Mechanisms, screening modalities and treatment options for individuals with non-alcoholic fatty liver disease and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to 'metabolic associated fatty liver disease' (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical.

What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

Exercise-induced improvements in liver fat and endothelial function are not sustained 12 months following cessation of exercise supervision in nonalcoholic fatty liver disease.

Supervised exercise reduces liver fat and improves endothelial function, a surrogate of cardiovascular disease (CVD) risk, in nonalcoholic fatty liver disease (NAFLD). We hypothesised that after a 16-week supervised exercise program, patients would maintain longer-term improvements in cardiorespiratory fitness, liver fat and endothelial function. Ten NAFLD patients (5/5 males/females, age 51±13 years, body mass index 31±3 kg m-2 (mean±s.d.)) underwent a 16-week supervised moderate-intensity exercise intervention. Biochemical markers, cardiorespiratory fitness (VO2peak), subcutaneous, visceral and liver fat (measured by magnetic resonance imaging and spectroscopy respectively) and brachial artery flow-mediated dilation (FMD) were assessed at baseline, after 16 weeks of supervised training and 12 months after ending supervision. Despite no significant change in body weight, there were significant improvements in VO2peak (6.5 ml kg-1 min-1 (95% confidence interval 2.8, 10.1); P=0.003), FMD (2.9% (1.5, 4.2); P=0.001), liver transaminases (P<0.05) and liver fat (-10.1% (-20.6, 0.5); P=0.048) immediately after the 16-week supervised training. Nevertheless, 12 months after ending supervision, VO2peak (0.9 ml kg-1 min-1 (-3.3, 5.1); P=0.65), FMD (-0.07% (-2.3, 2.2); P=0.95), liver transaminases (P>0.05) and liver fat (1.4% (-13.0, 15.9); P=0.83) were not significantly different from baseline. At 12 months following cessation of supervision, exercise-mediated improvements in liver fat and other cardiometabolic variables had reversed with cardiorespiratory fitness at baseline levels. Maintenance of high cardiorespiratory fitness and stability of body weight are critical public health considerations for the treatment of NAFLD (Clinicaltrials.gov identifier: NCT01834300).

Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity.

BACKGROUND: The term 'metabolically healthy obese (MHO)' is distinguished using body mass index (BMI), yet BMI is a poor index of adiposity. Some epidemiological data suggest that MHO carries a lower risk of cardiovascular disease (CVD) or mortality than being normal weight yet metabolically unhealthy. OBJECTIVES: We aimed to undertake a detailed phenotyping of individuals with MHO by using imaging techniques to examine ectopic fat (visceral and liver fat deposition) and myocardial function. We hypothesised that metabolically unhealthy individuals (irrespective of BMI) would have adverse levels of ectopic fat and myocardial dysfunction compared with MHO individuals. SUBJECTS: Individuals were categorised as non-obese or obese (BMI ⩾30 kg m(-2)) and as metabolically healthy or unhealthy according to the presence or absence of metabolic syndrome. METHODS: Sixty-seven individuals (mean±s.d.: age 49±11 years) underwent measurement of (i) visceral, subcutaneous and liver fat using magnetic resonance imaging and proton magnetic resonance spectroscopy, (ii) components of metabolic syndrome, (iii) cardiorespiratory fitness and (iv) indices of systolic and diastolic function using tissue Doppler echocardiography. RESULTS: Cardiorespiratory fitness was similar between all groups; abdominal and visceral fat was highest in the obese groups. Compared with age- and BMI-matched metabolically healthy counterparts, the unhealthy (lean or obese) individuals had higher liver fat and decreased early diastolic strain rate, early diastolic tissue velocity and systolic strain indicative of subclinical systolic and diastolic dysfunction. The magnitude of dysfunction correlated with the number of components of metabolic syndrome but not with BMI or with the degree of ectopic (visceral or liver) fat deposition. CONCLUSIONS: Myocardial dysfunction appears to be related to poor metabolic health rather than simply BMI or fat mass. These data may partly explain the epidemiological evidence on CVD risk relating to the different obesity phenotypes.

Dynapenic obesity and the risk of incident Type 2 diabetes: the English Longitudinal Study of Ageing.

AIM: Obesity is a well-established risk factor for developing Type 2 diabetes. Evidence suggests that sarcopenia, the age-related decline in muscle mass and strength, may exacerbate diabetes risk in obese individuals. The aim of this study was to determine the combined effect of obesity and low muscle strength, dynapenia, on the risk of incident Type 2 diabetes in older adults. METHODS: Participants were 5953 (1670 obese) men and women from the English Longitudinal Study of Ageing without known Type 2 diabetes at baseline and for whom handgrip strength, biochemical and other clinical data were collected. A diagnosis of Type 2 diabetes was recorded from self-reported physician diagnosis over 6 years. RESULTS: For each unit increase in grip strength, there was a reduction in diabetes risk (age-, sex- and BMI adjusted HR; 0.98; 95% CI 0.96-0.99). The risk of Type 2 diabetes was elevated in all obese participants, but was greatest in those with low handgrip strength (HR = 4.93, 95% CI 2.85, 8.53) compared with non-obese individuals with high handgrip strength. Eleven per cent of the sample met the threshold for weakness (handgrip strength: men < 26 kg; women < 16 kg) that was associated with elevated Type 2 diabetes risk in obese (HR = 3.57, 95% CI 2.04, 6.24) but not in non-obese (HR = 0.86, 95% CI, 0.44, 1.68) compared with normal/non-obese participants. CONCLUSION: Dynapenic obesity, determined by high BMI and low handgrip strength, is associated with increased risk of incident Type 2 diabetes in older people.

Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines.

Cerebral activations during viewing of food stimuli in adult patients with acquired structural hypothalamic damage: a functional neuroimaging study.

BACKGROUND/OBJECTIVES: Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. SUBJECTS/METHODS: In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. RESULTS: Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). CONCLUSIONS: Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

Presentation, management and outcomes in acute pituitary apoplexy: a large single-centre experience from the United Kingdom.

OBJECTIVE: To study the presentation, management and outcomes and to apply retrospectively the Pituitary Apoplexy Score (PAS) (United Kingdom (UK) guidelines for management of apoplexy) to a large, single-centre series of patients with acute pituitary apoplexy. DESIGN: Retrospective analysis of casenotes at a single neurosurgical centre in Liverpool, UK. RESULTS: Fifty-five patients [mean age, 52·4 years; median duration of follow-up, 7 years] were identified; 45 of 55 (81%) had nonfunctioning adenomas, four acromegaly and six prolactinomas. Commonest presenting features were acute headache (87%), diplopia (47·2%) and visual field (VF) defects (36%). The most frequent ocular palsy involved the 3rd nerve (81%), followed by 6th nerve (34·6%) and multiple palsies (19%). Twenty-three patients were treated conservatively, and the rest had surgery either within 7 days of presentation or delayed elective surgery. Indications for surgery were deteriorating visual acuity and persistent field defects. Patients presenting with VF defects (n = 20) were more likely to undergo surgery (75%) than to be managed expectantly (25%). There was no difference in the rates of complete/near-complete resolution of VF deficits and cranial nerve palsies between those treated conservatively and those who underwent surgery. Endocrine outcomes were also similar. We were able to calculate the PAS for 46 patients: for the group treated with early surgery mean, PAS was 3·8 and for those managed conservatively or with delayed surgery was 1·8. CONCLUSIONS: Patients without VF deficits or whose visual deficits are stable or improving can be managed expectantly without negative impact on outcomes. Clinical severity based on a PAS ≥ 4 appeared to influence management towards emergency surgical intervention.

Nitric oxide-mediated cutaneous microvascular function is impaired in polycystic ovary sydrome but can be improved by exercise training.

Polycystic ovary syndrome (PCOS) is associated with cardiovascular disease. The contribution of the nitric oxide (NO) dilator system to cutaneous endothelial dysfunction is currently unknown in PCOS. Our aim was to examine whether women with PCOS demonstrate impaired cutaneous microvascular NO function and whether exercise training can ameliorate any impairment. Eleven women with PCOS (age, 29 ± 7 years; body mass index, 34 ± 6 kg m(-2)) were compared with six healthy obese control women (age, 29 ± 7 years; body mass index, 34 ± 5 kg m(-2)). Six women with PCOS (30 ± 7 years; 31 ± 6 kg m(-2)) then completed 16 weeks of exercise training. Laser Doppler flowmetry, combined with intradermal microdialysis of l-N(G)-monomethyl-l-arginine, a nitric oxide antagonist, in response to incremental local heating of the forearm was assessed in women with PCOS and control women, and again in women with PCOS following exercise training. Cardiorespiratory fitness, homeostasis model assessment for insulin resistance, hormone and lipid profiles were also assessed. Differences between women with PCOS and control women and changes with exercise were analysed using Student's unpaired t tests. Differences in the contribution of NO to cutaneous blood flow [expressed as a percentage of maximal cutaneous vasodilatation (CVCmax)] were analysed using general linear models. At 42°C heating, cutaneous NO-mediated vasodilatation was attenuated by 17.5%CVCmax (95% confidence interval, 33.3, 1.7; P = 0.03) in women with PCOS vs. control women. Exercise training improved cardiorespiratory fitness by 5.0 ml kg(-1) min(-1) (95% confidence interval, 0.9, 9.2; P = 0.03) and NO-mediated cutaneous vasodilatation at 42°C heating by 19.6% CVCmax (95% confidence interval, 4.3, 34.9; P = 0.02). Cutaneous microvascular NO function is impaired in women with PCOS compared with obese matched control women but can be improved with exercise training.

Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to (90)Y-DOTATOC/(90)Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. METHODS: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. RESULTS: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. CONCLUSION: In patients with progressive metastatic NETs receiving (90)Y-DOTATOC/(90)Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit.

Effects of 6 months glucagon-like peptide-1 receptor agonist treatment on endothelial function in type 2 diabetes mellitus patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are used for treatment in type 2 diabetes mellitus (T2DM). Little is known about their cardiovascular (CV) impact. We sought to determine the effects of chronic treatment on vascular function in T2DM. Brachial artery endothelial-dependent flow-mediated dilation (FMD) and endothelial-independent glyceryl trinitrate (GTN) function and carotid intima-medial thickness (cIMT) were assessed in 11 severely obese T2DMs (4 females, 7 males: 55 ± 8 years, diabetes duration 8.3 ± 4.7 years mean ± s.d.) before and after 6 months GLP-1 RA. Body weight (5.3 ± 1.2 kg; p < 0.05) and magnetic resonance imaging determined total and subcutaneous fat, but not visceral fat, decreased. Glycaemic control improved. There were no significant changes in FMD, GTN and cIMT (-1.1 ± 0.4%, 0.3 ± 3.0% and 0.00 ± 0.04 mm, respectively). Despite significant improvements in body composition and glycaemic control, 6 months GLP-1 RA treatment did not modulate vascular function. Alternative strategies may therefore be needed to reduce the burden of CV risk in severely obese patients with long-standing T2DM.

Dynapenic Abdominal Obesity as a Risk Factor for Falls.

BACKGROUND: Obesity and low muscle strength (dynapenia) are independently associated with greater falls risk. It remains unclear whether dynapenia and obesity have an additive effect on falls risk, greater than either phenotype alone. OBJECTIVES: To determine whether a combination of abdominal obesity with dynapenia, dynapenic abdominal obesity (DAO), confers a greater risk of falls than either obesity or dynapenia alone in both men and women. DESIGN: An observational cohort study was conducted. SETTING AND PARTICIPANTS: Data from English adults (n=4239, 60-87 years) who took part in the English Longitudinal Study of Ageing were included. MEASUREMENTS: Dynapenia, was defined as hand-grip strength <20kg (female), <30kg (male). Abdominal obesity was defined as waist circumference >88cm (female), >102cm (male). Data on falls and fall-related injuries over a 2-year follow-up were collected. Multiple logistic regression analyses were performed adjusting for age and sex, with results expressed as odds ratios (OR) and areas under the receiver operating characteristic curve (AUC). RESULTS: Falls occurred in 1049 participants, with 284 reporting a related injury during follow-up. DAO was associated with greater OR of falls in men (OR 2.1, 95% Confidence Intervals (CI) 1.3-3.2). Dynapenia rather than obesity was associated with falls in women, with greatest OR observed in those with low hand-grip strength (OR 1.4, 95% CI 1.1-1.7). Individual discrimination was low for measures of obesity or dynapenia either alone or in combination (AUC 0.51-0.58). There was no relationship between fall-related injuries and obesity or dynapenia. CONCLUSION: Our findings suggest a synergistic effect of obesity with dynapenia on falls risk in men but not women.

Poor glycaemic control and ectopic fat deposition mediates the increased risk of non-alcoholic steatohepatitis in high-risk populations with type 2 diabetes: Insights from Bayesian-network modelling.

Background: An estimated 55.5% and 37.3% of people globally with type 2 diabetes (T2D) will have concomitant non-alcoholic fatty liver disease (NAFLD) and the more severe fibroinflammatory stage, non-alcoholic steatohepatitis (NASH). NAFLD and NASH prevalence is projected to increase exponentially over the next 20 years. Bayesian Networks (BNs) offer a powerful tool for modelling uncertainty and visualising complex systems to provide important mechanistic insight. Methods: We applied BN modelling and probabilistic reasoning to explore the probability of NASH in two extensively phenotyped clinical cohorts: 1) 211 participants with T2D pooled from the MODIFY study & UK Biobank (UKBB) online resource; and 2) 135 participants without T2D from the UKBB. MRI-derived measures of visceral (VAT), subcutaneous (SAT), skeletal muscle (SMI), liver fat (MRI-PDFF), liver fibroinflammatory change (liver cT1) and pancreatic fat (MRI-PDFF) were combined with plasma biomarkers for network construction. NASH was defined according to liver PDFF >5.6% and liver cT1 >800ms. Conditional probability queries were performed to estimate the probability of NASH after fixing the value of specific network variables. Results: In the T2D cohort we observed a stepwise increase in the probability of NASH with each obesity classification (normal weight: 13%, overweight: 23%, obese: 36%, severe obesity: 62%). In the T2D and non-T2D cohorts, elevated (vs. normal) VAT conferred a 20% and 1% increase in the probability of NASH, respectively, while elevated SAT caused a 7% increase in NASH risk within the T2D cohort only. In those with T2D, reducing HbA1c from the 'high' to 'low' value reduced the probability of NASH by 22%. Conclusion: Using BNs and probabilistic reasoning to study the probability of NASH, we highlighted the relative contribution of obesity, ectopic fat (VAT and liver) and glycaemic status to increased NASH risk, namely in people with T2D. Such modelling can provide insights into the efficacy and magnitude of public health and pharmacological interventions to reduce the societal burden of NASH.

Bayesian networks and imaging-derived phenotypes highlight the role of fat deposition in COVID-19 hospitalisation risk.

Objective: Obesity is a significant risk factor for adverse outcomes following coronavirus infection (COVID-19). However, BMI fails to capture differences in the body fat distribution, the critical driver of metabolic health. Conventional statistical methodologies lack functionality to investigate the causality between fat distribution and disease outcomes. Methods: We applied Bayesian network (BN) modelling to explore the mechanistic link between body fat deposition and hospitalisation risk in 459 participants with COVID-19 (395 non-hospitalised and 64 hospitalised). MRI-derived measures of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat were included. Conditional probability queries were performed to estimate the probability of hospitalisation after fixing the value of specific network variables. Results: The probability of hospitalisation was 18% higher in people living with obesity than those with normal weight, with elevated VAT being the primary determinant of obesity-related risk. Across all BMI categories, elevated VAT and liver fat (>10%) were associated with a 39% mean increase in the probability of hospitalisation. Among those with normal weight, reducing liver fat content from >10% to <5% reduced hospitalisation risk by 29%. Conclusion: Body fat distribution is a critical determinant of COVID-19 hospitalisation risk. BN modelling and probabilistic inferences assist our understanding of the mechanistic associations between imaging-derived phenotypes and COVID-19 hospitalisation risk.

Effects of chronic treatment with metformin on dipeptidyl peptidase-4 activity, glucagon-like peptide 1 and ghrelin in obese patients with Type 2 diabetes mellitus.

AIMS: Studies investigating the acute effects of metformin have demonstrated actions on the incretin system and appetite regulatory hormones. There are limited data to support that these effects are sustained in the long term. We therefore studied the effects of chronic treatment with metformin on endogenous glucagon-like peptide 1, dipeptidyl peptidase-4 activity and active ghrelin (an orexigenic hormone) in obese patients with Type 2 diabetes mellitus. METHODS: Eight subjects [six male, age 58.7 ± 2.6 years, BMI 41.1 ± 2.9 kg/m(2) , HbA(1c) 69 ± 6 mmol/mol (8.5 ± 0.5%), mean ± sem] with drug-naïve Type 2 diabetes were studied for 6 h following a standard mixed meal, before and after at least 3 months of metformin monotherapy (mean dose 1.75 g daily). RESULTS: The area under the curve (AUC(0-6 h) ) for active glucagon-like peptide 1 was significantly higher on metformin (pre-metformin 1750.8 ± 640 pmol l(-1) min(-1) vs. post-metformin 2718.8 ± 1182.3 pmol l(-1) min(-1) ; P=0.01). The areas under the curves for dipeptidyl peptidase-4 activity and ghrelin were not significantly different pre- and post-treatment with metformin. CONCLUSION: Three months or more of metformin monotherapy in obese patients with Type 2 diabetes was associated with increased postprandial active glucagon-like peptide 1 levels. The effects of metformin on the enteroinsular axis may represent yet another important mechanism underlying its glucose-lowering effects.

Hypopituitarism--a late consequence of aneurysmal subarachnoid haemorrhage?

Over the last decade subarachnoid haemorrhage (SAH) has increasingly been recognised as a cause of hypopituitarism. We report on the case of a patient with evidence of growth hormone deficiency manifesting after a period of time, with a favourable response to growth hormone replacement. This is followed by a review of the current literature.

Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD), more recently referred to as metabolic-associated fatty liver disease, refers to a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, associated with hepatic complications (including liver fibrosis, cirrhosis, and hepatocellular carcinoma) and extrahepatic complications (particularly cardiometabolic complications, including type 2 diabetes and cardiovascular disease). Treatment options include lifestyle interventions (dietary modification and physical activity programs) and pharmacologic interventions. Treatment aims should be broad, with a hepatic focus (to improve/reverse hepatic inflammation, fibrosis, and steatohepatitis), ideally with additional extrahepatic effects affecting metabolic co-morbidities (eg, insulin resistance, glucose dysregulation, dyslipidemia), causing weight loss and affording cardiovascular protection. NASH and fibrosis represent the main histopathological features that warrant treatment to prevent disease progression. Despite a paucity of established treatments, the array of potential molecular targets, pathways, and potential treatments is continually evolving. The goal of this article was to provide a narrative review summarizing the emerging and more established therapeutic options considering the complex pathophysiology of NAFLD and the important long-term sequelae of this condition. METHODS: The literature was reviewed by using PubMed, conference abstracts, and press releases from early-phase clinical studies to provide an overview of the evidence. FINDINGS: As understanding of the pathophysiology of NASH/NAFLD evolves, drugs with different mechanisms of action, targeting different molecular targets and aberrant pathways that mediate hepatic steatosis, inflammation, and fibrosis, have been developed and are being tested in clinical trials. Pharmacologic therapies fall into 4 main categories according to the molecular targets/pathways they disrupt: (1) meta-bolic targets, targeting insulin resistance, hepatic de novo lipogenesis, or substrate utilization; (2) inflam-matory pathways, inhibiting inflammatory cell recruitment/signaling, reduce oxidative/endoplasmic reticulum stress or are antiapoptotic; (3) the liver-gut axis, which modulates bile acid enterohepatic circulation/signaling or alters gut microbiota; and (4) antifibrotic targets, targeting hepatic stellate cells, decrease collagen deposition or increase fibrinolysis. IMPLICATIONS: Lifestyle modification must remain the cornerstone of treatment. Pharmacologic treatment is reserved for NASH or fibrosis, the presence of which requires histopathological confirmation. The disease complexity provides a strong rationale for combination therapies targeting multiple pathways simultaneously.

Current and Emerging Biomarkers and Imaging Modalities for Nonalcoholic Fatty Liver Disease: Clinical and Research Applications.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder that frequently coexists with obesity, metabolic syndrome, and type 2 diabetes. The NAFLD spectrum, ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, can be associated with long-term hepatic (hepatic decompensation and hepatocellular carcinoma) and extrahepatic complications. Diagnosis of NAFLD requires detection of liver steatosis with exclusion of other causes of chronic liver disease. Screening for NAFLD and identification of individuals at risk of end-stage liver disease represent substantial challenges that have yet to be met. NAFLD affects up to 25% of adults, yet only a small proportion will progress beyond steatosis to develop advanced disease (steatohepatitis and fibrosis) associated with increased morbidity and mortality. Identification of this cohort has required the gold standard liver biopsy, which is both invasive and expensive. The use of serum biomarkers and noninvasive imaging techniques is an area of significant clinical relevance. This narrative review outlines current and emerging technologies for the diagnosis of NAFLD, nonalcoholic steatohepatitis, and hepatic fibrosis. METHODS: We reviewed the literature using PubMed and reviewed national and international guidelines and conference proceedings to provide a comprehensive overview of the evidence. FINDINGS: Significant advances have been made during the past 2 decades that have enhanced noninvasive assessment of NAFLD without the need for liver biopsy. For the detection of steatosis, abdominal ultrasonography remains the first-line investigation, although a controlled attenuation parameter using transient elastography is more sensitive. For detecting fibrosis, noninvasive serum markers of fibrosis and algorithms based on routine biochemistry are available, in addition to transient elastography. These techniques are well validated and have been incorporated into national and international screening guidelines. These approaches have facilitated more judicious use of liver biopsy but are yet to entirely replace it. Although serum biomarkers present a pragmatic and widely available screening approach for NAFLD in large population-based studies, magnetic resonance imaging techniques offer the benefit of achieving high degrees of accuracy in disease grading, tumor staging, and assessing therapeutic response. IMPLICATIONS: This diagnostic clinical and research field is rapidly evolving; increasingly combined applications of biomarkers and transient elastography or imaging of selective (intermediate or high risk) cases are being used for clinical and research purposes. Liver biopsy remains the gold standard investigation, particularly in the context of clinical trials, but noninvasive options are emerging, using multimodality assessment, that are quicker, more tolerable, more widely available and have greater patient acceptability.