External validation of the fatty liver index and lipid accumulation product indices, using H-1-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals

Background and Aims. Simple clinical algorithms including the Fatty Liver Index (FLI) and Lipid Accumulation Product (LAP) have been developed as a surrogate marker for Non-Alcoholic Fatty Liver Disease (NAFLD). These algorithms have been constructed using ultrasonography, a semi-quantitative method. This study aimed to validate FLI and LAP as measures of hepatic steatosis, as measured quantitatively by proton magnetic resonance spectroscopy (1H-MRS). Methods. Data were collected from 168 patients with NAFLD and 168 controls who had undergone clinical, biochemical and anthropometric assessment in the course of research studies. Values of FLI and LAP were determined, and assessed both as predictors of the presence of hepatic steatosis (liver fat >5.5 %) and of actual liver fat content, as measured by 1H MRS. The discriminative ability of FLI and LAP was estimated using the area under the Receiver Operator Characteristic curve (AUROC). Since FLI can also be interpreted as a predictive probability of hepatic steatosis, we assessed how well calibrated it was in our cohort. Linear regression with prediction intervals was used to assess the ability of FLI and LAP to predict liver fat content. Results. FLI and LAP discriminated between patients with and without hepatic steatosis with an AUROC of 0.79 (IQR= 0.74, 0.84) and 0.78 (IQR= 0.72, 0.83), although quantitative prediction of liver fat content was unsuccessful. Additionally, the algorithms accurately matched the observed percentages of patients with hepatic steatosis in our cohort. Conclusions. FLI and LAP may be used clinically, and for metabolic and epidemiological research, to identify patients with hepatic steatosis, but not as surrogates for liver fat content

Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial

BACKGROUND: We sought to separately examine the effects of either weight loss or diets varying in protein content and glycemic index without further changes in body weight on cardiovascular risk factors within the Diet, Obesity, and Genes study (DiOGenes). METHODS AND RESULTS: DiOGenes is a pan-European controlled dietary intervention study in 932 overweight adults who first lost body weight on an 8-week low-calorie diet and were then randomized to 1 of 5 ad libitum diets for 26 weeks. The diets were either high or low protein or high or low glycemic index in 4 combinations or control. Weight loss (-11.23 kg; 95% confidence interval, -11.54 to -10.92; P<0.001) reduced high-sensitivity C-reactive protein (-1.15 mg/L; 95% confidence interval, -1.30 to -0.41; P<0.001), low- and high-density lipoprotein cholesterol, triglycerides, and blood pressure. During the 26-week weight maintenance period in the intention-to-treat analysis, the further decrease of high-sensitivity C-reactive protein blood levels was -0.46 mg/L greater (95% confidence interval, -0.79 to -0.13) in the groups assigned to low-glycemic-index diets than in those on high-glycemic-index diets (P<0.001). Groups on low-protein diets achieved a -0.25 mg/L greater reduction in high-sensitivity C-reactive protein (95% confidence interval, -0.59 to -0.17) than those on high-protein diets (P<0.001), whereas lipid profiles and blood pressure were not differently affected. CONCLUSIONS: This large-scale intervention study clearly separates weight loss from dietary composition-related effects. Low-glycemic-index carbohydrates and, to a lesser extent, low-protein intake may specifically reduce low-grade inflammation and associated comorbidities in overweight/obese adults

Medical management of secretory syndromes related to gastroenteropancreatic neuroendocrine tumours

Although recent epidemiological evidence indicates that the prevalence of non-functioning gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) is rising, a significant number of GEP-NETs still present with symptoms related to the secretion of biologically active substances leading to the development of distinct clinical syndromes. In the past, these syndromes were associated with substantial morbidity and mortality due to the lack of specific therapies; however, since the introduction of long-acting somatostatin analogues and medications such as proton pump inhibitors, their control has been greatly improved. As a result, nowadays, the main cause of morbidity and mortality in GEP-NETs is mostly directly related to tumour growth and the extent of metastatic disease. However, in some patients with functioning tumours and extensive disease, control of the secretory syndrome still remains problematic, necessitating the employment of several cytoreductive techniques, which may not always be sufficient. Recently, new agents directed against tumour growth, or exerting increased binding activity to receptors expressed in these tumours, or interfering with the synthetic pathway of some of the compounds secreted by these tumours, have been developed. Since there are no specific guidelines addressing the totality of the management of the secretory syndromes related to GEP-NETs, this review aims at critically analysing the medical management of previously recognised secretory syndromes; it also addresses areas of uncertainty, assesses the newer therapeutic developments and also addresses recently described but poorly characterised secretory syndromes related to GEP-NETs. © 2016 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain

Chemotherapy in NETs: When and how

The majority of neuroendocrine tumours (NETs) are well-differentiated tumours that follow an indolent course, in contrast to a minority of poorly differentiated neuroendocrine carcinomas (NECs) which exhibit an aggressive course and assocaited with an overall short survival. Although surgery is the only curative treatment for NETs it is not always feasible,necessitating the application of other therapies including chemotherapy. Streptozotocin (STZ)-based regimens have long been used for advanced or metastatic well-to-moderately differentiated (G1-G2) NETs, especially those originating from the pancreas (pNETs). In poorly differentiated grade 3 (G3) tumours, platinum-based chemotherapy is recommended as first-line therapy, albeit without durable responses. Although data for temozolomide (TMZ)-based chemotherapy are still evolving, this treatment may replace STZ-based regimens in pNETs due to its better tolerability and side effect profile. In addition, there is evidence that TMZ could also be used in the subgroup of well-differentiated G3 NETs. There is less clear-cut evidence of a benefit for chemotherapy in intestinal NETs, but still evolving data suggest that TMZ may be efficacious in particular patients. In lung and thymic carcinoids, chemotherapy is reserved for patients with progressive metastatic disease in whom other treatment options are unavailable. Overall, chemotherapy is indicated in patients who have progressed on first-line treatment with somatostatin analogues, have extensive tumour load or exhibit rapid growth following a period of follow-up, and/or have a high proliferative rate; it may occasionally can be used in a neo-adjuvant setting. Prospective randomised studies are awaited to substantiate the role of chemotherapy in the therapeutic algorithm of NETs along with other evolving treatments. © 2017, Springer Science+Business Media, LLC

Paraneoplastic endocrine syndromes

The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. However, occasionally neoplasms, with or without endocrine differentiation, acquire the ability to secrete a variety of bioactive substances or induce immune cross-reactivity with the normal tissues that can lead to the development of characteristic clinical syndromes. These syndromes are named endocrine paraneoplastic syndromes when the specific secretory components (hormones, peptides or cytokines) are unrelated to the anticipated tissue or organ of origin. Endocrine paraneoplastic syndromes can complicate the patient&apos;s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. These syndromes can precede, occur concomitantly or present at a later stage of tumour development, and along with the secreted substances constitute the biological &apos;fingerprint&apos; of the tumour. Their detection can facilitate early diagnosis of the underlying neoplasia, monitor response to treatment and/or detect early recurrences following successful initial management. Although when associated with tumours of low malignant potential they usually do not affect long-term outcome, in cases of highly malignant tumours, endocrine paraneoplastic syndromes are usually associated with poorer survival outcomes. Recent medical advances have not only improved our understanding of paraneoplastic syndrome pathogenesis in general but also enhanced their diagnosis and treatment. Yet, given the rarity of endocrine paraneoplastic syndromes, there is a paucity of prospective clinical trials to guide management. The development of well-designed prospective multicentre trials remains a priority in the field in order to fully characterise these syndromes and provide evidence-based diagnostic and therapeutic protocols. © 2017 Society for Endocrinology Printed in Great Britain

Mechanisms of central hypogonadism

Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (com-bined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti‐related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin re-sistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic‐androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within &gt;50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduc-tion or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vul-nerable, and their clinical management requires both sensitivity and empathy. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Effects of resistance exercise and whey protein supplementation on metabolic flexibility and glucose homeostasis in healthy older men

Rationale: Sarcopenia is associated with metabolic dysfunction. This study investigated the effects of resistance exercise (RE) and whey protein supplementation (WP) on metabolic flexibility (MF) and glucose homeostasis in healthy older men (60-80yrs). Methods: In a pooled-group analysis from a previous 4-arm randomised, double-blind, placebo-controlled trial1 , 33 healthy older men (age: 67±1yrs; BMI: 25.4±0.4 kg/m2 ) were pooled to either RE (2 /week; n¼17) or no exercise (NE; n¼16), and either WP (2 25g/d whey protein isolate; n¼17) or control (CON, 2 23.75g maltodextrin/d; n¼16) for 12weeks. A sub-analysis was also conducted between RE+CON (n¼8) and RE+WP (n¼9). At baseline and 12 weeks, participants resided in whole-room indirect calorimeters2 under highly-controlled conditions for 24-h for measurement of MF (defined as the difference between non-sleep and sleeping non-protein respiratory quotient (npRQ))3 , fasting plasma glucose and insulin concentration, insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR)) and insulin sensitivity (quantitative insulin sensitivity check index (QUICKI)), and 24-h mean interstitial glucose and 24-h glucose variability. Results: Compared to NE, RE significantly improved MF (+0.001±0.005 vs +0.022±0.004, p¼0.01), which was driven by a decrease in sleeping npRQ (-0.019±0.007, p¼0.02) rather than changes in non-sleep npRQ (+0.003±0.005, p¼0.48). No significant differences occurred between RE and NE for any other outcomes (p0.21). Compared to CON, WP tended to increase QUICKI (-0.01±0.01 vs +0.02±0.01, p¼0.06) and significantly decreased fasting plasma insulin concentration (+1.0±1.2 vs -2.3±1.1mU/L, p¼0.05), but no effects were observed on MF (p¼0.39). No differences occurred between RE+CON and RE+PRO for any outcome (p0.41). Conclusion: In healthy older men, RE significantly improves MF without effects on glucose homeostasis. Whilst WP did not affect MF, insulin sensitivity tended to improve. No synergistic effects occurred. References: 1. Griffen et al. (2022). Effects of resistance exercise and whey protein supplementation on skeletal muscle strength, mass, physical function, and hormonal and inflammatory biomarkers in healthy active older men: a randomised, double-blind, placebo-controlled trial. Experimental Gerontology, 158, 111651. 2. Griffen et al. (2022). Changes in 24-h energy expenditure, substrate oxidation, and body composition following resistance exercise and a high protein diet via whey protein supplementation in healthy older men. Physiological Reports, 10 (11), e15268. 3. Peterson et al. (2017). Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men. International Journal of Obesity, 41 (6), 887e893. Disclosure of Interest: None declared<br/

Clock genes alterations and endocrine disorders

Background: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock. Design: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases. Results: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers. Conclusions: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified. © 2018 Stichting European Society for Clinical Investigation Journal Foundatio