROC plot analysis the best peak GH cut-point was 1.0 μg/L, with 100% sensitivity, 78% specificity, ROC-AUC of 0.9089 and 81.82% accuracy. There were no relevant adverse events during any of the LOGT. Conclusions. The LOGT could be a cheap, safe, convenient and effective test for the diagnosis of AGHD.Instituto de Salud Carlos III; PI13/00322Instituto de Salud Carlos III; PI16/00884Xunta de Galicia; 10CSA916014P

Evaluation of Thyroid Hormone Replacement Dosing in Morbidly Obese Hypothyroid Patients after Bariatric Surgery-Induced Weight Loss

[Abstract] The most frequent endocrine disease in obese patients is hypothyroidism. To date, there are no clear data regarding what happens to the dose of levothyroxine (LT4) after bariatric surgery (BS). The objective of the present study was to evaluate thyroid hormone replacement dose in morbidly obese hypothyroid patients after BS-induced weight loss. We explore the best type of measured or estimated body weight for LT4 dosing. We performed an observational study evaluating patients with morbid obesity and hypothyroidism who underwent BS. We included 48 patients (three men). In morbidly obese hypothyroid patients 12 months after BS-induced weight loss, the total LT4 dose or the LT4 dose/kg ideal body weight did not change, while there was a significant increase in LT4 dose/body surface area, LT4 dose/kg weight, LT4 dose/kg adjusted body weight, LT4 dose/kg body fat, and LT4 dose/kg lean body weight. There were no differences in LT4 dose and its variation between sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). The present study strongly suggests that LT4 dosing in obese hypothyroid patients can be individually adapted more precisely if it is based on ideal body weight.The results of this work have been funded by the Project Nº PI16/00884 to F.C. and S.S-A.; integrated in the National Plan for Scientific Research, Development and Technological Innovation 2013–2016, Spain and funded by the ISCIII (Instituto de Salud Carlos III)-General Subdirection of Assessment and Promotion of the Research–European Regional Development Fund (FEDER) “A way of making Europe

Altered GH-IGF-1 Axis in Severe Obese Subjects is Reversed after Bariatric Surgery-Induced Weight Loss and Related with Low-Grade Chronic Inflammation

[Abstract] Endocrine disorders are common in obesity, including altered somatotropic axis. Obesity is characterized by reduced growth hormone (GH) secretion, although the insulin-like growth factor-1 (IGF-1) values are controversial. The aim of this study was to evaluate the effect of weight loss after bariatric surgery in the GH–IGF-1 axis in extreme obesity, in order to investigate IGF-1 values and the mechanism responsible for the alteration of the GH–IGF-1 axis in obesity. We performed an interventional trial in morbidly obese patients who underwent bariatric surgery. We included 116 patients (97 women) and 41 controls (30 women). The primary endpoint was circulating GH and IGF-1 values. Circulating IGF-1 values were lower in the obese patients than in the controls. Circulating GH and IGF-1 values increased significantly over time after surgery. Post-surgery changes in IGF-1 and GH values were significantly negatively correlated with changes in C-reactive protein (CRP) and free T4 values. After adjusting for preoperative body mass index (BMI), free T4 and CRP in a multivariate model, only CRP was independently associated with IGF-1 values in the follow-up. In summary, severe obesity is characterized by a functional hyposomatotropism at central and peripheral level that is progressively reversible with weight loss, and low-grade chronic inflammation could be the principal mediator.Instituto de Salud Carlos III; PI13/00322Instituto de Salud Carlos III; PI16/0088

PYY1-36 and PYY3-36 secretory response after a mixed meal in healthy individuals

[Resumen] Introducción. El péptido YY (PYY) tiene 36 aminoácidos y lo sintetizan fundamentalmente las células L del intestino. El PYY aumenta tras las comidas y alcanza su nadir tras el ayuno. Tras la ingestión se liberan dos formas: PYY1-36 y PYY3-36. Se ha demostrado que el PYY3-36 reduce la ingesta en humanos y roedores. Hay poca información sobre los valores plasmáticos de PYY, especialmente de PYY3-36, en respuesta a la ingestión y su relación con la respuesta de ghrelina. Objetivos. Estudiar la respuesta secretora de PYY1-36 y PYY3-36 en sujetos normales tras ingerir una comida mixta y su relación con la secreción de ghrelina total y acilada. Sujetos y métodos. Estudiamos a 8 sujetos sanos, 4 mujeres y 4 varones, con una mediana de edad de 53 (intervalo, 36-59) años. Tras el ayuno nocturno, recibieron en 2 días diferentes y de forma aleatoria: una comida oral mixta estándar, que consistía en 400 ml de Isosource Energy (159 kcal/100 ml) o placebo por vía oral (400 ml de agua). Se obtuvieron muestras sanguíneas en los tiempos 0, 30, 45, 60 y 120 min para la determinación de PYY1-36, PYY3-36, ghrelina total y ghrelina acilada. Las comparaciones se realizaron mediante la prueba de Wilcoxon. Las correlaciones numéricas se analizaron mediante la prueba de correlación de Spearman. Se consideró significativo un valor de p ≤ 0,05. Resultados. Tras ingerir la comida, se produce un máximo de PYY1-36 (mediana [intervalo]) de 141,5 (81-198) pg/ml y no hay respuesta tras placebo, con un máximo de 92,5 (46-219) pg/ml (p = 0,04). Los valores del área bajo la curva (ABC) de PYY1-36 tras la ingesta fueron 14.865 (8.032-19.822) pg/ml/min y tras placebo, 8.992 (4.455- 21.382) pg/ml/min (p = 0,06). Tras ingerir la comida se produce un máximo de PYY3-36 de 92,5 (59-135) pg/ml y no hay respuesta tras placebo, con un máximo de 46,5 (30- 66) pg/ml (p = 0,02). Los valores del ABC de PYY3-36 tras la ingesta fueron 9.086 (6.412-14.970) pg/ml/min y tras placebo, 4.984 (3.142-6.772) pg/ml/min (p = 0,012). El cociente nadir de ghrelina total/máximo de PYY1-36 disminuye de forma marcada tras la ingestión; los valores preprandiales son 7,44 (3,64-14,56) y los posprandiales, 3,55 (1,64-7,16) (p = 0,03), mientras que no se modifica tras placebo. El cociente nadir de ghrelina acilada/máximo de PYY3-36 disminuye de forma marcada tras la ingestión, y los valores preprandiales son 2,03 (0,92-3) y los posprandiales, 0,73 (0,26-1,27) (p = 0,02), mientras que no se modifican tras placebo. Conclusiones. En sujetos normales, PYY1-36 y PYY3-36 aumentan de forma paralela tras ingerir una comida mixta; simultáneamente, los valores de ghrelina total y acilada disminuyen. El cociente entre el nadir de ghrelina acilada y el máximo de PYY3-36 disminuye tras ingerir una comida mixta. Este conjunto de datos indica su posible participación en la regulación aguda del apetito tras la comida.[Abstract] Background. Peptide YY (PYY) is a 36 amino acid peptide synthesized mostly by intestinal L cells. This peptide reaches its nadir during fasting and increases immediately after meals. After food intake, two molecular forms are released, PYY1-36 and PYY3-36. PYY3-36 reduces food intake in both humans and rodents. There is scarce information about plasmatic concentrations of PYY, especially of PYY3-36, after food ingestion, and their relationship to ghrelin. Objectives. To study PYY1-36 and PYY3-36 secretory response after a mixed meal, and its relationship to total and acylated ghrelin secretion in healthy subjects. Subjects and method. We studied eight healthy subjects, 4 women and 4 men, with a median age of 53 (range, 36-59) years. After an overnight fast, the subjects received either a mixed standard meal (400 ml Isosource Energy® [159 kcal/100 ml]) or placebo (400 ml of water) orally in random order on two different days. Blood samples were obtained at 0, 30, 45, 60 and 120 min for measurement of PYY1-36, PYY3-36, total ghrelin and acylated ghrelin. Comparisons were made by Wilcoxon's test. Numerical correlations were performed using Spearman's test. P-values ≤ 0.05 were considered significant. Results. After a mixed meal, PYY1-36 reached a peak of (median [range]) 141.5 (81-198) pg/ml. There was no response to placebo, with a peak of 92.5 (46-219) pg/ml (p = 0.04). The area under the curve (AUC) of PYY1-36 levels after a mixed meal were 14,865 (8,032-19,822) pg/ml/min and after placebo were 8,992 (4,455-21,382) pg/ml/min (p = 0.06). After ingestion of a mixed meal, PYY3-36 reached a peak of 92.5 (59-135) pg/ml, with no response to placebo (46.5 [30-66] pg/ml) (p = 0.02). The AUC of PYY3-36 levels after a mixed meal were 9,086 (6,412-14,970) pg/ml/min, and after placebo were 4,984 (3,142-6,772) pg/ml/min (p = 0.012). The quotient between nadir total ghrelin/peak PYY1-36 was markedly diminished after food ingestion, with preprandial values of 7.44 (3.64-14.56) and postprandial values of 3.55 (1.64-7.16) (p = 0.03). The former quotient was unmodified by placebo. The quotient between nadir acylated ghrelin/peak PYY3-36 was markedly diminished after ingestion of a mixed meal, with preprandial values of 2.03 (0.92-3) and postprandial values of 0.73 (0.26-1.27) (p = 0.02). This quotient was unmodified by placebo. Conclusions. In healthy subjects, blood levels of both PYY1-36 and PYY3-36 increase after ingestion of a mixed meal. Simultaneously, total and acylated ghrelin levels diminish. The quotient between nadir acylated ghrelin/peak PYY3-36 diminishes after a mixed meal. All these data suggest the possible contribution of these peptides to appetite regulation after ingestion.Instituto de Salud Carlos III, PI051024Instituto de Salud Carlos III, PI070413Xunta de Galicia, PGIDT05PXIC91605PNXunta de Galicia, PS07/1

Central Resistance to Thyroid Hormones in Morbidly Obese Subjects is Reversed after Bariatric Surgery-Induced Weight Loss

[Abstract] Endocrine abnormalities are common in obesity, including altered thyroid function. The altered thyroid function of obesity may be due to a mild acquired resistance to the thyroid hormone. The aim of this study was to investigate the effect of weight loss after bariatric surgery (BS) on resistance to thyroid hormones in patients with extreme obesity compared with a control group. We performed an observational study evaluating patients with extreme obesity who underwent BS. We included 106 patients (83 women) and 38 controls (24 women). The primary endpoint was the thyrotroph thyroxine resistance index (TT4RI) and thyroid stimulating hormone (TSH) index (TSHRI). The parameters were studied before and after surgery. TSHRI and TT4RI were higher in the obese patients than in the control group. TT4RI and TSHI decreased significantly over time after surgery, with this decrease being associated with the excessive body mass index (BMI) loss and C-reactive protein (CRP). In extreme obesity, BS promotes a significant decrease in the increased TT4RI and TSHI. This decrease of TT4RI and TSHI is progressive over time after BS and significantly associated with excess BMI lost and CRP. Extreme obesity is characterized by a mild reversible central resistance to thyroid hormones.Instituto de Salud Carlos III; PI13/00322Instituto de Salud Carlos III; PI16/0088

Metabolic recovery after weight loss surgery is reflected in serum microRNAs.

Funder: Ministerio de Educación, Cultura y Deporte - SpainFunder: Fondation Leducq; FundRef: http://dx.doi.org/10.13039/501100001674Funder: Marie Skłodowska-Curie Innovative Training Network TRAIN-HEARTFunder: National Institute of Health ResearchINTRODUCTION: Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue. RESEARCH DESIGN AND METHODS: We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up. RESULTS: Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction. CONCLUSIONS: Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients