Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.

The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.

Blood glucose modulation and safety of efferent vagus nerve stimulation in a type 2 diabetic rat model.

Vagus nerve stimulation is emerging as a promising treatment for type 2 diabetes. Here, we evaluated the ability of stimulation of the vagus nerve to reduce glycemia in awake, freely moving metabolically compromised rats. A model of type 2 diabetes (n = 10) was induced using a high-fat diet and low doses of streptozotocin. Stimulation of the abdominal vagus nerve was achieved by pairing 15 Hz pulses on a distal pair of electrodes with high-frequency blocking stimulation (26 kHz, 4 mA) on a proximal pair of electrodes to preferentially produce efferent conducting activity (eVNS). Stimulation was well tolerated in awake, freely moving rats. During 1 h of eVNS, glycemia decreased in 90% of subjects (-1.25 ± 1.25 mM h, p = 0.017), and 2 dB above neural threshold was established as the most effective "dose" of eVNS (p = 0.009). Following 5 weeks of implantation, eVNS was still effective, resulting in significantly decreased glycemia (-1.7 ± 0.6 mM h, p = 0.003) during 1 h of eVNS. There were no overt changes in fascicle area or signs of histopathological damage observed in implanted vagal nerve tissue following chronic implantation and stimulation. Demonstration of the biocompatibility and safety of eVNS in awake, metabolically compromised animals is a critical first step to establishing this therapy for clinical use. With further development, eVNS could be a promising novel therapy for treating type 2 diabetes.

Whole genome investigation of an atypical autism case identifies a novel ANOS1 mutation with subsequent diagnosis of Kallmann syndrome.

We report an actionable secondary finding from whole-genome sequencing (WGS) of a 10-year-old boy with autism. WGS identified non-synonymous variants in several genes, including a nonsense mutation in the ANOS1 gene which is an X-linked cause of Kallmann syndrome. WGS can provide insights into complex genetic disorders such as autism, and actionable incidental findings can offer the potential for therapeutic interventions.

Sex Differences in the Risk of Barrett's Esophagus Associated With the Metabolic Effects of Obesity.

GOAL: The goal of this study was to determine if there is an association between the insulin-insulin-like growth factor axis, the metabolic syndrome (MetS), type 2 diabetes mellitus and risk of Barrett's esophagus (BE), and if these associations are modified by sex. BACKGROUND: BE is more common in males. Gastroesophageal reflux disease, the major risk factor for BE occurs at similar frequencies in both sexes, suggesting that sex-related factors such as the metabolic effects of abdominal obesity may be important in the causation of BE. MATERIALS AND METHODS: A structured interview, anthropometric measures, and fasting blood were collected within a population-based case-control study. We recruited 227 BE cases (70% male) and 241 population controls, frequency matched by age and sex. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for association with BE using multivariable logistic regression models. RESULTS: Hyperinsulinemia (highest vs. lowest tertile, OR=1.9; 95% CI: 1.2-3.1), Homeostatic Model Assessment of Insulin Resistance (OR=1.9; 95% CI: 1.2-3.1) and the MetS (OR=1.8; 95% CI: 1.2-2.6) were independently associated with an increased risk of BE. With each additional MetS criterion, there was a 20% increased risk of BE (OR=1.2; 95% CI: 1.0-1.4). When stratified by sex, these associations were found in males but not females. We found no association with serum measures of insulin-like growth factors or interleukin-6 and risk of BE. CONCLUSION: Hyperinsulinemia, insulin resistance, and the MetS are associated with the risk of BE in males but not females, suggesting these factors may contribute to the higher prevalence of BE in males.

The effect of glucocorticoids on Thrombospondin-1, Osteocalcin and the Thrombospondin-1:Osteocalcin ratio in humans.

OBJECTIVE: Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up- and down-regulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. DESIGN: Prospective observational study. SETTING: Tertiary university hospital in Queensland, Australia. PATIENTS AND MEASUREMENTS: Patients with Cushing's syndrome (CS, n = 19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n = 13), adrenal insufficiency (AI, n = 16) and healthy volunteers (HV, n = 20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4 mg dexamethasone and PRED patients predose at 800 and 4 hours post-dose at 1200 hours. RESULTS: Plasma TSP1 in CS was higher (P < .0001), and serum OCN was lower (P < .0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4 mg dexamethasone (P < .0001) and in AI after taking their hydrocortisone replacement therapy (P < .001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200 hours (both P < .001), but no significant change occurred from pre- to post-dose. A TSP1:OCN ratio of >73 at 800 hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans.

Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review.

BACKGROUND: The efficacy, safety and immunogenicity risk of switching between an originator biologic and a biosimilar or from one biosimilar to another are of potential concern. OBJECTIVES: The aim was to conduct a systematic literature review of the outcomes of switching between biologics and their biosimilars and identify any evidence gaps. METHODS: A systematic literature search was conducted in PubMed, EMBASE and Cochrane Library from inception to June 2017. Relevant societal meetings were also checked. Peer-reviewed studies reporting efficacy and/or safety data on switching between originator and biosimilar products or from one biosimilar to another were selected. Studies with fewer than 20 switched patients were excluded. Data were extracted on interventions, study population, reason for treatment switching, efficacy outcomes, safety and anti-drug antibodies. RESULTS: The systematic literature search identified 63 primary publications covering 57 switching studies. The reason for switching was reported as non-medical in 50 studies (23 clinical, 27 observational). Seven studies (all observational) did not report whether the reasons for switching were medical or non-medical. In 38 of the 57 studies, fewer than 100 patients were switched. Follow-up after switching went beyond 1 year in eight of the 57 studies. Of the 57 studies, 33 included statistical analysis of disease activity or patient outcomes; the majority of these studies found no statistically significant differences between groups for main efficacy parameters (based on P < 0.05 or predefined acceptance ranges), although some studies observed changes for some parameters. Most studies reported similar safety profiles between groups. CONCLUSIONS: There are important evidence gaps around the safety of switching between biologics and their biosimilars. Sufficiently powered and appropriately statistically analysed clinical trials and pharmacovigilance studies, with long-term follow-ups and multiple switches, are needed to support decision-making around biosimilar switching.

Gene networks associated with non-syndromic intellectual disability.

Non-syndromic intellectual disability (NS-ID) is a genetically heterogeneous disorder, with more than 200 candidate genes to date. Despite the increasing number of novel mutations detected, a relatively low number of recurrently mutated genes have been identified, highlighting the complex genetic architecture of the disorder. A systematic search of PubMed and Medline identified 245 genes harbouring non-synonymous variants, insertions or deletions, which were identified as candidate NS-ID genes from case reports or from linkage or pedigree analyses. From this list, 33 genes are common to syndromic intellectual disability (S-ID) and 58 genes are common to certain neurological and neuropsychiatric disorders that often include intellectual disability as a clinical feature. We examined the evolutionary constraint and brain expression of these gene sets, and we performed gene network and protein-protein interaction analyses using GeneGO MetaCoreTM and DAPPLE, respectively. The 245 NS-ID candidate genes were over-represented in axon guidance, synaptogenesis, cell adhesion and neurotransmission pathways, all of which are key neurodevelopmental processes for the establishment of mature neuronal circuitry in the brain. These 245 genes exhibit significantly elevated expression in human brain and are evolutionarily constrained, consistent with expectations for a brain disorder such as NS-ID that is associated with reduced fecundity. In addition, we report enrichment of dopaminergic and glutamatergic pathways for those candidate NS-ID genes that are common to S-ID and/or neurological and neuropsychiatric disorders that exhibit intellectual disability. Collectively, this study provides an overview and analysis of gene networks associated with NS-ID and suggests modulation of neurotransmission, particularly dopaminergic and glutamatergic systems as key contributors to synaptic dysfunction in NS-ID.

Uniting emergency and inpatient clinicians across the ED-inpatient interface: The last frontier?

Unwell patients in the ED requiring inpatient admission must negotiate the interface between the ED and inpatient wards. Despite its importance and scale, this ED-inpatient interface (EDii) is poorly characterised. The aim of this paper is to clearly define the EDii and to describe its importance to (i) the patient: delays to admission and errors in communication across the EDii can increase adverse outcomes; (ii) the hospital: poor EDii function reduces hospital efficiency and effectiveness; and (iii) the healthcare system: half of all hospital inpatient admissions occur via the EDii and so EDii affects system-wide performance. The EDii can be defined as the dynamic, transitional phase of patient care in which responsibility for, and delivery of care, is shared between ED and inpatient hospital services. The EDii is characterised by a complex interplay of patient, hospital and system factors. A clear definition of the EDii and an understanding of its importance will assist future research and interventions to improve patient outcomes.

Association of Sun Exposure, Skin Colour and Body Mass Index with Vitamin D Status in Individuals Who Are Morbidly Obese.

Vitamin D deficiency is a common issue, particularly in obese populations, and is tested by assessing serum 25(OH)D concentrations. This study aimed to identify factors that contribute to the vitamin D status in fifty morbidly obese individuals recruited prior to bariatric surgery. Data collected included serum 25(OH)D concentrations, dietary and supplement intake of vitamin D, sun exposure measures, skin colour via spectrophotometry, and genotype analysis of several single nucleotide polymorphisms in the vitamin D metabolism pathway. Results showed a significant correlation between serum 25(OH)D concentrations and age, and serum 25(OH)D and ITAC score (natural skin colour). Natural skin colour accounted for 13.5% of variation in serum 25(OH)D, with every 10° increase in ITAC score (i.e., lighter skin) leading to a 9 nmol/L decrease in serum 25(OH)D. Multiple linear regression using age, ITAC score, and average UV index in the three months prior to testing, significantly predicted serum 25(OH)D concentrations (R² = 29.7%). Single nucleotide polymorphisms for all vitamin D genes tested, showed lower serum 25(OH)D for those with the rare genotype compared to the common genotype; this was most pronounced for fok1 and rs4588, where those with the rare genotype were insufficient (<50 nmol/L), and those with the common genotype were sufficient (≥50 nmol/L). Assessing vitamin D status in individuals with morbid obesity requires testing of 25(OH)D, but potential risk factors for this population include natural skin colour and age.

Intensity of early correction of hyperglycaemia and outcome of critically ill patients with diabetic ketoacidosis.

OBJECTIVES: To determine the impact of the intensity of early correction of hyperglycaemia on outcomes in patients with diabetic ketoacidosis (DKA) admitted to the intensive care unit. METHODS: We studied adult patients with DKA admitted to 171 ICUs in Australia and New Zealand from 2000 to 2013. We used their blood glucose levels (BGLs) in the first 24 hours after ICU admission to determine whether intensive early correction of hyperglycemia to ≤ 180 mg/dL was independently associated with hypoglycaemia, hypokalaemia, hypo-osmolarity or mortality, compared with partial early correction to > 180 mg/dL as recommended by DKA-specific guidelines. RESULTS: Among 8553 patients, intensive early correction of BGL was applied to 605 patients (7.1%). A greater proportion of these patients experienced hypoglycaemia (20.2% v 9.1%; P < 0.001) and/or hypo-osmolarity (29.4% v 22.0%; P < 0.001), but not hypokalaemia (16.7% v 15.6%; P = 0.47). Overall, 11 patients (1.8%) in the intensive correction group and 112 patients (1.4%) in the partial correction group died (P = 0.42). However, after adjustment for illness severity, partial early correction of BGL was independently associated with a lower risk of hypoglycaemia (odds ratio [OR], 0.38; 95% CI, 0.30-0.48; P < 0.001), lower risk of hypo-osmolarity (OR, 0.80; 95% CI, 0.65-0.98; P < 0.03) and lower risk of death (OR, 0.44; 95% CI, 0.22-0.86; P = 0.02). CONCLUSIONS: In a large cohort of patients with DKA, partial early correction of BGL according to DKA-specific guidelines, when compared with intensive early correction of BGL, was independently associated with a lower risk of hypoglycaemia, hypo-osmolarity and death.

Living well after breast cancer randomized controlled trial protocol: evaluating a telephone-delivered weight loss intervention versus usual care in women following treatment for breast cancer.

BACKGROUND: Obesity, physical inactivity and poor diet quality have been associated with increased risk of breast cancer-specific and all-cause mortality as well as treatment-related side-effects in breast cancer survivors. Weight loss intervention trials in breast cancer survivors have shown that weight loss is safe and achievable; however, few studies have examined the benefits of such interventions on a broad range of outcomes and few have examined factors important to translation (e.g. feasible delivery method for scaling up, assessment of sustained changes, cost-effectiveness). The Living Well after Breast Cancer randomized controlled trial aims to evaluate a 12-month telephone-delivered weight loss intervention (versus usual care) on weight change and a range of secondary outcomes including cost-effectiveness. METHODS/DESIGN: Women (18-75 years; body mass index 25-45 kg/m2) diagnosed with stage I-III breast cancer in the previous 2 years are recruited from public and private hospitals and through the state-based cancer registry (target n = 156). Following baseline assessment, participants are randomized 1:1 to either a 12-month telephone-delivered weight loss intervention (targeting diet and physical activity) or usual care. Data are collected at baseline, 6-months (mid-intervention), 12-months (end-of-intervention) and 18-months (maintenance). The primary outcome is change in weight at 12-months. Secondary outcomes are changes in body composition, bone mineral density, cardio-metabolic and cancer-related biomarkers, metabolic health and chronic disease risk, physical function, patient-reported outcomes (quality of life, fatigue, menopausal symptoms, body image, fear of cancer recurrence) and behaviors (dietary intake, physical activity, sitting time). Data collected at 18-months will be used to assess whether outcomes achieved at end-of-intervention are sustained six months after intervention completion. Cost-effectiveness will be assessed, as will mediators and moderators of intervention effects. DISCUSSION: This trial will provide evidence needed to inform the wide-scale provision of weight loss, physical activity and dietary interventions as part of routine survivorship care for breast cancer survivors. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry (ANZCTR) - ACTRN12612000997853 (Registered 18 September 2012).

Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease.

AIM: To investigate the independent effects of 6-mo of dietary energy restriction or exercise training on whole-body and hepatic fat oxidation of patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Participants were randomised into either circuit exercise training (EX; n = 13; 3 h/wk without changes in dietary habits), or dietary energy restriction (ER) without changes in structured physical activity (ER; n = 8). Respiratory quotient (RQ) and whole-body fat oxidation rates (Fatox) were determined by indirect calorimetry under basal, insulin-stimulated and exercise conditions. Severity of disease and steatosis was determined by liver histology; hepatic Fatox was estimated from plasma ß-hydroxybutyrate concentrations; cardiorespiratory fitness was expressed as VO2peak. Complete-case analysis was performed (EX: n = 10; ER: n = 6). RESULTS: Hepatic steatosis and NAFLD activity score decreased with ER but not with EX. ß-hydroxybutyrate concentrations increased significantly in response to ER (0.08 ± 0.02 mmol/L vs 0.12 ± 0.04 mmol/L, P = 0.03) but remained unchanged in response to EX (0.10 ± 0.03 mmol/L vs 0.11 ± 0.07 mmol/L, P = 0.39). Basal RQ decreased (P = 0.05) in response to EX, while this change was not significant after ER (P = 0.38). VO2peak (P < 0.001) and maximal Fatox during aerobic exercise (P = 0.03) improved with EX but not with ER (P > 0.05). The increase in ß-hydroxybutyrate concentrations was correlated with the reduction in hepatic steatosis (r = -0.56, P = 0.04). CONCLUSION: ER and EX lead to specific benefits on fat metabolism of patients with NAFLD. Increased hepatic Fatox in response to ER could be one mechanism through which the ER group achieved reduction in steatosis.

Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis.

Adipose tissue expansion occurs through a combination of hypertrophy of existing adipocytes and generation of new adipocytes via the process of hyperplasia, which involves the proliferation and subsequent differentiation of preadipocytes. Deficiencies in hyperplasia contribute to adipose tissue dysfunction and the association of obesity with chronic cardiometabolic diseases. Thus, increased understanding of hyperplastic pathways may be expected to afford novel therapeutic strategies. We have reported that fibroblast growth factor (FGF)-1 promotes proliferation and differentiation of human preadipocytes and recently demonstrated that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a central, proximal effector. Herein, we describe the identification and characterization of carboxypeptidase X (CPX)-1, a secreted collagen-binding glycoprotein, as a novel downstream effector in human primary and Simpson-Golabi-Behmel syndrome preadipocytes. CPX-1 expression increased after treatment of preadipocytes with FGF-1, BAMBI knockdown, or induction of differentiation. CPX-1 knockdown compromised preadipocyte differentiation coincident with reduced collagen expression. Furthermore, preadipocytes differentiated on matrix derived from CPX-1 knockdown cells exhibited reduced Glut4 expression and insulin-stimulated glucose uptake. Finally, CPX-1 expression was increased in adipose tissue from obese mice and humans. Collectively, these findings establish CPX-1 as a positive regulator of adipogenesis situated downstream of FGF-1/BAMBI that may contribute to hyperplastic adipose tissue expansion via affecting extracellular matrix remodeling.-Kim, Y.-H., Barclay, J. L., He, J., Luo, X., O'Neill, H. M., Keshvari, S., Webster, J. A., Ng, C., Hutley, L. J., Prins, J. B., Whitehead, J. P. Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis.

Oxidative and endoplasmic reticulum stress in ß-cell dysfunction in diabetes.

The inability of pancreatic ß-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on ß-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in ß-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic ß-cell defects in rare forms of diabetes, in T2D ß-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to ß-cell stress in diabetes and our discovery that interleukin 22 protects ß-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that ß-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.

Thrombospondin-1 is a glucocorticoid responsive protein in humans.

OBJECTIVE: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. DESIGN AND METHODS: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. RESULTS: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P<0.0001) and plasma TSP1 concentrations (P<0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P<0.0001). Plasma TSP1 >400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P<0.01) in patients with secondary adrenal insufficiency. CONCLUSIONS: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

Longitudinal evaluation of the natural history of conservatively managed nonfunctioning pituitary adenomas.

CONTEXT: The optimal management of nonfunctioning pituitary adenomas presenting without symptomatic mass effect remains uncertain. The objective of this study was to elucidate the natural history of nonfunctioning pituitary adenomas managed conservatively. DESIGN: Volumetric evaluation of tumour growth in serial pituitary MRI scans by a single observer and retrospective review of changes in pituitary function. PATIENTS: Patients with nonfunctioning pituitary adenomas who underwent at least 2 serial pituitary MRI scans over ≥6 months between 2003 and 2013 prior to any intervention. MEASUREMENTS: Primary end-point was a ≥20% increase in volume or surgery. Secondary end-points were rate of pituitary dysfunction and pituitary apoplexy. RESULTS: Fifty nonfunctioning pituitary adenomas (23 macroadenomas and 27 microadenomas, mean age 49, range 17-85 years) were identified. Mean follow-up was 36 months (range 6-79). An increase in volume occurred in macroadenomas (P < 0·01) but not in microadenomas (P = 0·44). A ≥20% increase in volume occurred in nine of 23 macroadenomas compared with two of 27 microadenomas (P < 0·05). Five macroadenomas (one with new visual field defect) and one microadenoma proceeded to surgery (P = 0·08). Hormone deficiency was present in four of 24 macroadenomas vs 0 of 27 microadenomas (P < 0·05) at baseline, while new hormone deficiency developed in only two macroadenomas during follow-up. Pituitary apoplexy occurred in one microadenoma. A growth rate of >10 mm3 /month assessed at approximately 2 years of follow-up among the macroadenoma group was highly predictive (sensitivity and specificity of 90%) of a ≥20% increase in volume or surgery. CONCLUSIONS: Nonfunctioning pituitary macroadenomas have a greater tendency to grow and require surgical intervention while microadenomas rarely progress.

Effect of 1-h moderate-intensity aerobic exercise on intramyocellular lipids in obese men before and after a lifestyle intervention.

Intramyocellular lipids (IMCL) are depleted in response to an acute bout of exercise in lean endurance-trained individuals; however, it is unclear whether changes in IMCL content are also seen in response to acute and chronic exercise in obese individuals. We used magnetic resonance spectroscopy in 18 obese men and 5 normal-weight controls to assess IMCL content before and after an hour of cycling at the intensity corresponding with each participant's maximal whole-body rate of fat oxidation (Fatmax). Fatmax was determined via indirect calorimetry during a graded exercise test on a cycle ergometer. The same outcome measures were reassessed in the obese group after a 16-week lifestyle intervention comprising dietary calorie restriction and exercise training. At baseline, IMCL content decreased in response to 1 h of cycling at Fatmax in controls (2.8 ± 0.4 to 2.0 ± 0.3 A.U., -39%, p = 0.02), but not in obese (5.4 ± 2.1 vs. 5.2 ± 2.2 A.U., p = 0.42). The lifestyle intervention lead to weight loss (-10.0 ± 5.4 kg, p < 0.001), improvements in maximal aerobic power (+5.2 ± 3.4 mL/(kg·min)), maximal fat oxidation rate (+0.19 ± 0.22 g/min), and a 29% decrease in homeostasis model assessment score (all p < 0.05). However, when the 1 h of cycling at Fatmax was repeated after the lifestyle intervention, there remained no observable change in IMCL (4.6 ± 1.8 vs. 4.6 ± 1.9 A.U., p = 0.92). In summary, there was no IMCL depletion in response to 1 h of cycling at moderate intensity either before or after the lifestyle intervention in obese men. An effective lifestyle intervention including moderate-intensity exercise training did not impact rate of utilisation of IMCL during acute exercise in obese men.

Nutrient and immune sensing are obligate pathways in metabolism, immunity, and disease.

The growth and survival of multicellular organisms depend upon their abilities to acquire and metabolize nutrients, efficiently store and harness energy, and sense and fight infection. Systems for sensing and using nutrients have consequently coevolved alongside systems for sensing and responding to danger signals, including pathogens, and share many of the same cell signaling proteins and networks. Diets rich in carbohydrates and fats can overload these systems, leading to obesity, metabolic dysfunction, impaired immunity, and cardiovascular disease. Excessive nutrient intake promotes adiposity, typically altering adipocyte function and immune cell distribution, both of which trigger metabolic dysfunction. Here, we discuss novel mechanistic links between metabolism and immunity that underlie metabolic dysfunction in obesity. We aim to stimulate debate about how the endocrine and immune systems are connected through autocrine, paracrine, and neuroendocrine signaling in sophisticated networks that are only now beginning to be resolved. Understanding the expression and action of signaling proteins, together with modulating their receptors or pattern recognition using agonists or antagonists, will enable rational intervention in immunometabolism that may lead to novel treatments for obesity and metabolic dysfunction.

Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus.

OBJECTIVE: New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. METHODS: In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (≥50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. RESULTS: On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4±2.6 years (range 0.6-9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37%; normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10; p=0.04), as was systolic blood pressure (HR=1.02; p<0.001) and levels of glycosylated haemoglobin (HR=1.28; p=0.011). Patients with LVD had significantly worse outcome than those without (χ(2)=4.73; p=0.030). CONCLUSIONS: Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831).