Proteomic Alterations of HDL in Youth with Type 1 Diabetes and their Associations with Glycemic Control: A Case-Control Study

Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition. Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification. Results: Samples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P \u3c 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P \u3c 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin. Conclusions: Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM. Trial registration NCT0227509

Effect of Metformin on the High-Density Lipoprotein Proteome in Youth with Type 1 Diabetes

Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown. Objective: To determine the effect of metformin on the HDL proteome. Subjects: Youth (12-20 years old) with T1D who had a BMI \u3e 90th percentile, HbA1c \u3e 8.0% and Tanner stage 5. Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined. Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%, p = .0058) and alpha-2-macroglobulin (A2MG; +29.8%, p = .049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC. Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions

Polycystic ovaries in adolescents and their relationship with adrenal hyperplasia

Context: Androgen excess may be adrenal and/or ovarian in origin; we hypothesized that a subgroup of patients with polycystic ovarian syndrome (PCOS) may have some degree of abnormal adrenocortical function.Objective: The objective of the study was to evaluate the pituitary adrenal axis with an oral low and high-dose dexamethasone-suppression test (Liddle’s test) in women with PCOS.Design: This was a case-control study.Setting: The study was conducted at the National Institutes of Health Clinical Center.Participants: A total of 38 women with PCOS and 20 healthy volunteers (HV) aged 16–29 years participated in the study.Main Outcome Measures: Urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS) before and after low- and high-dose dexamethasone and assessment of adrenal volume by computed tomography scan were measured.Results: Twenty-four hour urinary 17OHS and UFC were measured during day 1 to day 6 of the Liddle’s test. Baseline UFC levels were not different between PCOS and HVs; on the day after the completion of high-dose dexamethasone administration (d 6), UFC was higher in the PCOS group (2.0 +/- 0.7 μg/m2/d) than the HV group (1.5+/-0.5 μg/m2/d) (P=0.038). On day 5, 17OHS and UFC were negatively correlated with adrenal volumes (left side, rp=-0.47, P=0.009, and rp=-0.61, P=0.001, respectively). PCOS patients above the 75th percentile for UFC and/or 17OHS after high-dose dexamethasone (n =15) had a significantly smaller total adrenal volume (6.9+/- 1.9 cm3 vs 9.2+/- 1.8 cm3, P=0.003) when compared with the remaining PCOS patients (n= 22), but they did not have worse insulin resistance or hyperandrogenism.Conclusions: In a subset of young women with PCOS, we detected a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia: they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared with the group of PCOS with appropriate response to dexamethasone. (J Clin Endocrinol Metab 101: 3353–3360, 2016)Πλαίσιο: Η περίσσεια ανδρογόνων μπορεί να είναι από τα επινεφρίδια και / ή τις ωοθήκες. Υποθέσαμε ότι μια υποομάδα ασθενών με σύνδρομο πολυκυστικών ωοθηκών (PCOS) μπορεί να έχει κάποιο βαθμό μη φυσιολογικής επινεφριδιακής λειτουργίας.Στόχος: Σκοπός της μελέτης ήταν να αξιολογηθεί ο άξονας επινεφριδίων υπόφυσης μετά από χορήγηση από του στόματος χαμηλής και υψηλής δοκιμασίας καταστολής δεξαμεθαζόνης (δοκιμασία Liddle) σε γυναίκες με PCOS. Η μελέτη διεξήχθη στο Κλινικό Κέντρο Εθνικών Ινστιτούτων Υγείας (ΝΙΗ, ΗΠΑ)Συμμετέχοντες: Συνολικά 38 γυναίκες με PCOS και 20 υγιείς εθελοντές (HV) ηλικίας 16-29 ετών συμμετείχαν στη μελέτη.Κύρια αποτελέσματα λήψης: Μετρήθηκαν κορτιζόλη ούρων 24ωρου (UFC) και 17-υδροξυστεροειδή ούρων 24ωρου (17OHS) πριν και μετά τη χορήγηση χαμηλής και υψηλής δόσης δεξαμεθαζόνης και έγινε εκτίμηση όγκου επινεφριδίων με υπολογιστική τομογραφία σάρωσης.Αποτελέσματα: Τα 17OHS και τα UFC μετρήθηκαν κατά τη διάρκεια της δοκιμασίας του Liddle από την ημέρα 1 έως την ημέρα 6. Η αρχική τιμή UFC δεν ήταν διαφορετική μεταξύ των PCOS και HVs .Μετά την ολοκλήρωση της υψηλής δόσης (ημέρα 6), τα UFC ήταν υψηλότερα στην ομάδα PCOS (2,0 0,7 μg /m2/d) από την ομάδα HV ομάδα (1,5 0,5 μg /m2/d) (P=0.038) . Ακόμη, την ημέρα 5, τα 17ΟHS και τα UFC συσχετίστηκαν αρνητικά με τον όγκο των επινεφριδίων (αριστερά πλευρά, rp=- 0,47, Ρ=0.009 και δεξιά πλευρά rp=-0,61, Ρ=0.001, αντιστοίχως). Ασθενείς με PCOS άνω του 75ου εκατοστημορίου για UFC και / ή 17OHS μετά από υψηλή δόση δεξαμεθαζόνης (n=15) είχαν σημαντικά μικρότερο ολικό επινεφριδιακό όγκο (6,9+/-1,9 cm3 έναντι 9,2+/- 1,8 cm3, Ρ=0.003) σε σύγκριση με τους υπόλοιπους ασθενείς με PCOS (n=22), αλλά δεν είχαν χειρότερη αντίσταση στην ινσουλίνη ή υπερανδρογονισμό.Συμπεράσματα: Σε μια υποομάδα νεαρών ασθενών με PCOS, έχει επισημανθεί ότι υπάρχει έκκριση υπερπαραγωγής γλυκοκορτικοειδών που μιμείται τον τύπο έκκρισης στεροειδών που παρουσιάζεται στους ασθενείς με μικροσωματιδιακή υπερπλασία επινεφριδίων :μικρότερα επινεφρίδια και υψηλότερη έκκριση στεροειδών ορμονών μετά από δεξαμεθαζόνη σε σύγκριση με την ομάδα των ασθενών με PCOS που έχουν κατάλληλη απάντηση στη δεξαμεθαζόνη. (J Clin Endocrinol Metab 101: 3353-3360,201

Πολυκυστικές ωοθήκες σε εφήβους και συσχέτιση με υπερπλασία επινεφριδίων

Πλαίσιο: Η περίσσεια ανδρογόνων μπορεί να είναι από τα επινεφρίδια και / ή τις ωοθήκες. Υποθέσαμε ότι μια υποομάδα ασθενών με σύνδρομο πολυκυστικών ωοθηκών (PCOS) μπορεί να έχει κάποιο βαθμό μη φυσιολογικής επινεφριδιακής λειτουργίας. Στόχος: Σκοπός της μελέτης ήταν να αξιολογηθεί ο άξονας επινεφριδίων υπόφυσης μετά από χορήγηση από του στόματος χαμηλής και υψηλής δοκιμασίας καταστολής δεξαμεθαζόνης (δοκιμασία Liddle) σε γυναίκες με PCOS. Η μελέτη διεξήχθη στο Κλινικό Κέντρο Εθνικών Ινστιτούτων Υγείας (ΝΙΗ, ΗΠΑ) Συμμετέχοντες: Συνολικά 38 γυναίκες με PCOS και 20 υγιείς εθελοντές (HV) ηλικίας 16-29 ετών συμμετείχαν στη μελέτη. Κύρια αποτελέσματα λήψης: Μετρήθηκαν κορτιζόλη ούρων 24ωρου (UFC) και 17-υδροξυστεροειδή ούρων 24 ωρου (17OHS) πριν και μετά τη χορήγηση χαμηλής και υψηλής δόσης δεξαμεθαζόνης και έγινε εκτίμηση όγκου επινεφριδίων με υπολογιστική τομογραφία σάρωσης. Αποτελέσματα: Τα 17OHS και τα UFC μετρήθηκαν κατά τη διάρκεια της δοκιμασίας του Liddle από την ημέρα 1 έως την ημέρα 6. Η αρχική τιμή UFC δεν ήταν διαφορετική μεταξύ των PCOS και HVs .Μετά την ολοκλήρωση της υψηλής δόσης (ημέρα 6), τα UFC ήταν υψηλότερα στην ομάδα PCOS (2,0 0,7 μg /m2/d) από την ομάδα HV ομάδα (1,5 0,5 μg /m2/d) (P=0.038) . Ακόμη, την ημέρα 5, τα 17ΟHS και τα UFC συσχετίστηκαν αρνητικά με τον όγκο των επινεφριδίων (αριστερά πλευρά, rp=- 0,47, Ρ=0.009 και δεξιά πλευρά rp=-0,61, Ρ=0.001, αντιστοίχως). Ασθενείς με PCOS άνω του 75ου εκατοστημορίου για UFC και / ή 17OHS μετά από υψηλή δόση δεξαμεθαζόνης (n=15) είχαν σημαντικά μικρότερο ολικό επινεφριδιακό όγκο (6,9 1,9 cm3 έναντι 9,2, 1,8 cm3, Ρ=0.003) σε σύγκριση με τους υπόλοιπους ασθενείς με PCOS (n=22), αλλά δεν είχαν χειρότερη αντίσταση στην ινσουλίνη ή υπερανδρογονισμό. Συμπεράσματα: Σε μια υποομάδα νεαρών ασθενών με PCOS, έχει επισημανθεί ότι υπάρχει έκκριση υπερπαραγωγής γλυκοκορτικοειδών που μιμείται τον τύπο έκκρισης στεροειδών που παρουσιάζεται στους ασθενείς με μικροσωματιδιακή υπερπλασία επινεφριδίων :μικρότερα επινεφρίδια και υψηλότερη έκκριση στεροειδών ορμονών μετά από δεξαμεθαζόνη σε σύγκριση με την ομάδα των ασθενών με PCOS που έχουν κατάλληλη απάντηση στη δεξαμεθαζόνη. (J Clin Endocrinol Metab 101: 3353-3360,2016Context: Androgen excess may be adrenal and/or ovarian in origin; we hypothesized that a subgroup of patients with polycystic ovarian syndrome (PCOS) may have some degree of abnormal adrenocortical function. Objective: The objective of the study was to evaluate the pituitary adrenal axis with an oral low and high-dose dexamethasone-suppression test (Liddle’s test) in women with PCOS. Design: This was a case-control study. Setting: The study was conducted at the National Institutes of Health Clinical Center. Participants: A total of 38 women with PCOS and 20 healthy volunteers (HV) aged 16–29 years participated in the study. Main Outcome Measures: Urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS) before and after low- and high-dose dexamethasone and assessment of adrenal volume by computed tomography scan were measured. Results: Twenty-four hour urinary 17OHS and UFC were measured during day 1 to day 6 of the Liddle’s test. Baseline UFC levels were not different between PCOS and HVs; on the day after the completion of high-dose dexamethasone administration (d 6), UFC was higher in the PCOS group (2.0 +/- 0.7 μg/m2/d) than the HV group (1.5+/-0.5 μg/m2/d) (P=0.038). On day 5, 17OHS and UFC were negatively correlated with adrenal volumes (left side, rp=-0.47, P=0.009, and rp=-0.61, P=0.001, respectively). PCOS patients above the 75th percentile for UFC and/or 17OHS after high-dose dexamethasone (n =15) had a significantly smaller total adrenal volume (6.9+/- 1.9 cm3 vs 9.2+/- 1.8 cm3, P=0.003) when compared with the remaining PCOS patients (n= 22), but they did not have worse insulin resistance or hyperandrogenism. Conclusions: In a subset of young women with PCOS, we detected a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia: they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared with the group of PCOS with appropriate response to dexamethasone. (J Clin Endocrinol Metab 101: 3353–3360, 2016

Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case–control study

Abstract Background Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition. Methods This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification. Results Samples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P < 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P < 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin. Conclusions Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM. Trial registration NCT0227509

Pharmacologic Weight Management in the Era of Adolescent Obesity

CONTEXT: Pediatric obesity is a serious health problem in the United States. While lifestyle modification therapy with dietary changes and increased physical activity are integral for the prevention and treatment of mild to moderate obesity in youth, only a modest effect on sustained weight reduction is observed in children and young adults with severe obesity. This underscores the need for additional evidence-based interventions for children and adolescents with severe obesity, including pharmacotherapy, before considering invasive procedures such as bariatric surgery. EVIDENCE ACQUISITION: This publication focuses on recent advances in pharmacotherapy of obesity with an emphasis on medications approved for common and rarer monogenic forms of pediatric obesity. EVIDENCE SYNTHESIS: We review medications currently available in the United States, both those approved for weight reduction in children and off-label medications that have a broad safety margin. CONCLUSION: It is intended that this review will provide guidance for practicing clinicians and will encourage future exploration for successful pharmacotherapy and other interventions for obesity in youth