Corticosteroid-binding globulin (CBG) is a serum glycoprotein that binds and delivers anti-inflammatory cortisol to inflammatory sites through neutrophil elastase-mediated proteolysis of an exposed reactive centre loop (RCL) on CBG. Timely and tissue-specific delivery of cortisol is critical to alleviate inflammation including in life-threatening septic shock conditions. Herein, we firstly summarise our recently published report of functional RCL O- and N-glycosylation events of serum CBG (Chernykh, J Biol Chem, 2023). A key finding of that published work was the LC-MS/MS-based discovery of RCL O-glycans at Thr342 and Thr345 of serum CBG and their inhibitory roles in neutrophil elastase-mediated RCL proteolysis. While these observations are of significance as they implicate RCL O-glycosylation as a potential regulator of cortisol delivery, the link to septic shock remains unexplored. To this end, we used a similar LC-MS/MS approach to profile the RCL O-glycosylation of CBG purified from serum of twelve septic shock patients. Serum CBG from all patients exhibited RCL O-glycosylation comprising (di)sialyl T (NeuAc1-2Gal1GalNAc1) core 1-type O-glycan structures decorating exclusively the Thr342 site. Importantly, relative to less severe cases, individuals presenting with the most severe illness displayed elevated RCL O-glycosylation upon ICU admission, suggesting a previously unknown link to septic shock severity. Overall, we have elucidated the coordinated RCL N- and O-glycosylation events of serum CBG, which improve our understanding of molecular mechanisms governing the timely and tissue-specific delivery of cortisol to inflammatory sites. This work provides clues to molecular aberrations and disease mechanisms underpinning septic shock.

Background: Corticosteroid-binding globulin (CBG) modulates tissue cortisol availability via modification of cortisol:CBG binding affinity in response to multiple factors, including neutrophil elastase (NE) cleavage of the reactive centre loop (RCL), converting high affinity CBG (haCBG) to low affinity CBG (laCBG). In vitro, glycosylation of the RCL at Asn347 affects NE cleavage susceptibility. To date, no direct measurement of laCBG, which would verify NE cleavage, has been reported. Objective: To measure serum laCBG in septic shock patients by mass spectrometry to confirm NE cleavage in vivo, with Asn347 site glycosylation profiling to determine its impact on NE cleavage, and determine effect of %laCBG on septic shock clinical outcome. Methods: Serum from septic shock patients from a tertiary hospital intensive care unit was analysed by mass spectrometry for CBG affinity forms and Asn347 glycosylation profile, following CBG immunoprecipitation. Data was correlated with septic shock clinical outcome. Results: N-terminal peptide of NE cleaved RCL (AVLQLNEEGVDTAGSTGV) was consistently detected in patient serum, although at low concentrations. Mean %laCBG/total CBG was 0.23 % in septic shock (range = 0.07-0.74 %, SD = 0.12 %); in comparison healthy controls mean %laCBG was 0.04 % (range 0.02-0.08 %, SD = 0.03 %). There was a negative correlation between %laCBG and serum concentrations of CBG with triantennary Asn347 glycans; TS3 (r =-0.190, p = 0.040) and TS3F (r =-0.252, p = 0.006). Conclusions: NE cleaved CBG (laCBG) is present in septic shock patient serum, and %laCBG correlates with Asn347 glycosylation occupancy and composition. However, serum %laCBG did not correlate with septic shock clinical outcome.

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Corticosteroid-binding globulin (CBG) is a 50–60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality.

Liver InternationalVolume 43, Issue 3 p. 740-741 LETTER TO THE EDITOR Plasma corticosteroid-binding globulin concentrations are preserved in mild cirrhosis Jessica H. Lee, Corresponding Author Jessica H. Lee [email protected] orcid.org/0000-0001-8643-1773 Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Correspondence Jessica H. Lee, Department of Medicine, University of Adelaide, Adelaide, SA, Australia. Email: [email protected]Search for more papers by this authorMarni A. Nenke, Marni A. Nenke Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia Diabetes and Endocrine Service, The Queen Elizabeth Hospital, Woodville South, South Australia, AustraliaSearch for more papers by this authorKaterina Flabouris, Katerina Flabouris Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Diabetes and Endocrine Service, The Queen Elizabeth Hospital, Woodville South, South Australia, AustraliaSearch for more papers by this authorDavid J. Torpy, David J. Torpy orcid.org/0000-0002-5069-0981 Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaSearch for more papers by this authorEmily J. Meyer, Emily J. Meyer Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia Diabetes and Endocrine Service, The Queen Elizabeth Hospital, Woodville South, South Australia, AustraliaSearch for more papers by this author Jessica H. Lee, Corresponding Author Jessica H. Lee [email protected] orcid.org/0000-0001-8643-1773 Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Correspondence Jessica H. Lee, Department of Medicine, University of Adelaide, Adelaide, SA, Australia. Email: [email protected]Search for more papers by this authorMarni A. Nenke, Marni A. Nenke Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia Diabetes and Endocrine Service, The Queen Elizabeth Hospital, Woodville South, South Australia, AustraliaSearch for more papers by this authorKaterina Flabouris, Katerina Flabouris Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Diabetes and Endocrine Service, The Queen Elizabeth Hospital, Woodville South, South Australia, AustraliaSearch for more papers by this authorDavid J. Torpy, David J. Torpy orcid.org/0000-0002-5069-0981 Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaSearch for more papers by this authorEmily J. Meyer, Emily J. Meyer Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia Diabetes and Endocrine Service, The Queen Elizabeth Hospital, Woodville South, South Australia, AustraliaSearch for more papers by this author First published: 23 January 2023 https://doi.org/10.1111/liv.15524Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume43, Issue3March 2023Pages 740-741 RelatedInformation

Adrenal insufficiency requires prompt diagnosis in pregnancy, as untreated, it can lead to serious consequences such as adrenal crisis, intrauterine growth restriction and even foetal demise. Similarities between symptoms of adrenal insufficiency and those of normal pregnancy can complicate diagnosis. Previously diagnosed adrenal insufficiency needs monitoring and, often, adjustment of adrenal hormone replacement. Many physiological changes occur to the hypothalamic–pituitary–adrenal (HPA) axis during pregnancy, often making diagnosis and management of adrenal insufficiency challenging. Pregnancy is a state of sustained physiologic hypercortisolaemia; there are multiple contributing factors including high plasma concentrations of placental derived corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH) and increased adrenal responsiveness to ACTH. Despite increased circulating concentrations of CRH-binding protein (CRH-BP) and the major cortisol binding protein, corticosteroid binding globulin (CBG), free concentrations of both hormones are increased progressively in pregnancy. In addition, pregnancy leads to activation of the renin–angiotensin–aldosterone system. Most adrenocortical hormone diagnostic thresholds are not applicable or validated in pregnancy. The management of adrenal insufficiency also needs to reflect the physiologic changes of pregnancy, often requiring increased doses of glucocorticoid and at times mineralocorticoid replacement, especially in the last trimester. In this review, we describe pregnancy induced changes in adrenal function, the diagnosis and management of adrenal insufficiency in pregnancy and areas requiring further research.

Aim To analyse data on diabetic ketoacidosis (DKA) admissions to better understand characteristics of those presenting with DKA and identify high-risk groups. Method Study population consisted of people with type 1 diabetes discharged from Middlemore Hospital between 01 July 2015 and 30 June 2016 with the diagnosis of DKA. Basic demographic data and socioeconomic status as defined by 2013 New Zealand deprivation index quintiles were obtained, in addition to the cause of DKA. Results There were 69 DKA admissions from 57 people; 35% were Pasifika and 23% Māori. Fifty-six percent were from quintile 5, the quintile with the lowest socioeconomic status. The most common cause of DKA was non-adherence to insulin (59%), followed by infection (16%) and new diagnosis of type 1 diabetes (14%). There was greater proportion of Pasifika and Māori population in those with non-adherence as the cause. Conclusion Non-adherence is a major cause of DKA admissions at Middlemore Hospital. When compared to the regional census data, there is over-representation of Pasifika and Māori population and those of lower socioeconomic status in those admitted with DKA. Similar pattern was seen in those with non-adherence as the cause of DKA and those with recurrent DKAs.

Introduction In people accepted onto a bariatric surgery program we compared diabetes-related outcomes in those who completed surgery with those who withdrew before having surgery—examining rates of insulin use in people with type 2 diabetes (T2D), and rates of incident diabetes in people without pre-existing T2D. Research design and methods 771 people were accepted onto the program. 463 people (60%) had T2D at referral, of which 48% completed surgery and 52% withdrew. Of 308 people without T2D at referral, 49% completed surgery, and 51% withdrew. Rates of insulin use and incident diabetes were compared by Kaplan-Meier analyses. Among those with pre-existing T2D, we examined rates of remission and relapse after surgery. Results People without T2D who withdrew from the program had higher mean body mass index and glycated hemoglobin levels than those completing surgery (p<0.005). The rate of incident diabetes at 5 years was 19% in those who withdrew versus 0% in those completing surgery (p<0.001). 30% of people with T2D were taking insulin at referral and all stopped insulin after surgery. During follow-up, the rate of insulin (re)introduction was lower in those who completed surgery (8% vs 26% at 5 years, p<0.001). Of those with T2D who completed surgery, 80% had remission, but 34% had relapsed by 5 years. Diabetes relapse was associated with less weight loss after surgery, a longer duration of T2D and previous insulin use. Conclusions Despite a high relapse rate, people with T2D who completed surgery had lower insulin use at 5 years than those withdrawing from the program. In people without T2D, bariatric surgery prevented incident diabetes. People without T2D who withdrew from the program were at greater risk of diabetes, suggesting those who could benefit the most in terms of T2D prevention are not completing bariatric surgery.

Camurati-Engelmann disease (OMIM 31300) is a rare cranio-tubular bone dysplasia characterized by osteosclerosis of the long bones and skull caused by dominantly-inherited mutations in the transforming growth factor beta 1 (TGFB1) gene. A wide variation in phenotype has been recognized, even within families carrying the same mutation. In addition, aspects of the natural history of the disorder, in particular whether it is always progressive or can remit spontaneously, remain uncertain. In a large kindred carrying a TGFB1 gene mutation (c.653G>A; p.R218H) we have attempted to clarify the extent of phenotypic variability and the natural history of the disease through detailed individual histories of symptoms, and skeletal imaging by both radiography and scintigraphy. Only one subject had the classical childhood onset with bone pain in the legs and gait disturbance. Eight subjects reported the onset of leg pain in their teenage years that, by their early 20s, had either resolved or persisted at a low level. Two of these eight later developed cranial nerve palsies. There was a wide variation in the radiographic appearance in adults, but disease extent and activity in long bones, as assessed by scintigraphy, was inversely correlated with age (p < 0.025). In younger subjects the radiographic and scintigraphic appearances were concordant, but in older subjects the scintigram could be quiescent despite florid radiographic changes. Sequential scintigrams in two subjects showed reduced activity in the later scan. One subject had suffered meningoencephalitis in early childhood that resulted in paresis of one arm. The affected arm showed markedly less disease involvement, implicating mechanical or growth factors in its etiology. Our data suggest that the natural history of Camurati-Engelmann disease can be benign, and that disease activity commonly attenuates in adulthood. Severe cases of childhood onset and/or with cranial nerve involvement, may occur only in a minority of mutation carriers. (c) 2019 American Society for Bone and Mineral Research.