Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.

The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in ß-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

A Critical View over the Newest Antidiabetic Molecules in Light of Efficacy-A Systematic Review and Meta-Analysis.

The increase in life expectancy without a decrease in the years lived without disability leads to the rise of the population aged over 65 years prone to polypharmacy. The novel antidiabetic drugs can improve this global therapeutic and health problem in patients with diabetes mellitus (DM). We aimed to establish the efficacy (A1c hemoglobin reduction) and safety of the newest antidiabetic drugs (considered so due to their novelty in medical practice use), specifically DPP-4i, SGLT-2i, GLP-1 Ra, and tirzepatide. The present meta-analysis followed the protocol registered at Prospero with the CRD42022330442 registration number. The reduction in HbA1c in the DPP4-i class for tenegliptin was 95% CI -0.54 [-1.1, 0.01], p = 0.06; in the SGLT2-iclass for ipragliflozin 95% CI -0.2 [-0.87, 0.47], p = 0.55; and for tofogliflozin 95% CI 3.13 [-12.02, 18.28], p = 0.69, while for tirzepatide it was 0.15, 95% CI [-0.50, 0.80] (p = 0.65). The guidelines for treatment in type 2 DM are provided from cardiovascular outcome trials that report mainly major adverse cardiovascular events and data about efficacy. The newest antidiabetic non-insulinic drugs are reported to be efficient in lowering HbA1c, but this effect depends between classes, molecules, or patients' age. The newest antidiabetic drugs are proven to be efficient molecules in terms of HbA1c decrease, weight reduction, and safety, but more studies are needed in order to characterize exactly their efficacy and safety profiles.

Timing Is Important-Management of Metabolic Syndrome According to the Circadian Rhythm.

Physiological processes occur in accordance with a rhythm regulated by the endogenous biological clock. This clock is programmed at the molecular level and synchronized with the daily light-dark cycle, as well as activities such as feeding, exercise, and social interactions. It consists of the core clock genes, Circadian Locomotor Output Cycles Protein Kaput (CLOCK) and Brain and Muscle Arnt-Like protein 1 (BMAL1), and their products, the period (PER) and cryptochrome (CRY) proteins, as well as an interlocked feedback loop which includes reverse-strand avian erythroblastic leukemia (ERBA) oncogene receptors (REV-ERBs) and retinoic acid-related orphan receptors (RORs). These genes are involved in the regulation of metabolic pathways and hormone release. Therefore, circadian rhythm disruption leads to development of metabolic syndrome (MetS). MetS refers to a cluster of risk factors (RFs), which are not only associated with the development of cardiovascular (CV) disease (CVD), but also with increased all-cause mortality. In this review, we consider the importance of the circadian rhythm in the regulation of metabolic processes, the significance of circadian misalignment in the pathogenesis of MetS, and the management of MetS in relation to the cellular molecular clock.

Non-alcoholic Fatty Liver Disease in Children.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the paediatric age. The growing prevalence of NAFLD and its advanced phenotype, non-alcoholic steatohepatitis (NASH), in children and adolescents parallels similar trends in obesity and type 2 diabetes mellitus. This trend may have serious long-term implications, including hepatic and extra-hepatic morbidity and mortality, the latter being related mostly due to cardiovascular disease and malignancies. This narrative review, which included 236 articles, summarizes current evidence on paediatric NAFLD, including pathophysiology, risk factors, complications, prevention and treatment (existing and emerging). Early recognition of NAFLD followed by timely and adequate management seems to be important on an individual basis. A global "call to action" regarding paediatric NAFLD seems appropriate to mitigate the burden of this disease.

Glucagon-Like Peptide-1 Receptor Agonists and Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity/Metabolic Syndrome, Prediabetes/Diabetes and Non-Alcoholic Fatty Liver Disease-Current Evidence.

The obesity pandemic is accompanied by increased risk of developing metabolic syndrome (MetS) and related conditions: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease (CVD). Lifestyle, as well as an imbalance of energy intake/expenditure, genetic predisposition, and epigenetics could lead to a dysmetabolic milieu, which is the cornerstone for the development of cardiometabolic complications. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs promote positive effects on most components of the "cardiometabolic continuum" and consequently help reduce the need for polypharmacy. In this review, we highlight the main pathophysiological mechanisms and risk factors (RFs), that could be controlled by GLP-1 and dual GIP/GLP-1 RAs independently or through synergism or differences in their mode of action. We also address the evidence on the use of GLP-1 and dual GIP/GLP-1 RAs in the treatment of obesity, MetS and its related conditions (prediabetes, T2DM and NAFLD/NASH). In conclusion, GLP-1 RAs have already been established for the treatment of T2DM, obesity and cardioprotection in T2DM patients, while dual GIP/GLP-1 RAs appear to have the potential to possibly surpass them for the same indications. However, their use in the prevention of T2DM and the treatment of complex cardiometabolic metabolic diseases, such as NAFLD/NASH or other metabolic disorders, would benefit from more evidence and a thorough clinical patient-centered approach. There is a need to identify those patients in whom the metabolic component predominates, and whether the benefits outweigh any potential harm.

Parathyroid hormone and calcitonin response during the calcium infusion test in patients with primary hyperparathyroidism.

OBJECTIVE: While activation of the calcium (Ca) sensing receptor (CaSR) suppresses parathyroid hormone (PTH) secretion, calcitonin (CT) secretion is stimulated via CaSR. The aim of this study was to evaluate PTH and CT responses during a calcium infusion test (CIT) in patients with primary hyperparathyroidism (PHPT). METHODS: This pivotal prospective study included 64 patients (44 PHPT patients vs. 20 healthy controls [HCs], median age 57 [25-79] vs. 56 [39-74] years). All PHPT patients underwent parathyroidectomy (PTX). A week before and 1 month after PTX, the CIT was performed (bolus infusion of Ca gluconate 0.2 ml/kg body weight), followed by plasma sampling for Ca2+, PTH, and CT at 0, 1, 2, 3, 5, 8, and 10 min. RESULTS: PTH suppression was lower in PHPT patients compared to HCs (49.82 vs. 64.06%, p = 0.006), but after PTX suppression, it was higher (76.3%, p < 0.001). PHPT patients had attenuated CT response vs. HCs during the CIT (3.1- vs. 8.0-fold increase, p < 0.001), but after PTX, it improved (5.8-fold increase). The PTHmin > 19.3 ng/l and CTmax ≤ 27.5 ng/l cut-off values predict diagnosis of PHPT (sensitivity 90.9%, 97.7%, and specificity 100%, 75%, respectively). Patients with adenoma had lower basal CT levels vs. hyperplasia both before and after PTX (4.5 vs. 6.8 and 5.4 vs. 7.9 ng/l, respectively, p = 0.008, p = 0.018). CONCLUSION: PTH and CT responses during the CIT in PHPT patients may be an additional diagnostic tool. The CIT could play a role in both the diagnosis of PHPT and in the differential diagnosis between adenoma and hyperplasia.

Primary hyperparathyroidism associated with acquired long QT interval and ventricular tachycardia.

SUMMARY: We present a 54-year-old patient admitted to the emergency department due to loss of consciousness. The initial ECG registered monomorphic ventricular extrasystoles and prolonged QT interval (QT corrected (QTc) >500 ms). Sustained ventricular tachycardia (VT) was registered on 24-h Holter ECG monitoring, which clinically was presented as a crisis of consciousness. Coronary angiography and other visualization methods were normal. Implantable cardioverter-defibrillator (ICD) implantation was planned for the purpose of secondary prevention of sudden cardiac death (SCD). Laboratory and hormonal analyzes revealed primary hyperparathyroidism (PHPT), chronic kidney disease, and hypokalemia. Neck ultrasound showed a 25 mm, sharply outlined homogenous tumor mass which was separated from thyroid gland (TG) and exerted a mild impression on lower parts of the left lobe. Dual wash technetium-99m sestamibi parathyroid scintigraphy with single-photon emission CT (SPECT)/CT also showed the uptake of tracer behind the lower half of the left lobe of the TG. Surgical treatment, lower left parathyroidectomy, was performed, and pathohistological analysis verified parathyroid adenoma. The patient was rhythmically and hemodynamically stable for 7 days after surgery, without additional complaints, and was discharged from the hospital. Timely diagnosis of PHPT, correct assessment and surgical treatment, did not lead our patient to unnecessary ICD implantation. Our case suggests an additional intertwining of electrolyte disorders and ventricular arrhythmias in PHPT and more importantly emphasizes the need for caution when indicating ICD, even in patients with the most serious life-threatening arrhythmias. LEARNING POINTS: Electrolyte abnormalities in PHPT can have highly malignant consequences, and the occurrence of hypokalemia in the presence of hypercalcemia is underestimated in PHPT, and the consequences can be life-threatening. Although hypercalcemia causes shortened QT interval, concomitant severe hypokalemia may overcome hypercalcemia and prolong QT interval, even in the absence of structural heart disease or LQTS. Timely diagnosis of PHPT, correct assessment and surgical treatment, do not lead to unnecessary ICD implantation.

Diagnosis and treatment of mediastinal ectopic thyroid tissue with normally located thyroid gland and primary hyperparathyroidism: a case report.

Mediastinal ectopic thyroid tissue (ETT) is rare entity, accounting for 1% of all mediastinal tumours. A 53-year-old lady, presented with cough and atypical chest pain. A computed tomography (CT) scan of chest showed a 95 mm × 75 mm × 115 mm tumour mass; CT guided biopsy of mediastinal mass showed ETT. Thyroid scintigraphy with Technetium-99m (99mTc) pertechnetate showed homogenous and intense uptake in the thyroid gland (TG) lodge and in the mediastinum. Primary hyperparathyroidism (PHPT) was diagnosed during laboratory evaluation. Technetium-99m sestamibi (99mTc-MIBI) parathyroid scintigraphy with single photon emission CT (SPECT)/CT showed uptake of radionuclide in two locations, one in the eutopic position [right inferior parathyroid gland (PTG)] and second ectopic (mediastinal). After surgery, histopathological examination confirmed mediastinal ETT and two PTG adenomas. During follow-up, laboratory analyzes were maintained within the reference range and the patient remained stable and free of symptoms and clinical signs, which supports a good prognosis. The existence of an ectopic mediastinal thyroid and an ectopic parathyroid tissue may be partly explained by a similar embryological origin. Diagnosis of ectopic thyroid and parathyroid tissues is demanding; requires a multidisciplinary team and approach using highly accurate radiological and nuclear imaging. The simultaneous existence of mediastinal ETT, nodular eutopic TG and PHPT for which two adenomas are responsible (cervical eutopic and mediastinal ectopic) is a complex diagnostic and therapeutic challenge, which we have described so far as unique. Comprehensive and multidisciplinary surgery planning is a cornerstone of treatment, when recommendations in guidelines are lacking.

Approach to patients with European Network for the Study of Adrenal Tumor stages I and II adrenocortical carcinomas.

PURPOSE OF REVIEW: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis depending mostly on the disease stage and tumor grade. The staging system proposed by the European Network for the Study of Adrenal Tumors has a reliable prognostic potential and defines ACC stages I-IV. Due to the absence of extraadrenal tissue invasion, patients with stage I-II have a lower recurrence rate and better prognosis. This article elaborates on the current understanding of the clinical approach to this group of patients. RECENT FINDINGS: Concerning the treatment, complete surgical resection of the tumor provides the only chance for cure. However, even after tumor removal, the risk of recurrence remains high and the main predictors of recurrence include tumor stage, grade (measured by Ki-67 proliferative index), and the tumor resection status. Adjuvant mitotane and/or adjuvant radiotherapy should be considered in patients with high risk of recurrence taking into account potential harmful effects of such treatment. Accordingly, careful selection of patients who may benefit from adjuvant treatment is of the utmost importance both for improving disease outcome and for avoiding potential overtreatment in patients who are at low risk of disease recurrence. SUMMARY: Many aspects of the management of patients with ACC stages I and II are not entirely evidence-based, and treatment decisions rely mostly on expert opinions and data from retrospective studies. Therefore, the treatment of these patients should be restricted to specialized centers with high expertise in ACC.