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Diabetic cardiomyopathy (DCM) is a serious complication of type 2 diabetes mellitus (T2DM) that contributes to cardiovascular morbidity and mortality. However, the metabolic alterations and specific biomarkers associated with DCM in T2DM remain unclear. In this study, we conducted a comprehensive metabolomic analysis using liquid chromatography–mass spectrometry (LC-MS) to investigate the plasma metabolite profiles of T2DM patients with and without DCM. We identified significant differences in metabolite levels between the groups, highlighting the dysregulation of various metabolic pathways, including starch and sucrose metabolism, steroid hormone biosynthesis, tryptophan metabolism, purine metabolism, and pyrimidine metabolism. Although several metabolites showed altered abundance in DCM, they also shared characteristics of DCM and T2DM rather than specific to DCM. Additionally, through biomarker analyses, we identified potential biomarkers for DCM, such as cytidine triphosphate, 11-ketoetiocholanolone, saccharopine, nervonic acid, and erucic acid. These biomarkers demonstrated distinct patterns and associations with metabolic pathways related to DCM. Our findings provide insights into the metabolic changes associated with DCM in T2DM patients and highlight potential biomarkers for further validation and clinical application. Further research is needed to elucidate the underlying mechanisms and validate the diagnostic and prognostic value of these biomarkers in larger cohorts.
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Faculty of Life Sciences and Medicine, School of Life Course Sciences, King’s College London, London, UK
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Quebec Heart and Lung Institute, Laval University, Quebec, Canada
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Barts and the London School of Medicine, Centre for Endocrinology, William Harvey Institute, London, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
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Obesity, Type 2 Diabetes and Immunometabolism Research Group, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Course Sciences, King’s College London, London, UK
Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK
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Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression.
Aim
The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort.
Methods
Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI.
Results
Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1–133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: −19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups.
Conclusion
Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.
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The aim of the study was to investigate the changes in serum glypican 4 (GPC4) and clusterin (CLU) levels in patients with polycystic ovary syndrome (PCOS) as well as their correlation with sex hormones and metabolic parameters. A total of 40 PCOS patients and 40 age-matched healthy women were selected. Serum GPC4 and CLU levels were compared between the PCOS and control groups, and binary logistic regression was used to analyze the relative risk of PCOS at different tertiles of serum GPC4 and CLU concentrations. Stepwise linear regression was used to identify the factors influencing serum GPC4 and CLU levels in PCOS patients. Serum GPC4 (1.82 ± 0.49 vs 1.30 ± 0.61 ng/mL, P < 0.001) and CLU (468.79 ± 92.85 vs 228.59 ± 82.42 µg/mL, P < 0.001) were significantly higher in PCOS patients than in healthy women after adjustment for body mass index (BMI). In the PCOS group, serum GPC4 was positively correlated with follicle-stimulating hormone, fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), triglyceride, and CLU (P < 0.05), whereas serum CLU was positively correlated with BMI, FPG, FINS, and HOMA-IR (P < 0.05). Multiple stepwise linear regression analysis showed that HOMA-IR was independently associated with serum GPC4, and BMI and HOMA-IR were independently associated with CLU (P < 0.05). Serum GPC4 and CLU levels were significantly higher in PCOS patients than in healthy women, suggesting that GPC4 and CLU may be markers associated with insulin resistance in women with PCOS.
Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
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Servicio de Endocrinología y Nutrición. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, España
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, España
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Servicio de Endocrinología y Nutrición. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, España
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Servicio de Endocrinología y Nutrición. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, España
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Servicio de Endocrinología y Nutrición. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, España
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Introduction
Hypoaldosteronism is characterized by hyperkalemia, and/or hypovolemic hyponatremia (HH), often accompanied by metabolic acidosis. HH is typical of hypoaldosteronism, whereas euvolemic hyponatremia (EH) is not. The purpose of the current study is to describe the characteristics of hyponatremia in hypoaldosteronism and elucidate whether EH can be considered part of the disease’s spectrum.
Methods
In a hypoaldosteronism cohort, we analyzed the factors associated with hyponatremia, comparing the characteristics of EH and HH and their associated factors. Correlation analyses of mineralocorticoid biomarkers, such as the transtubular potassium gradient (TTKG), the urinary Na+/K+ ratio (UNa+/UK+) with serum, and urinary electrolytes were performed in both types of hyponatremia.
Results
Of 112 hypoaldosteronism episodes, 77.7% were ≥65 years old, 44.6% were women, and 80 (71.4%) had hyponatremia. Hyponatremia was negatively associated with the presence of chronic kidney disease, and positively with a hypovolemic state, malnutrition, a prior history of hyponatremia, and glucocorticoid therapy. HH: 61/80 and EH: 19/80 episodes. HH was associated with an age ≥65 years and the use of diuretics, as well as factors related to an aldosterone deficit and/or mineralocorticoid resistance. In HH but not in EH, urinary potassium was correlated with the TTKG, and urinary sodium with both the TTKG and the UNa+/UK+.
Conclusion
Both HH and EH can be observed in hypoaldosteronism. However, only the former would be related to insufficient mineralocorticoid activity.
Significance statement
Isolated hypoaldosteronism is a poorly understood and underdiagnosed endocrinological disorder, classically recognized only when hyperkalemia is present. The development of hypovolemic hyponatremia, however, is also easily explained by the physiopathology of the disorder. The current study addresses the features of hyponatremia when found in the context of mineralocorticoid insufficiency, and confirms an association between hypovolemic hyponatremia and isolated hypoaldosteronism. Thus, the clinical spectrum of hypoaldosteronism is extended to include hypovolemic hyponatremia as a frequent manifestation of the disorder.
Search for other papers by Mireille N M van Poppel in
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Pancreas agenesis is a rare condition underlying a variant of permanent neonatal diabetes mellitus. Neonates with this condition are born small for gestational age, but less is known about which components of growth are impacted, the timing of the growth restriction and potential sex differences. Our objective was to assess in which periods in gestation complete pancreas agenesis restricts fetal growth and possible sex differences in susceptibility. Published cases (n = 49) with pancreas agenesis providing relevant data (gestational age, fetal sex, birth weight, birth length, head circumference, placental weight) were identified by MEDLINE and secondary literature search covering the years 1950–January 2023. Semiquantitative analysis of these case reports used centiles based on Intergrowth-21 reference charts. Neonates with pancreas agenesis were severely growth restricted; however, median centiles for birth weight, birth length, and head circumference of those born before week 36 were significantly higher compared to those born from 36 weeks. Similar results were found when data were separated by before and from 38 weeks. Head circumference was less affected than birth weight or birth length. No sex differences were found. In conclusion, pancreas agenesis severely restricts fetal length and head circumference in addition to weight growth, with stronger effects evident from 36 weeks of gestation. In addition to the well-known effects of insulin on growth of fetal fat mass, the pronounced effect on birth length and head circumference indicates effects of insulin on fetal lean body growth as well. Lack of power may account for failure to find sex differences.
Significance statement
Neonates with complete pancreas agenesis are born small, but the details of their growth deviation, timing, and potential sex differences remain uncertain. All neonates with pancreas agenesis in our study had reduced birth weight, length, and head circumference, with milder effects in those born before 36 weeks compared to after 36 weeks. This trend persisted when data were separated into before and after 38 weeks, with no discernible sex differences. The absence of the pancreas, and therefore insulin, significantly reduces fetal growth, especially after 36 weeks of gestation. In addition to insulin’s known role in fetal fat mass, our findings suggest it has a substantial influence on birth length and head circumference, underscoring its impact on fetal lean body growth.
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Hypothyroidism is a relatively common finding during pregnancy. This may be due either to the presence of existing thyroid disease and/or to the increased demands that pregnancy places the thyroid gland to provide thyroid hormones for the mother and the developing fetus. There is no doubt that overt hypothyroidism is associated strongly with adverse pregnancy outcomes, including miscarriage. Meta-analyses show that thyroid hormone replacement with levothyroxine (LT4) reduces the risk of adverse pregnancy outcomes in the setting of overt hypothyroidism. Accordingly, management guidelines in this area are unanimous in recommending intervention with to control the level of thyrotropin (TSH) to below 2.5 μIU/mL. The evidence for an adverse impact of subclinical hypothyroidism (SCH) on pregnancy outcomes is less clear, although meta-analyses suggest that SCH reduces the chance of a successful pregnancy outcome. Guidelines also support intervention for some patients with SCH, particularly where TSH is high (>10 μIU/mL), or where TSH is above its trimester-specific reference range in a woman with thyroid autoimmunity (giving LT4 to euthyroid women with thyroid autoimmunity is not supported). Real-world evidence suggests that hypothyroidism in pregnancy is often overlooked or that LT4 is not given appropriately to gain tight control of TSH. More research is needed to identify the barriers to optimal thyroid care with LT4 at this crucial time.
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Objectives
It has not been established whether vitamin D deficiency is associated with anthropometric state; therefore, this systematic review examined the relationship between serum vitamin D levels with anthropometrics and adiposity across different ages.
Methods
Studies that examined vitamin D deficiency with adiposity measures in different age groups were searched in the PubMed, Scopus, Embase, and Google Scholar databases until November 2023. Two investigators independently reviewed titles and abstracts, examined full-text articles, extracted data, and rated the quality in accordance with the Newcastle–Ottawa criteria.
Results
Seventy-two studies, with a total of 59,430 subjects, were included. Of these studies, 27 cross-sectional studies and one longitudinal study (with 25,615 participants) evaluated the possible link between 25(OH)D serum concentrations and anthropometric/adiposity indices in the pediatric population. Forty-two cross-sectional studies and two cohort investigations (with 33,815 participants) investigated the relationship between serum 25(OH)D levels and adiposity measures in adults and/or the elderly population. There is evidence supporting links between vitamin D deficiency and obesity, and revealed an inverse association between vitamin D and adiposity indicators, specifically in female subjects. However, the effects of several confounding factors should also be considered.
Conclusion
Most published studies, most of which were cross-sectional, reported a negative association between vitamin D and female adiposity indicators. Therefore, serum vitamin D levels should be monitored in overweight/obese individuals.
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Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Objective
The associations between adrenal histopathology, lateralization studies, and surgical outcomes in primary aldosteronism remain poorly characterized. We examined the value of immunohistochemical analysis of CYP11B2 for evaluation of adrenalectomy outcomes after anatomical versus functional subtyping.
Design
A retrospective multicenter study of 277 patients operated for primary aldosteronism who had an adrenalectomy sample available in the Finnish biobanks from 1 January 2000 to 31 December 2019. Adrenal slides from biobanks were analyzed centrally after CYP11B2 and CYP11B1 staining. Clinical data were obtained from patient registries. Histopathological diagnosis and cure after surgery were assessed as outcome measures.
Results
Re-evaluation with CYP11B2 staining changed the histopathological diagnosis in 91 patients (33%). The presence of a CYP11B2-positive adenoma and the use of functional subtyping independently predicted clinical cure of primary aldosteronism. CYP11B2-positive <7 mm nodules were more frequent in patients without clinical cure, whereas CYP11B2-positive micronodules were common in all patients and had no impact on adrenalectomy outcomes. Small CYP11B2-positive nodules and micronodules were equally prevalent regardless of the subtyping method applied. Clinical cure rates were lower and CYP11B2-negative adenomas more common after adrenalectomy based on anatomical imaging than functional studies.
Conclusions
Incorporating CYP11B2 staining in histopathological diagnosis enhances the prediction of surgical outcomes in primary aldosteronism. A finding of CYP11B2-positive adenoma is indicative of cure of primary aldosteronism, whereas smaller CYP11B2-positive nodules associate with poorer results at postoperative evaluation. Functional subtyping methods decrease the operations of CYP11B2-negative adenomas and are superior to anatomical imaging in identifying unilateral primary aldosteronism.
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Xiamen Key Laboratory for Clinical Efficacy and Evidence-Based Research of Traditional Chinese Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Fujian Province Key Laboratory of Diabetes Translational Medicine, The First Affiliated Hospital of Xiamen University, School of medicine, Xiamen University, Xiamen, China
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Objective
The aim of this study was to compare the differences in incident population, comorbidities, and glucose-lowering drug prescriptions between newly diagnosed patients with early-onset type 2 diabetes mellitus (T2DM) and those with late-onset T2DM to provide real-world evidence for clinical practice.
Methods
This study was based on the Shanghai Hospital Link Database (SHLD). Anonymized electronic medical record (EHR) data from 2013 to 2021 were included in this study. Newly diagnosed patients with T2DM were defined as those without related diagnostic records or glucose-lowering medicine prescriptions in the past 3 years. Early-onset T2DM was defined as patients who were aged 18–40 years old at the first visit for T2DM to represent those who were born after the 1980s. And late-onset T2DM was defined as those aged 65–80 years old to represent those who were born in a relatively undeveloped period. Descriptive statistical analyses were performed to describe their incidence number, glucose-lowering drug prescriptions, and comorbidities at the first visit to the hospital between two T2DM groups.
Results
There were a total of 35,457 newly diagnosed patients with early-onset T2DM and 149,108 newly diagnosed patients with late-onset T2DM included in this study. Patients with late-onset T2DM constituted the majority and their number increased by 2.5% on average by years, while the number of patients with early-onset T2DM remained stable each year. Compared with late-onset T2DM patients, more early-onset T2DM patients had dyslipidemia at the first visit to hospitals (9.5% vs 7.7%, P < 0.01) despite their significant age differences. Patients with early-onset T2DM were more likely to use metformin (74.8% vs 46.5, P < 0.01), dipeptidyl peptidase-4 inhibitors (DDP-4i) (16.7% vs 11.2%, P < 0.01), thiazolidinediones (TZD) (14.9% vs 8.4%, P < 0.01), sodium glucose cotransporter 2 inhibitors (SGLT2-i) (0.8% vs 0.3%, P < 0.01), and glucagon-like peptide 1 receptor agonists (GLP-1 RA) (3.7% vs 0.5%, P < 0.01) at their first visit to the hospital.
Conclusions
Different characteristics were observed between patients with early-onset T2DM and those with late-onset T2DM. Compared with patients with late-onset T2DM, those with early-onset T2DM were more prone to dyslipidemia and had novel organ-protective drugs prescribed.
Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
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Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
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Department of Geriatrics, Aalborg University Hospital, Aalborg, Denmark
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Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
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Endometriosis and polycystic ovary syndrome (PCOS) are common gynecological disorders that constitute a significant burden of disease in women of fertile age. The disorders share a link to female reproduction and infertility; however, divergent effects on menstrual cycle, related hormones, and body composition have been proposed. Disorders of the thyroid gland including abnormal thyroid dysfunction (hyperthyroidism or hypothyroidism) and/or markers of thyroid autoimmunity similarly show a female predominance and onset in younger age groups. We reviewed the literature on the association between endometriosis, PCOS, and thyroid disease up until July 1, 2023, and identified 8 original studies on endometriosis and thyroid disease and 30 original studies on PCOS and thyroid disease. The studies were observational and heterogeneous regarding the design, sample size, and definitions of exposure and outcome; however, a tendency was seen toward an association between hyperthyroidism and endometriosis. Especially an association between endometriosis and slightly elevated levels of thyroid-stimulating hormone receptor antibodies has been found and corroborated in studies from different populations. On the other hand, the literature review turned a focus toward an association between hypothyroidism and PCOS, however, with uncertainties as to whether the association is caused by hypothyroidism per se and/or the thyroid autoantibodies (thyroid peroxidase and thyroglobulin antibodies). More evidence is needed to substantiate an association between endometriosis, PCOS, and thyroid disease, and to differentiate between the role of thyroid function and thyroid autoimmunity. Furthermore, studies are warranted to extend knowledge on the different disease characteristics and underlying mechanisms.
