Harnessing IL-22 for metabolic health: promise and pitfalls.

Primarily perceived as an anti-inflammatory and antimicrobial mediator in mucosa and skin, interleukin-22 (IL-22) has emerged as a pivotal metabolic regulator. Central to IL-22 signaling is its receptor, IL-22RA1. Through IL-22RA1, IL-22 orchestrates glucose homeostasis by modulating insulin secretion, reducing cellular stress in pancreatic islets, promoting beta-cell regeneration, and influencing hepatic glucose and lipid metabolism.

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 β-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.

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.

Whole genome investigation of an atypical autism case identifies a novel 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 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.

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.

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.

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.

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.

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.

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; = 13; 3 h/wk without changes in dietary habits), or dietary energy restriction (ER) without changes in structured physical activity (ER; = 8). Respiratory quotient (RQ) and whole-body fat oxidation rates (Fat) were determined by indirect calorimetry under basal, insulin-stimulated and exercise conditions.

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.

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.

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

The inability of pancreatic β-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 β-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 β-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response.

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.

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.

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.

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.

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress.

In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent.

Total body fat and the risk of Barrett's oesophagus - a bioelectrical impedance study.

Background: Body mass index is associated with the risk of Barrett's oesophagus (BO). It is uncertain whether this is related to total body fat or other factors that correlate with body mass index. We aimed to quantify the association between total body fat (measured by bioelectrical impedance) and risk of BO and examine if this association was modified by gastro-oesophageal reflux (GOR) and abdominal obesity.

Resveratrol does not benefit patients with nonalcoholic fatty liver disease.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism.

The effect of 25-hydroxyvitamin D on insulin sensitivity in obesity: is it mediated via adiponectin?

There has been substantial recent interest in using vitamin D to improve insulin sensitivity and preventing/delaying diabetes in those at risk. There is little consensus on the physiological mechanisms and whether the association is direct or indirect through enhanced production of insulin-sensitising chemicals, including adiponectin. We examined cross-sectional associations between serum 25-hydroxyvitamin D (25(OH)D) and insulin sensitivity (Matsuda index), parathyroid hormone (PTH), waist circumference, body mass index (BMI), triglycerides (TG), total and high molecular weight (HMW) adiponectin, HMW : total adiponectin ratio (HMW : total adiponectin), and total cholesterol : HDL cholesterol ratio (TC:HDL cholesterol) in 137 Caucasian adults of mean age 43.