The Journal of Clinical Endocrinology & Metabolism

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ISSN / EISSN : 0021-972X / 1945-7197
Published by: The Endocrine Society (10.1210)
Total articles ≅ 48,913
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Xi Chen,
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab728

Abstract:
Roy et al (1) analyzed plasma glucagon levels in relation to insulin sensitivity in Asian Indians with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) and found that their observations are mostly consistent with the results seen in Mexican Americans, particularly in the fasting state (2). Since underlying metabolic abnormalities in pathogenesis of type 2 diabetes mellitus (T2DM) in different populations should be similar, one should not expect to see major differences in results across different ethnicities.
Ayan Roy, Sadishkumar Kamalanathan, JayaPrakash Sahoo
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab727

Abstract:
We read the article titled “Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-cell Function” by Chen and colleagues (1) with great interest. The study has evaluated the relationship of glucagon suppression with insulin resistance and beta-cell function assessed by oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp studies in obese normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2DM) Hispanic population. It demonstrated a progressive increase in both fasting and 2-hour plasma glucagon levels during OGTT, which had a positive correlation with the severity of insulin...
Pavel Hruska, Jan Kucera, Matej Pekar, Pavol Holeczy, Miloslav Mazur, Marek Buzga, Daniela Kuruczova, Peter Lenart, Jana Fialova Kucerova, David Potesil, et al.
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab756

Abstract:
Objective Adipose tissue distribution is a key factor influencing metabolic health and risk in obesity-associated comorbidities. Here we aim to compare the proteomic profiles of mature adipocytes from different depots. Methods Abdominal subcutaneous (SA) and omental visceral adipocytes (VA) were isolated from paired AT biopsies obtained during bariatric surgery of 19 severely obese women (BMI > 30 kg/m 2) and analysed using state-of-the-art mass spectrometry. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to investigate proteome signature properties and to examine a possible association of the protein expression with the clinical data. Results We identified 3,686 protein groups and found 1,140 differentially expressed proteins (adj. p-value < 0.05), of which 576 proteins were upregulated in SA and 564 in VA samples. We provide a global protein profile of abdominal SA and omental VA, present the most differentially expressed pathways and processes distinguishing SA from VA, and correlate them with clinical and body composition data. We show that SA are significantly more active in processes linked to vesicular transport and secretion, and to increased lipid metabolism activity. Conversely, the expression of proteins involved in the mitochondrial energy metabolism and translational or biosynthetic activity is higher in VA. Conclusion Our analysis represents a valuable resource of protein expression profiles in abdominal SA and omental VA, highlighting key differences in their role in obesity.
Tae Hoon Kim, , , Jeffrey L Deaton, David P Schammel, Wilder Alberto Palomino A., ,
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab753

Abstract:
Context Progesterone resistance, a known pathologic condition associated with a reduced cellular response to progesterone and heightened estrogen responses, appears to have a normal physiologic role in mammalian reproduction. The molecular mechanism responsible for progesterone resistance in normal and abnormal endometrium remains unclear. Objective To examine the roles of Sirtuin-1 (SIRT1) in normal endometrium as well as endometrium associated with infertility and endometriosis, as an epigenetic modulator associated with progesterone resistance. Methods SIRT1 expression was examined by Western blot, RT-qPCR and immunohistochemistry in mouse uterus and human endometrium. Mice with uterine specific Sirt1 overexpression were developed to examine SIRT1’s role in endometrial function and endometriosis development. EX-527, a SIRT1 inhibitor, and SRT1720, a SIRT1 agonist, were also used to evaluate SIRT1 effect on endometriosis. Results In normal healthy women, endometrial SIRT1 is expressed only during menses. SIRT1 was dramatically overexpressed in the endometrium from women with endometriosis in both the epithelium and strom. In mice, SIRT1 is expressed at the time of implantation between day 4.5 and 5.5 of pregnancy. Overexpression of SIRT1 (Sirt1 over) in the mouse uterus leads to subfertility due to implantation failure and decidualization defects and progesterone resistance. SIRT1 overexpression in endometriotic lesion promotes worsening endometriosis development. EX-527 (SIRT1 inhibitor) significantly reduced the number of endometriotic lesions in the mouse endometriosis model. Conclusions SIRT1 expression and progesterone resistance appears to play -roles in normal endometrial functions. Aberrant SIRT1 expression contributes to progesterone resistance and may participate in the pathophysiology of endometriosis. SIRT1 is a novel and targetable protein for the diagnosis as well as treatment of endometriosis and the associated infertility seen in this disease.
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab730

Abstract:
In the above-named article by Kelly A, Sheikh S, Stefanovski D, Peleckis AJ, Nyirjesy SC, Eiel JN, Sidhaye A, Localio R, Gallop R, De Leon DD, Hadjiliadis D, Rubenstein RC, and Rickels MR (J Clin Endo Metab. 2021; 106(9): 2617–2634; doi: 10.1210/clinem/dgab365), an error appeared in Figure 7 of the published paper:
, , Patricia Y Fechner, Maria G Vogiatzi, Erik A Imel, Shanlee M Davis, Nagdeep Giri, Julia Sturgeon, Eiry Roberts, Jean L Chan, et al.
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab749

Abstract:
Context Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective To evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Design Open-label, phase 2 study, with sequential cohort design (NCT03525886). Setting United States (6 centers). Participants Men and women, 18-50 years, with 21OHD. Interventions Four crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg oncedaily at bedtime (Cohorts 1 and 2, respectively); 100 mg once-daily in the evening (Cohort 3); 100 mg twice-daily (BID, Cohort 4). Participants could enroll in >1 cohort. Main Outcomes Changes from baseline to Day 14 in adrenocorticotropic hormone (ACTH), 17hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eighteen participants (11 women, 7 men) were enrolled: Cohort 1 (n=8), Cohort 2 (n=7), Cohort 3 (n=8), Cohort 4 (n=8). Mean age was 31 years; 94% were white. Median percent reductions were >60% for ACTH (-66%), 17OHP (64%), and androstenedione (64%) with crinecerfont 100 mg BID. In female participants, 73% (8/11) had ≥50% reduction in testosterone levels; male participants had median 26-65% decreases in androstenedione/testosterone ratios. Conclusions Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical endpoints of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab733

Abstract:
In the above-named article by Itoh H, Kaneko H, Okada A, Yano Y, Morita K, Seki H, Kiriyama H, Kamon T, Fujiu K, Matsuoka S, Nakamura S, Michihata N, Jo T, Takeda N, Morita H, Nishiyama A, Node K, Yasunaga H, and Komuro I (J Clin Endo Metab. 2021; doi: 10.1210/clinem/dgab466), the following errors appeared within the published the text owing to a coding error of the statistical team during data analysis:
Ashley J Han, Elena V Varlamov,
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab748

Abstract:
Context Characterization of the clinical features and natural history of non-functioning pituitary microadenomas (NFPmA) is limited by heterogenous and small-scale studies. Objective To characterize the clinical presentation and natural history of NFPmA and evaluate if imaging follow-up interval can be extended. Methods Retrospective single-center cohort study (years 2006-2021) of conservatively managed patients with NFPmA. Initial symptoms, pituitary function, and tumor size were assessed. A change in NFPmA size ≥ 2mm, as determined by pituitary or brain magnetic resonance imaging (MRI), was considered significant. Results There were 347 patients in the study cohort. Headache (78.4%) and fatigue (70.0%) were commonly reported despite no evidence of mass effect or significant pituitary hypofunction. Pituitary deficiencies at baseline were rare, with hypogonadism being most common (5.1%). During a median imaging follow-up period of 29 months (range 3-154), 8.1% of NFPmA grew. Growth incidence was 2.1 per 100 person-years with a mean and median time to growth of 38.1(SD± 36.4) and 24.5 (IQR12.0-70.8) months, respectively. Tumor growth was mild and not associated with new pituitary deficiencies or visual deficits. Conclusions These data indicate that the natural history of NFPmA is overall benign. Consequently, we propose that the initial MRI follow-up timeline for NFPmA can be extended up to 3 years unless a lesion is close to the optic chiasm, there are worrisome mass effect symptoms, or new pituitary deficiencies.
Natalia Genere, Ravinder Jeet Kaur, , Melinda A Thomas, Todd Nippoldt, Molly Van Norman, Ravinder Singh, Stefan Grebe,
The Journal of Clinical Endocrinology & Metabolism; https://doi.org/10.1210/clinem/dgab724

Abstract:
Context Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding Objective We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders, and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic work up. Design and Setting Cross-sectional study conducted in a tertiary medical center Participants Adult volunteers without adrenal disorders (n=168; 47 women on oral contraceptive therapy (OCP), 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n=196; 16 women on OCP) Measurements Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). Main Outcome Measures Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. Results Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared to post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95%CI 81.7-91.7); all false positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false positive results (21.1% vs 4.9%, p=0.02). Conclusions Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.
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