Gastric ghrelin cells in obese patients are hyperactive.

BACKGROUND/OBJECTIVES: Distribution and activity of ghrelin cells in the stomach of obese subjects are controversial. SUBJECTS/METHODS: We examined samples from stomachs removed by sleeve gastrectomy in 49 obese subjects (normoglycemic, hyperglycemic and diabetic) and quantified the density of ghrelin/chromogranin endocrine cells by immunohistochemistry. Data were compared with those from 13 lean subjects evaluated by gastroscopy. In 44 cases (11 controls and 33 obese patients) a gene expression analysis of ghrelin and its activating enzyme ghrelin O-acyl transferase (GOAT) was performed. In 21 cases (4 controls and 17 obese patients) the protein levels of unacylated and acylated-ghrelin were measured by ELISA tests. In 18 cases (4 controls and 14 obese patients) the morphology of ghrelin-producing cells was evaluated by electron microscopy. RESULTS: The obese group, either considered as total population or divided into subgroups, did not show any significant difference in ghrelin cell density when compared with control subjects. Inter-glandular smooth muscle fibres were increased in obese patients. In line with a positive trend of the desacylated form found by ELISA, Ghrelin and GOAT mRNA expression in obese patients was significantly increased. The unique ghrelin cell ultrastructure was maintained in all obese groups. In the hyperglycemic obese patients, the higher ghrelin expression matched with ultrastructural signs of endocrine hyperactivity, including expanded rough endoplasmic reticulum and reduced density, size and electron-density of endocrine granules. A positive correlation between ghrelin gene expression and glycemic values, body mass index and GOAT was also found. All obese patients with type 2 diabetes recovered from diabetes at follow-up after 5 months with a 16.5% of weight loss. CONCLUSIONS: Given the known inhibitory role on insulin secretion of ghrelin, these results suggest a possible role for gastric ghrelin overproduction in the complex architecture that takes part in the pathogenesis of type 2 diabetes.

Management of Osteoporosis in Men: A Narrative Review.

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.

Perchlorates in the treatment of hyperthyroidism and thyrotoxicosis: a comprehensive review.

INTRODUCTION: Perchlorates are ionic inhibitors antagonizing iodine transport into thyrocytes, hampering thyroid hormone synthesis. Nevertheless, perchlorates are not considered as first-line treatment in hyperthyroidism and thyrotoxicosis as compared to other pharmacological and non-pharmacological interventions. AIM: Reassessing the therapeutic role of perchlorates in hyperthyroidism and thyrotoxicosis throughout a systematic review of the Literature. METHODS: Guidelines were searched and examined to summarize current recommendations on the use of perchlorates in the management of hyperthyroidism. Randomized and non-randomized clinical trials were also searched and reviewed to summarize the efficacy/effectiveness and safety of perchlorates in hyperthyroidisms and thyrotoxicosis. RESULTS: The management of specific forms of hyperthyroidism was considered, including Graves' disease (GD) in non-pregnant adults, hyperthyroidisms in pregnancy, iodine media contrast-induced hyperthyroidism, amiodarone-induced hyperthyroidisms, and thyroid storm. Most of the reported studies had remarkable limitations in terms of study design (non-controlled trials, lack of blinding), low number of participants, and the lack of clinically relevant endpoints, such as cardiovascular events, cardiovascular mortality, and teratogenicity. Overall, perchlorates could be considered a second-line treatment after thionamides, radioiodine, and total thyroidectomy in both GD and hyperthyroidisms in pregnancy. The therapeutic potential of perchlorates alone or in combination with other agents could be considered a second-line treatment of iodine-related hyperthyroidisms and thyroid storm. CONCLUSION: Despite the low level of evidence, perchlorates could be considered in such specific forms of thyroid disorders, including iodine-induced hyperthyroidism and thyroid storm.

Once-Weekly Insulin Icodec in Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Clinical Trials (ONWARDS Clinical Program).

BACKGROUND: One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D). METHODS: PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks. RESULTS: The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of -0.14% [95%CI -0.25; -0.03], p = 0.01, and I2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of -0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (-5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]). CONCLUSION: Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients' education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.

Glucagon-like peptide 1 receptor agonists and thyroid cancer: is it the time to be concerned?

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have changed considerably the management of type 2 diabetes (T2D). However, recently published data from retrospective cohort studies suggest that chronic exposure to GLP-1RAs in T2D may increase the risk of papillary and medullary thyroid cancer. In this perspective, the role of the incretin system in thyroid carcinogenesis has been reviewed and critically commented on, aiming to understand if the time has arrived to be concerned about the risk. Although evidence suggested, speculative hypotheses should be verified, and further studies are urgently needed to clarify the issue.

Sarcopenia and Diabetes: A Detrimental Liaison of Advancing Age.

Sarcopenia is an age-related clinical complaint characterized by the progressive deterioration of skeletal muscle mass and strength over time. Type 2 diabetes (T2D) is associated with faster and more relevant skeletal muscle impairment. Both conditions influence each other, leading to negative consequences on glycemic control, cardiovascular risk, general health status, risk of falls, frailty, overall quality of life, and mortality. PubMed/Medline, Scopus, Web of Science, and Google Scholar were searched for research articles, scientific reports, observational studies, clinical trials, narrative and systematic reviews, and meta-analyses to review the evidence on the pathophysiology of di-abetes-induced sarcopenia, its relevance in terms of glucose control and diabetes-related outcomes, and diagnostic and therapeutic challenges. The review comprehensively addresses key elements for the clinical definition and diagnostic criteria of sarcopenia, the pathophysiological correlation be-tween T2D, sarcopenia, and related outcomes, a critical review of the role of antihyperglycemic treatment on skeletal muscle health, and perspectives on the role of specific treatment targeting myokine signaling pathways involved in glucose control and the regulation of skeletal muscle metabolism and trophism. Prompt diagnosis and adequate management, including lifestyle inter-vention, health diet programs, micronutrient supplementation, physical exercise, and pharmaco-logical treatment, are needed to prevent or delay skeletal muscle deterioration in T2D.

Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: A rapid review of randomized controlled trials and meta-analysis.

Tirzepatide, a dual agonist of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide 1 (GLP-1) receptors, improved glucose control and reduced body weight in different therapeutic approaches. Herein, we overviewed the role of GIP and GLP-1 in the pathophysiology of type 2 diabetes and systematically reviewed the efficacy and safety of injectable incretin-based therapy added to basal insulin in light of the results of the SURPASS-5 trial. We identified eleven randomized clinical trials. GLP-1 receptor agonists (GLP-1RAs) or Tirzepatide added to basal insulin than rigorously titrated basal insulin significantly ameliorates glucose control (Δ HbA1c = -1%, 95% CI -1.25; -0.74, I2 94%; Δ FPG = -14.6 mg/dL, 95% CI -21.6-; -7.6, I2 90%; chance to achieve HbA1c <7% = RR 2.62, 95% CI 2.10; 3.26, I2 89%), reduces body weight (Δ = -3.95 kg, 95% CI -5.1, -2.79, I2 96%) without increasing the risk of hypoglycemia (RR = 1.01, 95% CI 0.86; 1.18, I2 7.7%). Tirzepatide provides an impressive weight loss exceeding that observed with GLP-1RAs. Injectable incretin-based therapy plus basal insulin remains a potent and safe therapeutic approach in uncontrolled type 2 diabetes patients previously treated with basal insulin alone. Tirzepatide is expected to ameliorate the management of "diabesity" in this usually difficult-to-treat cluster of patients.

Thyroid Function and Obesity: From Mechanisms to the Benefits of Levothyroxine in Obese Patients.

BACKGROUND: Thyroid disease and obesity are widespread clinical conditions in the population. They can occur together in the same subject, but their relationship does not seem exclusively stochastic. AIM: Literature was critically reviewed to explain the association between thyroid disease and obesity and to understand the possible benefits of levothyroxine therapy in euthyroid obese patients. RESULTS: A low energy expenditure rate can lead to obesity. Maintaining Basal Metabolic Rate (BMR) is the leading cause of energy expenditure in the body, which is regulated by thermogenesis. Thyroid hormone receptors (TR) play different roles in the induction of thermogenetic mechanisms; TRα is fundamental to induce thermogenesis, and TRß triggers the expression of uncoupling protein 1(UCP1). Despite such mechanisms, there is no current evidence related to the treatment of subjects suffering from obesity with thyroid hormones. CONCLUSION: Replacement therapy should be reserved only for patients with clear signs of subclinical or clinical hypothyroidism. DEFINITIONS: Basal metabolic rate (BMR) or basal energy expenditure (BEE): measurement obtained under total inactivity and controlled research conditions; resting energy expenditure (REE): measurement obtained when an individual is sitting quietly (is mildly higher than BMR/BEE).

Assessment of Burnout Levels Before and During COVID-19 Pandemic: A Web-Based Survey by the (Italian) Association of Medical Endocrinologists (AME).

BACKGROUND: Some endocrinologists were involved in the management of patients with suspected or confirmed COVID-19 during the first wave of the pandemic. This study aims to analyze burnout levels among the Association of Medical Endocrinologists (AME) members before and during the pandemic. METHODS: We recruited two AME members samples at two different times: before COVID-19 (n = 811) and during the first wave of the ongoing pandemic (n = 579). Both the samples filled the Maslach Burnout Inventory. We performed MANOVAs to evaluate demographic and COVID-19 related differences in burnout levels and Pearson's Chi-square test to compare burnout severity before and during the pandemic. RESULTS: Women reported higher Emotional Exhaustion and reduced Professional Accomplishment than men. The oldest physicians had lower levels of Emotional Exhaustion and Depersonalization and higher Professional Accomplishment than younger workers. Independent contractors displayed lower levels of burnout compared to established contractors. Finally, the pandemic, per se, did not lead to changes in burnout levels. DISCUSSION: Women and young physicians are at higher risk of burnout. It is also possible that front- line professionals are at higher risk during a health care crisis. Moreover, it is likely that the length of exposure to the pandemic has not been sufficient to impact burnout levels. CONCLUSION: Short-term exposure to pandemic-related activities seemed to have a low impact on burnout severity, except for physicians directly involved in managing COVID-19 cases. It is strongly recommended the availability of psychological support in public hospitals.

Selenium: A Trace Element for a Healthy Skeleton - A Narrative Review.

Inadequate serum selenium levels may delay the growth and physiological changes in bone metabolism. In humans, reduced serum selenium concentrations are associated with both increased bone turnover and reduced bone mineral density. Moreover, a reduced nutritional intake of selenium may lead to an increased risk of bone disease. Therefore, selenium is an essential nutrient playing a role in bone health, probably due to specific selenium-proteins. Some selenium-proteins have an antioxidation enzymatic activity and participate in maintaining the redox cellular balance, regulating inflammation and proliferation/differentiation of bone cells too. At least nine selenium-proteins are known to be expressed by fetal osteoblasts and appear to protect bone cells from oxidative stress at bone microenvironment. Mutations of selenium-proteins and reduced circulating levels of selenium are known to be associated with skeletal diseases such as the Kashin-Beck osteoarthropathy and postmenopausal osteoporosis. In addition, the intake of selenium appears to be inversely related to the risk of hip fragility fractures. Recent data suggest that an altered selenium state may affect bone mass even in males and selenium-proteins and selenium concentrations were positively associated with the bone mass at femoral, total and trochanteric sites. However, selenium, but not selenium-proteins, seems to be associated with femoral neck bone mass after adjustment for many bone fracture risk factors. The present review summarizes the findings of observational and interventional studies, which have been designed for investigating the relationship between selenium and bone metabolism.