Mild autonomous cortisol secretion (MACS) is the most frequent form of cortisol excess in patients with adrenal incidentalomas. Although it lacks the classical phenotype of overt Cushing’s syndrome, MACS is increasingly recognized as a clinically relevant condition associated with multisystem complications rather than a benign biochemical finding. This narrative review summarizes current evidence on the pathophysiology, clinical manifestations, diagnostic limitations, and management of MACS, with particular focus on cardiometabolic, skeletal, muscular, neuropsychiatric, frailty-related, reproductive, and emerging microbiome-related consequences. Chronic exposure to low-grade cortisol excess is being recognized as a factor associated with hypertension, disorders of glucose metabolism, dyslipidemia, increased cardiovascular risk, metabolic dysfunction-associated steatotic liver disease, skeletal fragility, impaired muscle function, frailty, sleep and circadian disturbances, cognitive and mood alterations, hypogonadism, and possible changes in gut microbiota. The 1 mg overnight dexamethasone suppression test remains the cornerstone of diagnosis, but its interpretation is limited by assay variability, medication interference, comorbidities, and imperfect reflection of long-term tissue glucocorticoid exposure. Emerging approaches, including steroid profiling, hair cortisol/cortisone, salivary cortisone, inflammatory indices, metabolomic tools, and exploratory biomarkers related to microbial metabolites, may improve risk stratification in the future but remain investigational. Management should be individualized. Adrenalectomy may benefit selected patients with unilateral disease and clinically relevant cortisol-related comorbidities, whereas evidence supporting pharmacological therapy remains limited. MACS should be regarded as a heterogeneous multisystem condition requiring structured clinical assessment and individualized management. Prospective studies are needed to define clinically meaningful endpoints, refine diagnostic thresholds, and identify patients most likely to benefit from intervention.
Diminished ovarian reserve (DOR) is a major reproductive disorder characterised by accelerated follicular depletion and impaired ovarian responsiveness, yet its molecular basis remains incompletely understood. This review integrates current evidence across the major biological processes that determine ovarian reserve and follicular competence. Primordial follicle activation governed by PI3K–AKT–FOXO3/PTEN–mTOR, Hippo–YAP, KIT/KITL and AMH signaling represents an upstream determinant of follicle-pool consumption, while bidirectional oocyte–granulosa cell communication and the stromal microenvironment sustain follicular development. Genomic instability, defective DNA repair, chromatin remodeling and epigenetic dysregulation further compromise cellular integrity and reproductive longevity. Mitochondrial bioenergetic failure, mtDNA instability, altered mitochondrial dynamics and oxidative stress form a central mechanistic hub linking metabolic dysfunction to follicular damage. Emerging evidence additionally highlights the autophagy–mitophagy–lysosome system, including stress-granule clearance and lysosomal proteostasis, as a context-dependent quality-control network rather than an intrinsically lethal pathway. Downstream cell-fate responses, particularly granulosa-cell apoptosis, cellular senescence and ferroptosis, together with immune–inflammatory and endocrine disturbances, further promote follicular attrition. Importantly, the strength of evidence varies substantially across mechanisms, with direct human DOR data available for only a subset of pathways and many proposed mechanisms remaining dependent on animal or cellular models. Clinically, AMH and antral follicle count remain the principal reserve markers, whereas molecular biomarkers and targeted interventions are largely investigational. By organizing these mechanisms into an integrated framework, this review identifies key evidence gaps and priorities for mechanistically informed biomarker development and therapeutic translation in DOR.
ObjectiveDiabetic kidney disease (DKD) is a common microvascular complication in patients with type 2 diabetes mellitus (T2DM), yet reliable biomarkers for disease assessment and effective risk stratification remain limited. Succinate is a signaling molecule implicated in kidney diseases. This study aimed to investigate the association between urinary succinate and kidney injury in patients with T2DM.MethodsCross-sectional study of 240 participants: healthy controls (n = 25), patients with non-DKD (n =40), and 175 patients with T2DM (85 without DKD and 90 with DKD). Urinary succinate levels were measured using a colorimetric assay kit.ResultsUrinary succinate levels were significantly elevated in patients with T2DM but not in patients with non-DKD, with the highest levels observed in patients with DKD. Urinary succinate correlated negatively with estimated glomerular filtration rate (eGFR) and positively with serum creatinine, urinary albumin-to-creatinine ratio (UACR), urinary N-acetyl-β-D-glucosaminidase (NAG), and urinary neutrophil gelatinase-associated lipocalin (NGAL) in patients with DKD, but only correlated with urinary NAG in patients with T2DM without DKD. In multivariable liner regression analysis, urinary succinate was found to be independently associated with eGFR in patients with DKD after adjustment for age, male sex, smoking history, hypertension, HbA1c > 7.0%, uric acid, UACR, and the use of renin-angiotensin system inhibitors (RASi) and sodium-glucose co-transporter 2 inhibitors (SGLT2i). Receiver operating characteristic (ROC) analysis for detecting eGFR < 60 mL/min/1.73m2 in DKD yielded an AUC of 0.70, with a sensitivity of 57.14% and a specificity of 75.00%.ConclusionUrinary succinate levels are elevated in patients with T2DM, particularly in DKD, but not increased in patients with non-DKD. Urinary succinate is independently associated with eGFR, and shows moderate diagnostic performance for renal insufficiency in DKD. These findings suggest that urinary succinate may serve as a potential non-invasive biomarker for diabetes-related kidney injury. Prospective studies are needed to evaluate its predictive value for early detection and disease progression of DKD.
BackgroundMaternal obesity is associated with adverse pregnancy outcomes and may influence fetal metabolic programming through alterations in the intrauterine environment. While leptin has been extensively investigated in pregnancies complicated by maternal obesity, the contribution of emerging adipokines, including neuregulin-4 (NRG4) and isthmin-1 (ISM1), to the fetal adipokine profile remains incompletely understood. This study aimed to characterize alterations in the umbilical cord blood adipokine profile associated with maternal obesity and to evaluate their relationship with early neonatal outcomes.Materials and methodsThis prospective exploratory cohort study was conducted at Balıkesir University Faculty of Medicine Hospital, Balıkesir, Türkiye, and included 82 term singleton pregnancies delivered by cesarean section between March and May 2026. Participants were classified as obese (first-trimester BMI ≥30 kg/m², n=40) or non-obese (BMI <30 kg/m², n=42). Maternal demographic and biochemical characteristics, together with neonatal clinical outcomes, were recorded. Umbilical cord blood leptin, NRG4, and ISM1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Between-group comparisons, partial correlation analysis, multivariate analysis of covariance (MANCOVA), and analysis of covariance (ANCOVA) were performed.ResultsMaternal glucose concentrations were significantly higher, whereas neonatal glucose concentrations were significantly lower, in the obese group (p = 0.009 and p < 0.001, respectively). Compared with the non-obese group, cord blood leptin and ISM1 concentrations were significantly increased, while NRG4 concentrations were significantly decreased (all p < 0.05). MANCOVA demonstrated a significant overall effect of maternal obesity on the adipokine profile, with leptin contributing most strongly to this association. Following adjustment, leptin remained independently associated with maternal obesity (ANCOVA: p < 0.001, η² = 0.28), whereas ISM1 and NRG4 were no longer independently significant. Partial correlation analysis demonstrated positive associations among the investigated adipokines, with the strongest correlation observed between ISM1 and NRG4 (r = 0.88, p < 0.001). No significant differences were observed between the groups regarding neonatal complications, Apgar scores, umbilical cord blood pH, lactate, bilirubin concentrations, or neonatal intensive care unit admission.ConclusionMaternal obesity was associated with an altered umbilical cord adipokine profile characterized by a robust increase in leptin together with coordinated alterations in emerging adipokines. Although these biochemical changes were not accompanied by differences in early neonatal outcomes, they may represent early metabolic adaptations to an obesogenic intrauterine environment. These findings support the potential role of cord blood adipokines as biomarkers of fetal metabolic programming and warrant confirmation in larger prospective longitudinal studies.
Hemichorea-hemiballism associated with ketotic hyperglycemia is a rare movement disorder. We report a case of right-sided hemichorea-hemiballism occurring in the setting of diabetic ketosis in a 70-year-old man with a 15-year history of poorly controlled type 2 diabetes mellitus. The patient presented with subacute involuntary choreiform movements of the right limbs, accompanied by foot pain, significant weight loss, and multiple diabetic complications. Intensive insulin therapy combined with short-term symptomatic treatment resulted in rapid resolution of ketonuria, stabilization of blood glucose, and marked improvement of the movement disorder. Notably, brain MRI showed no classic striatal T1 hyperintensity. At the 3-month follow-up, the patient remained free of choreiform movements. This case highlights that diabetic ketosis can trigger hemichorea-hemiballism in elderly patients even in the absence of typical imaging findings, and underscores the central role of prompt glycemic optimization
