Wojciech Zgliczyński

Otyłość jest coraz częściej postrzegana nie tylko jako czynnik ryzyka chorób metabolicznych i sercowo-naczyniowych, ale również jako przyczyna zaburzeń funkcji obwodowego i autonomicznego układu nerwowego Coraz więcej danych eksperymentalnych i klinicznych wskazuje na ryzyko rozwoju neuropatii przy braku jawnej hiperglikemii, co sugeruje udział mechanizmów niezależnych od toksycznego działania glukozy. Celem niniejszej pracy jest podsumowanie aktualnej wiedzy na temat neuropatii związanej z otyłością, ze szczególnym uwzględnieniem roli przewlekłego stanu zapalnego o niskim nasileniu oraz interakcji neurometabolicznych. Dysfunkcja tkanki tłuszczowej prowadzi do przewlekłego stanu zapalnego, stresu oksydacyjnego oraz zaburzeń funkcji mitochondriów, co przyczynia się do uszkodzenia neuronów oraz komórek Schwanna. Wczesne zmiany neuropatyczne mają często charakter subkliniczny i dotyczą głównie cienkich włókien czuciowych i autonomicznych, co utrudnia diagnostykę. Część tych zmian może być odwracalna we wczesnych stadiach, jednak utrwalona pamięć metaboliczna może ograniczać możliwość regeneracji. Neuropatia w otyłości powinna być traktowana jako integralny element choroby metabolicznej, wymagający wczesnego rozpoznania i kompleksowego leczenia.

Insulin resistance is a metabolic disorder and a key factor in the pathogenesis of conditions such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and atherosclerosis. Risk factors for insulin resistance include genetic and environmental influences, such as overweight/obesity, low physical activity, and the use of certain medications, including glucocorticosteroids or antipsychotics. Antipsychotics (neuroleptics) are widely used in the treatment of various mental disorders, primarily schizophrenia, and such therapy is often lifelong. Due to the mechanism of action via receptors, including serotonergic, muscarinic, and histaminergic, atypical (second-generation) antipsychotics cause metabolic disorders of varying severity. Clozapine and olanzapine have the worst metabolic profiles and aripiprazole and lurasidone are associated with the mildest profiles. Regardless of the potential for developing metabolic complications from specific antipsychotics, baseline predictors of susceptibility are sought in patients. To date, studies have identified risk factors such as higher body weight, male gender, and non-white ethnicity. In addition, patients with schizophrenia are at greater risk for insulin resistance, as shown in studies involving individuals with a first episode of psychosis. This supports the hypothesis that schizophrenia and diabetes may share a common pathogenesis. Despite clear evidence of an increased risk for insulin resistance and, consequently, metabolic syndrome and high cardiovascular risk, insufficient attention is paid to early diagnosis, prevention, and treatment of carbohydrate and lipid metabolism disorders in patients taking neuroleptics. Improved management in this area could benefit not only physical health but also adherence to medical recommendations and the overall effectiveness of psychiatric treatment.

The steady increase in human life expectancy in the 21st century is considered one of the major public health challenges. However, current achievements in longevity, are most often associated with increasing years in disability. Current studies indicate that healthy longevity is achieved, through harmonised ageing of the whole body. Due to the complexity of ageing, a number of biological age markers have been determined to describe the intensity of changes limiting biophysiological functions at different levels of the body. Biological age markers can be divided into two categories: parameters determining the level of severity of molecular and cellular hallmarks of ageing: genomic incapacity, telomere length changes, mitochondrial dysfunction, loss of proteostasis, epigenetic changes, cellular senescence, deregulation of nutrient sensitivity, stem cell depletion, altered intercellular communication. The second group are parameters defining age at the systemic level: bone age, muscle age, vascular age, neuronal age, endocrine age, pulmonary age, glycan age. Modern methods of measuring biological age markers allow the identification of weak points in ageing and illustrate the unevenness of the ageing process. It is worth considering the study of biological age markers to prioritise interventions promoting sustainable ageing. Stały wzrost średniej długości życia człowieka w XXI wieku jest uważany za jedno z głównych wyzwań zdrowia publicznego. Jednak obecne osiągnięcia w zakresie długowieczności, najczęściej wiążą się z wydłużaniem lat w niepełnosprawności. Obecne doniesienia wskazują, że zdrową długowieczność osiąga się, dzięki zharmonizowanemu starzeniu się całego organizmu. Ze względu na kompleksowość starzenia się wyznaczono szereg markerów wieku biologicznego opisujących natężenie zmian ograniczających funkcje biofizjologiczne na różnych poziomach organizmu. Markery wieku biologicznego można podzielić na dwie kategorie: parametry określające poziom nasilenia molekularnych i komórkowych znaczników starzenia: niezdolność genomowa, zmiany długości telomerów, dysfunkcja mitochondriów, utrata proteostazy, zmiany epigenetyczne, senescencja komórkowa, deregulacja wrażliwości na składniki odżywcze, wyczerpanie komórek macierzystych, zmieniona komunikacja międzykomórkowa. Druga grupa to parametry określające wiek na poziomie układowym: wiek kostny, wiek mięśniowy, wiek naczyniowy, wiek neuronalny, wiek hormonalny, wiek pulmonologiczny, wiek glikanowy. Nowoczesne metody pomiaru markerów wieku biologicznego pozwalają na identyfikację słabych punktów starzenia i obrazują nierównomierność procesu starzenia. Warto rozważyć badanie biologicznych markerów wieku w celu ustalenia priorytetów interwencji promujących zrównoważone starzenia się.

Growth hormone (GH) is a key peptide hormone in the regulation of bone metabolism, through its systemic and paracrine action mediated directly as well as by insulin-like growth factor-1 (IGF-1). Growth hormone exerts pleiotropic effects leading to an increase in linear bone growth, accumulation of bone mineral content and preservation of peak bone mass. Furthermore, it influences protein, lipid, and carbohydrate metabolism. Growth hormone deficiency (GHD) causes a low bone turnover rate leading to reduced bone mineral density (BMD) and increased bone fragility. The results of GH insufficiency are the most pronounced among children as it negatively affects longitudinal bone growth, causing short stature and in adolescents, in whom it hinders the acquisition of peak bone mass. Most studies show that treatment with recombinant human growth hormone (rhGH) in GHD patients could improve BMD and decrease fracture risk. This review aims to summarize the pathophysiology, clinical picture and management of bone complications observed in GHD.

Obesity is a chronic disease that leads to the development of secondary metabolic disturbances and diseases and strongly contributes to increased morbidity and mortality. On the other hand, musculoskeletal disorders are currently the main cause of disability and the second most frequent reason for visits to the doctor. Many studies clearly show that excessive body weight adversely affects the course of almost all musculoskeletal system diseases, from osteoarthritis, through metabolic, systemic connective tissue, to rarely diagnosed diseases. The impact of increased fat mass on the musculoskeletal system is presumably complex in nature and involves the influence of biomechanical, dietary, genetic, inflammatory and metabolic factors. Due to the epidemic nature of obesity and its serious health consequences, this disease requires energetic treatment. It is always based on lifestyle modification enriched, if necessary, by pharmacological and, in justified cases, surgical treatment.

Acromegaly is a rare chronic disorder due to growth hormone (GH) - secreting pituitary tumor. The first-line treatment of acromegaly is a transsphenoidal adenomectomy. Surgical remission rates range from 30-50% for macroadenomas to 70-90% for microadenomas. Thus in patients with active acromegaly after surgery, medical treatment is recommended. Treatment outcome on medical therapy differs a lot depending on medications. The aim of this paper is to summerize the current knowledge of factors predicting acromegaly remission after surgery and biochemical control on medical treatment. Factors affecting treatment outcome, not related to the patient and the tumor, are neurosurgeon’s experience and visualisation tools used during surgery. Younger patients, as well as women tend to achieve acromegaly remission after surgery less often. Patients with lower GH and insulin-like growth factor-1 (IGF-1) concentrations at diagnosis, in oral glucose tolerance test (OGTT) and postoperatively have a greater chance of surgical remission. However, some publications do not confirm that. Patients presenting with larger and more invasive tumors achieve surgical remisson less often. Hypointensive tumors on T2-weighted magnetic resonance imaging (MRI) scans are associated with better response to first-generation somatostatin receptor ligands (SRLs) and to pasireotide. Pathologic factors increasing the chance of acromegaly remission are densely granulated tumors, lower Ki-67 index, high expression of somatostatin receptors (SSTRs) and high expression of E-cadherin. A thorough analysis of the abovementioned factors predicting the treatment outcome in acromegaly may be helpful for selecting the best treatment option for each patient.

Acromegaly is a systemic disease significantly affecting cardiovascular system. As a result of increased GH and IGF-1 values, changes occur in the heart, which are commonly called acromegaly cardiomyopathy. The progress in the treatment of acromegaly and comorbidities has changed the characteristics of this cardiomyopathy, and its 3rd stage is very rare today, it is reported from 1 to 4%. In turn, progress in diagnostics and the possibility of using new echocardiographic techniques, like speckle tracking echocardiography (STE), allows to recognize the changes at the subclinical level. Due to the reversibility of some symptoms, early detection of changes and implementation of treatment is very important. This reduces the risk of cardiac complications, and consequently improves the quality and prolongs life. Streszczenia: Akromegalia jest chorobą ogólnoustrojową, która w istotny sposób wpływa na układ sercowo-naczyniowy. W wyniku podwyższonych wartości GH i IGF-1 dochodzi do zmian w sercu, które potocznie nazywane są kardiomiopatią akromegaliczną. Postęp w leczeniu akromegalii i chorób współistniejących zmienił obraz tej kardiomiopatii, a jej 3-ie ostatnie stadium jest obecnie bardzo rzadko spotykane, od 1 do 4%. Postęp w diagnostyce i możliwość zastosowania nowych technik echokardiograficznych, takich jak technika śledzenia “plamki obrazu” (STE), pozwala rozpoznawać zmiany na poziomie subklinicznym. Ze względu na odwracalność niektórych objawów, bardzo ważne jest wczesne wykrycie zmian i wdrożenie leczenia. Zmniejsza to ryzyko powikłań kardiologicznych, a w konsekwencji poprawia jakość i wydłuża życie.

DOI: 10.20452/pamw.16178, Published online: December 22, 2021, Authors: Maria Stelmachowska-Banaś, Maria Maksymowicz, Agnieszka Kolasińska-Ćwikła, Grzegorz Zieliński, Márta Korbonits, Wojciech Zgliczyński

Context: Pasireotide-LAR, a second-generation somatostatin receptor ligand (SRL), is recommended for patients with acromegaly as second-line treatment. Its efficacy and safety were assessed in clinical trials; however, the real-world evidence is still scarce. Objective: The aim of this study was to evaluate the impact of 1-year treatment with pasireotide-LAR on disease control and glucose metabolism in acromegaly patients resistant to first-generation SRLs. Design: A single-center prospective study. Methods: Twenty-eight patients with active acromegaly or acrogigantism on first-generation SRLs following ineffective pituitary surgery were switched to treatment with pasireotide-LAR 40 or 60 mg i.m. every 28 days. To assess the efficacy of the treatment GH and IGF-1 levels were measured every 3 months. Safety of treatment was carefully evaluated, especially its impact on glucose metabolism. Results: Complete biochemical control (GH ≤ 1 ng/mL and IGF-1 ≤ 1 × ULN) was achieved in 26.9% of patients and partial + complete response (GH ≤ 2.5 ng/mL and IGF-1 ≤ 1.3 × ULN) in 50.0% of patients. Mean GH level decrease was the largest within first 6 months (P = 0.0001) and mean IGF-1 level decreased rapidly within the first 3 months (P < 0.0001) and they remained reduced during the study. Blood glucose and HbA1c levels increased significantly within 3 months (P = 0.0001) and stayed on stable level thereafter. Otherwise, the treatment was well tolerated and clinical improvement was noticed in majority of patients. Conclusions: This real-life study confirmed good effectiveness of pasireotide-LAR in patients resistant to first-generation SRLs. Pasireotide-LAR was overall safe and well tolerated, however significant glucose metabolism worsening was noted.

Introduction: First generation somatostatin analogs (SSAs) are the treatment of choice in persistent acromegaly after transsphenoidal surgery. However, they are effective in 25% to 45 % of patients and a second generation SSA - pasireotide LAR may be a more effective alternative. Aim Our aim was to evaluate the impact of 1-year treatment with pasireotide LAR on disease control and on glucose metabolism in patients with acromegaly after debulking surgery resistant to first-generation SSAs. Material and methods In this single-center prospective study 29 consecutive patients with resistant acromegaly were treated with pasireotide LAR. The initial drug dose was 40 mg i.m. every 28 days. If patient did not achieve biochemical control (GH <2.5 ng/mL and IGF-1 ≤ULN for age and sex) at month 3, the dose was increased to 60 mg i.m. every 28 days. Assessment (GH, IGF-1, glucose, HbA1c) was performed at month 3, 6, 9 and 12. Results: In total, 22 patients (10 females, 12 males) completed a 1-year treatment. Mean age was 41.8±13.8 years. Twelve patients (54.5%) were ≤ 40 years old (including 6 (27.3%) patients of age ≤30 years). At baseline, mean IGF-1 level was 2.3 (SD 0.7) x ULN (age- and sex-specific) (583.9 ng/mL; SD 182.2) and mean GH concentration was 3.9 (SD 2.8) ng/mL. Both values decreased significantly after 1 year of treatment (P<0.001). Pasireotide LAR dose was increased to 60 mg in 16 (72.7%) patients and decreased to 20 mg in one patient patient due to worsening of diabetes control. The magnitude of mean GH level decrease was the largest within first 6 months (mean change from baseline: -1.75 ng/mL, 95% CI: -2.64, -0.85, P=0.0006). Mean IGF-1 level decreased rapidly within the first 3 months (mean change from baseline: -153.20 ng/mL, 95% CI: -203.20, -103.19, P<0.0001) and remained low during 12-month follow-up. GH level ≤ 1 ng/mL and ≤2.5 ng/mL was achieved by 7 (31.8%) and 17 (77.3%) patients, respectively. Six patients (27.3%) achieved normal IGF-1 level (IGF-1 ≤1 x ULN) (P=0.0275). IGF-1 ≤1.3 x ULN was observed in 11 (50.0%) of patients. Full biochemical control (GH ≤1 ng/mL and IGF-1 ≤1 x ULN) was achieved in 3 (13.6%) patients. Pasireotide LAR treatment resulted in significant increase of mean fasting glucose level: 119.2 (SD 17.3) vs. 107.5 (SD 13.9) mg/dL, P<0.001. The largest change was observed in first 3 months, and it remained stable until month 12. HbA1c level also increased significantly during first 3 months and stayed on similar level during follow-up (mean for month 12: 6.3 (SD 0.6) vs. 5.9 (SD 0.5) % at baseline, P<0.001). Conclusions: Pasireotide LAR is an effective treatment in most patients with persistent acromegaly after surgical debulking resistant to first generation SSAs. The largest increase of glycemia occurs during first 3 months of treatment and it remains stable afterwards.