Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), ...improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.
Background Obesity-related dysregulation of leptin signaling (e.g., hyperleptinemia due to central functional resistance) may affect mood. However, evidence for leptin dysregulation in major ...depressive disorder (MDD) is conflicting. Inconclusive findings may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the relationship of leptin with MDD, its common subtypes (typical and atypical), and clinical features. Methods The sample consisted of participants (aged 18 to 65 years) from the Netherlands Study of Depression and Anxiety with current ( n = 1062) or remitted ( n = 711) MDD and healthy control subjects ( n = 497). Diagnoses of MDD and subtypes were based on DSM-IV symptoms. Additional symptoms were measured with the Inventory of Depressive Symptomatology. Blood levels of leptin and adiposity indexes (body mass index and waist circumference) were assessed. Results As compared to control subjects, higher leptin was associated with the atypical MDD subtype both for remitted ( n = 144, odds ratio = 1.53, 95% confidence interval = 1.16–2.03, p = .003) and current ( n = 270, odds ratio = 1.90, 95% confidence interval = 1.51–2.93, p = 5.3e-8) cases. This association was stronger for increasing adiposity levels (leptin by body mass index interaction, p < .02), strengthening the hypothesis of the involvement of leptin resistance. No association with leptin was found for overall MDD or the typical subtype. Among currently depressed patients, higher leptin was associated with key symptoms identifying the atypical subtype, such as hyperphagia, increased weight, and leaden paralysis. Conclusions Leptin dysregulation (resistance) may represent an underlying mechanism connecting obesity and MDD with atypical features. Development of treatment effectively targeting leptin resistance may benefit patients with atypical depression characterized by obesity-related metabolic alterations.
Highlights • Cross-sectional associations of depression and anxiety with plasma IGF-I are studied • Depression and anxiety are related to higher plasma IGF-I levels • Antidepressant medication use is ...related to lower plasma IGF-I levels
Objective
Diagnostic delay is high in acromegaly and leads to increased morbidity and mortality. The aim of this study is to systematically assess the most prevalent clinical signs, symptoms and ...comorbidities of acromegaly at time of diagnosis.
Design
A literature search (in PubMed, Embase and Web of Science) was performed on November 18, 2021, in collaboration with a medical information specialist.
Methods
Prevalence data on (presenting) clinical signs, symptoms and comorbidities at time of diagnosis were extracted and synthesized as weighted mean prevalence. The risk of bias was assessed for each included study using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data.
Results
Risk of bias and heterogeneity was high in the 124 included articles. Clinical signs and symptoms with the highest weighted mean prevalence were: acral enlargement (90%), facial features (65%), oral changes (62%), headache (59%), fatigue/tiredness (53%; including daytime sleepiness: 48%), hyperhidrosis (47%), snoring (46%), skin changes (including oily skin: 37% and thicker skin: 35%), weight gain (36%) and arthralgia (34%). Concerning comorbidities, acromegaly patients more frequently had hypertension, left ventricle hypertrophy, dia/systolic dysfunction, cardiac arrhythmias, (pre)diabetes, dyslipidemia and intestinal polyps- and malignancy than age- and sex matched controls. Noteworthy, cardiovascular comorbidity was lower in more recent studies. Features that most often led to diagnosis of acromegaly were typical physical changes (acral enlargement, facial changes and prognatism), local tumor effects (headache and visual defect), diabetes, thyroid cancer and menstrual disorders.
Conclusion
Acromegaly manifests itself with typical physical changes but also leads to a wide variety of common comorbidities, emphasizing that recognition of a combination of these features is key to establishing the diagnosis.
Adiponectin circulates in blood in multiple isoforms. High molecular weight (HMW) adiponectin is thought to be most biologically active and promotes glucose uptake, insulin sensitivity, and fatty ...acid oxidation. In obesity, adiponectin isoform formation is disrupted, leading to an inverse association between metabolic disease and HMW and total adiponectin. Adiponectin isoforms also function as acute-phase reactants influencing inflammation in acute and chronic disease. Interestingly, adiponectin and mortality have a U-shaped association. Unfortunately, data concerning adiponectin and its pathophysiologic function conflict. This is predominantly due to difficulties in adequate measurement of adiponectin isoforms and lack of a gold standard. In this review we provide a general overview of the formation and function of adiponectin and its isoforms under physiologic conditions. We highlight the ways adiponectin isoform formation is disrupted in obesity and its ensuing pathologic conditions. Furthermore, we will elaborate on the role of adiponectin isoforms as inflammatory proteins with respect to cardiac and kidney disease and discuss the association of adiponectin with mortality. Finally, we will provide a historical perspective on the measurement of adiponectin isoforms, current limitations, and future challenges.
The aim of the present study was to investigate the effect of low-normal and high-normal levels of IGF-1 in growth hormone (GH) deficient adults on cognition and wellbeing during GH treatment.
A ...randomized, open-label, clinical trial including 32 subjects receiving GH therapy for at least 1 year. Subjects were randomized to receive either a decrease (IGF-1 target level of - 2 to - 1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Memory was measured by the Cambridge Neuropsychological Test Automated Battery, selecting the Pattern Recognition Memory task and the Spatial Working Memory. Wellbeing was measured as mood by the Profile of Moods States questionnaire, and quality of life by the Nottingham Health Profile and QoL Assessment in GH Deficiency in Adults questionnaires.
Data from 30 subjects (65.6% male, mean age 46.6 (9.9 SD) years), who fulfilled the target levels, were analyzed. Females in the low dose treatment arm were found to have a better working memory and a better strategic memory control after 24 weeks as opposed to the females in the high treatment arm. With respect to mood, the decrease in IGF-1 levels in females within the low treatment arm was associated with more fatigue and less vigor.
The adjustment of GH dose in female patients seems to have a narrow window. A dose too high may impair prefrontal cognitive functioning, while a dose too low may result in decreased vigor.
This study is registered with ClinicalTrials.gov , number NCT01877512.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of ...MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population.
Patients and Methods
Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis.
Results
Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations.
Conclusion
The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.
The size of 115 small NF-pNETs from 99 MEN1 patients was followed over time. Most tumors were stable. In the subgroup of growing tumors a genotype-phenotype correlation was seen.
Abstract
Objective:
Multiple endocrine neoplasia type 1 (MEN1) is associated with an early-onset elevated breast cancer risk. This finding potentially has implications for breast cancer screening for ...women with MEN1, and therefore it is necessary to assess whether other risk factors are involved to identify those at greatest risk.
Design:
A cross-sectional case control study was performed using the Dutch MEN1 cohort, including >90% of the adult Dutch MEN1 population. All women with a confirmed MEN1 mutation received a questionnaire regarding cancer family history and breast cancer–related endocrine and general cancer risk factors.
Results:
A total of 138 of 165 (84%) eligible women with MEN1 completed the questionnaire. Eleven of the 138 women had breast cancer. Another 34 relatives with breast cancer were identified in the families of the included women, of whom 11 were obligate MEN1 carriers, 14 had no MEN1 mutation, and 9 had an unknown MEN1 status. The median age at breast cancer diagnosis of women with MEN1 (n = 22) was 45 years (range, 30 to 80 years), in comparison with 57.5 years (range, 40 to 85 years) in female relatives without MEN1 (n = 14; P = 0.03) and 61.2 years in the Dutch reference population. Known endocrine risk factors and general risk factors were not different for women with and without breast cancer.
Conclusion:
The increased breast cancer risk in MEN1 carriers was not related to other known breast cancer risk factors or familial cancer history, and therefore breast cancer surveillance from the age of 40 years for all women with MEN1 is justifiable.
MEN1 is associated with an early-onset elevated breast cancer risk and is not related to other breast cancer risk factors. Early breast cancer surveillance is justified for all women with MEN1.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS).
...We performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 ± 4.1 years, mean BMI 32 ± 4.7 kg/m(2)), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake.
After 12 weeks, the decrease in HbA1c was larger with liraglutide versus insulin glargine (Δ-0.7% vs. -0.2%, P < 0.001). Body weight decreased during liraglutide versus insulin glargine (Δ-3.3 kg vs. 0.8 kg, P < 0.001). After 10 days, patients treated with liraglutide, compared with insulin glargine, showed decreased responses to food pictures in insula and putamen (P ≤ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P ≤ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks.
Compared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment.
Increasing physical activity is one of the most promising and challenging interventions to delay or prevent cognitive decline and dementia.
We conducted a randomized controlled trial to assess the ...effects of a physical activity intervention, aimed at increasing step count, in elderly with low levels of physical activity on measures of strength, balance, aerobic capacity, and cognition. Participants were assigned to 9 months of exercise counseling or active control.
The intention-to-treat analyses show that the intervention, compared to control, increases the level of physical activity, but has no significant effect on physical fitness and cognition. Those who increased their physical activity with 35% or more show significant improvements in aerobic capacity, gait speed, verbal memory, executive functioning, and global cognition, compared to those who did not achieve a 35% increase.
The number of participants that achieved the intended improvement was lower than expected.
Responder analyses suggest an improvement of physical fitness and cognition in those who achieved an increase in physical activity of at least 35%.
The trial protocol is registered at the Dutch Trial Register NL5675, August 1, 2016.
PDF
