Samantha L. Hocking

Intrinsic depot-specific differences in the secretome of adipose tissue, preadipocytes and adipose tissue derived microvascular endothelial cells

OBJECTIVE Visceral adipose tissue (VAT) is more closely linked to insulin resistance than subcutaneous adipose tissue (SAT). We conducted a quantitative analysis of the secretomes of VAT and SAT to identify differences in adipokine secretion that account for the adverse metabolic consequences of VAT. RESEARCH DESIGN AND METHODS We used lectin affinity chromatography followed by comparison of isotope-labeled amino acid incorporation rates to quantitate relative differences in the secretomes of VAT and SAT explants. Because adipose tissue is composed of multiple cell types, which may contribute to depot-specific differences in secretion, we isolated preadipocytes and microvascular endothelial cells (MVECs) and compared their secretomes to those from whole adipose tissue. RESULTS Although there were no discrete depot-specific differences in the secretomes from whole adipose tissue, preadipocytes, or MVECS, VAT exhibited an overall higher level of protein secretion than SAT. More proteins were secreted in twofold greater abundance from VAT explants compared with SAT explants (59% versus 21%), preadipocytes (68% versus 0%), and MVECs (62% versus 15%). The number of proteins in the whole adipose tissue secretome was greater than the sum of its cellular constituents. Finally, almost 50% of the adipose tissue secretome was composed of factors with a role in angiogenesis. CONCLUSIONS VAT has a higher secretory capacity than SAT, and this difference is an intrinsic feature of its cellular components. In view of the number of angiogenic factors in the adipose tissue secretome, we propose that VAT represents a more readily expandable tissue depot.

Studies of regional adipose transplantation reveal a unique and beneficial interaction between subcutaneous adipose tissue and the intra-abdominal compartment

To the Editor: Obesity is associated with insulin resistance and type 2 diabetes, with accumulation of intra-abdominal fat carrying a more severe disease risk than accumulation of subcutaneous fat. It remains unclear whether increased visceral fat has an adverse metabolic effect due to its location or to the unique properties of intra-abdominal adipocytes. Konrad et al. [1] reported that increasing intra-abdominal fat mass by transplantation of epididymal fat from normal mice into lean recipients improved fasting glucose tolerance and insulin sensitivity, achieving an effect opposite to the expectedmetabolicconsequenceofincreasedintra-abdominal fat. This suggests that obesity-induced alterations in adipose tissue function rather than mass are responsible for the adverse metabolic consequences of obesity. We hypothesised that the intrinsic properties of adipocytes are responsible for their metabolic effects, irrespective of their anatomical location. We have addressed this using regional adipose tissue cross-transplantation in which subcutaneous (inguinal) and intra-abdominal (epididymal) fat pads from donor mice were transplanted into the subcutaneous (group 1) or intra-abdominal (group 2) compartment of recipient mice on a high-fat diet. Our studies revealed that transplantation of intra-abdominal fat into either the intraabdominal or subcutaneous space had no effect on the metabolism of a recipient animal, whereas transplantation of subcutaneous fat into the intra-abdominal space had a significant protective effect on adiposity, insulin sensitivity and glucose tolerance.

Pharmacotherapy for the treatment of obesity

The recognition of the complex counter-regulatory hormonal, metabolic and neurochemical mechanisms that promote weight regain following weight loss and the conceptualisation of obesity as a chronic disease requiring long-term management has led to increasing focus on the role of adjunctive therapies for obesity, particularly pharmacotherapy. Currently available pharmacotherapy achieves a weight loss intermediate between that commonly attained by lifestyle intervention and bariatric surgery, however its accessibility, compared to bariatric surgery increases its appeal. Despite the poor history of obesity pharmacotherapy, novel agents that are in development appear to have several advantages over predecessors. They are generally more selective in their mechanism of action, thereby potentially minimising adverse sequelae and improving the risk-benefit ratio of pharmacotherapy. Another approach has been to use combined pharmacotherapy to better counteract the multiple counter-regulatory neuroendocrine mechanisms which promote weight regain, as well as allowing lower constituent doses of the combined monotherapy agents, which improves the safety and tolerability of these agents that are usually required long-term for chronic weight maintenance. This review will provide an overview of past, present and future pharmacotherapy for obesity. The efficacy and safety profile of currently available pharmacotherapy will be discussed in the setting of stringent regulatory review processes now in place given the fraught history of pharmacological interventions for obesity. Potential novel therapies that seek to better target the multiple complex counter-regulatory mechanisms promoting weight regain while improving the efficacy/safety profile, will also be examined.

Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes

The use of metformin in gestational diabetes is safe and effective, yet some women require additional insulin therapy to achieve glycaemic targets. We found a significant association between earlier gestational age at initiation of metformin therapy and the necessity for supplemental insulin in women treated with metformin during pregnancy.

Central Functions of Glucagon-like Peptide-1: Roles in Energy Regulation andNeuroprotection

The identification of the glucagon-like peptide-1 receptor in the central nervous system has led to an array of studies exploring the functions of central GLP-1 signalling. Originally identified as a gastrointestinal incretin hormone responsible for the potentiation of insulin secretion following ingestion of nutrients, the role of GLP-1 has been expanded to include specific neural activities. Two distinct actions of GLP-1 receptor activation in the brain have been identified, namely the regulation of appetite via promotion of satiety, as well as anti-inflammatory and anti-apoptotic activity to promote neuronal cell survival. Both of these features are now being exploited clinically, with GLP-1 receptor agonists, initially designed and marketed for the treatment of hyperglycaemia in type 2 diabetes, now being directed towards use in obesity and as potential neuroprotective agents. This review gives a summary of the functional role of GLP-1 in the central nervous system, in terms of promoting satiety, modulating food intake and aiding in the regulation of peripheral glycaemia. In addition, the molecular mechanisms underpinning the beneficial effects of central GLP-1 receptor agonist therapy in protecting against neuronal cell inflammation and death, including neurodegenerative processes, are described.

Association Between Glycemic Variability, HbA1c, and Large-for-Gestational-Age Neonates in Women With Type 1 Diabetes

Fetal exposure to hyperglycemia is a major determinant of large-for-gestational-age (LGA; birth weight >90th centile for gender) neonates (1), yet targets for glycemic control beyond the first trimester in type 1 diabetes (T1D) pregnancy remain controversial. As HbA1c represents a summary measure of glycemic control, it might not adequately reflect acute glucose fluctuations or glycemic variability (GV) that contributes to excess fetal growth. Moreover, neonates born to women who attain HbA1c <6% (42 mmol/mol) in the third trimester of pregnancy have an LGA prevalence of 25% (2), with associated adverse perinatal outcomes (3). In contrast to HbA1c, continuous glucose monitoring (CGM) allows precise observation of GV. Several studies have demonstrated an association between higher GV and increased birth weight (1,4,5). The capability of GV compared with HbA1c to identify women likely to have LGA neonates is, however, unclear. We evaluated the association between various measures of GV, HbA1c, and LGA neonates in T1D pregnancy. Twenty-one pregnant women with T1D were recruited over a 2-year period, and measurements of HbA1c and GV (EasyGV, University …

Identification of Patients With Diabetes Who Benefit Most From a Health Coaching Program in Chronic Disease Management, Sydney, Australia, 2013

Introduction Chronic disease management programs (CDMPs) that include health coaching can facilitate and coordinate diabetes management. The aim of this study was to assess changes in patients’ general knowledge of diabetes, self-reported health status, diabetes distress, body mass index (BMI), and glycemic control after enrollment in a face-to-face CDMP group health coaching session (with telephone follow-up) compared with participation in telephone-only health coaching, during a 12-month period. Methods Patients with diabetes were enrolled in a health coaching program at Royal North Shore Hospital, Sydney, Australia, in 2013. Questionnaires were administered at baseline and at 3, 6, and 12 months, and the results were compared with baseline. Glycemic control, measured with glycated hemoglobin A1c (HbA1c) and BMI, were measured at baseline and 12 months. Results Overall, 238 patients attended a face-to-face CDMP session with telephone follow-up (n = 178) or participated in telephone-only health coaching (n = 60). We found no change in BMI in either group; however, HbA1c levels in patients with baseline above the current recommended target (>7%) decreased significantly from 8.5% (standard deviation [SD], 1.0%) to 7.9% (SD, 1.0%) (P = .03). Patients with the lowest self-reported health status at baseline improved from 4.4 (SD, 0.5) to 3.7 (SD, 0.9) (P = .001). Diabetes knowledge improved in all patients (24.4 [SD, 2.4] to 25.2 [SD, 2.4]; P < .001), and diabetes distress decreased among those with the highest levels of distress at baseline (3.0 [SD, 0.4] vs 3.8 [SD, 0.6]; P = .003). Conclusion Diabetes health coaching programs can improve glycemic control and reduce diabetes distress in patients with high levels of these at baseline.

Outcomes of twin pregnancies complicated by gestational diabetes: a meta-analysis of observational studies

Objective:Gestational diabetes mellitus (GDM) in singleton pregnancy is associated with large for gestational age neonates and adverse perinatal outcomes; however, the impact of GDM in twin pregnancy is unclear. Thus, the aim of this study is to assess the perinatal outcomes of twin pregnancies complicated by GDM by performing a meta-analysis of observational studies.Study Design:Studies investigating GDM in twin pregnancy were identified through an online search of three databases: Medline, Embase and Web of Science. Selection criteria comprised full paper observational studies (retrospective or prospective) published in English that examined GDM in twin pregnancy compared with non-GDM twin pregnancy and reported on birth weight and/or adverse perinatal outcomes. Random-effects models with inverse-variance weighting were used to calculate standardized mean differences and unadjusted odds ratios. Sensitivity analyses were carried out to determine the impact of possible maternal confounders (body mass index and age) and GDM diagnostic criteria on perinatal outcomes.Results:Thirteen observational studies were included. GDM twins were born at the same gestation as non-GDM twins, with marginally lower birth weight. There was no difference in the incidence of large or small for gestational age neonates. Although there was no correlation between GDM in twin pregnancy and respiratory distress, neonatal hypoglycemic or low Apgar score, GDM twins had a higher rate of neonatal intensive care unit admission (OR 1.49; 95% confidence interval: 1.10, 2.02; P<0.01).Conclusion:Identification and subsequent treatment of GDM in twin pregnancy demonstrates a similar risk of adverse perinatal outcomes compared with non-GDM twin pregnancies.

Rationale and design of Short-Term EXenatide therapy in Acute ischaemic Stroke (STEXAS): a randomised, open-label, parallel-group study

Introduction Both hyperglycaemia and hypoglycaemia in acute ischaemic stroke (AIS) are associated with increased infarct size and worse functional outcomes. Thus, therapies that can maintain normoglycaemia during stroke are clinically important. Glucagon-like peptide 1 (GLP-1) analogues, including exenatide, are routinely used in the treatment of hyperglycaemia in type 2 diabetes, but data on the usefulness of this class of agents in the management of elevated glucose levels in AIS are limited. Owing to their glucose-dependent mechanism of action, GLP-1 analogues are associated with a low risk of hypoglycaemia, which may give them an advantage over intensive insulin therapy in the acute management of hyperglycaemia in this setting. Methods and analysis The Short-Term EXenatide therapy in Acute ischaemic Stroke study is a randomised, open-label, parallel-group pilot study designed to investigate the efficacy of exenatide at lowering blood glucose levels in patients with hyperglycaemia with AIS. A total of 30 patients presenting with AIS and blood glucose levels >10 mmol/L will be randomised to receive the standard therapy (intravenous insulin) or intravenous exenatide for up to 72 h. Outcomes including blood glucose levels within the target range (5–10 mmol/L), the incidence of hypoglycaemia and the feasibility of administering intravenous exenatide in this patient population will be assessed. A follow-up visit at 3 months will facilitate evaluation of neurological outcomes post-stroke. Ethics and dissemination This study has been approved by the local Institutional Review Board (Northern Sydney Local Health District Human Research Ethics Committee). The study results will be communicated via presentations at scientific conferences and through publication in peer-reviewed journals. Conclusions As GLP-1 analogues require elevated glucose levels to exert their insulin potentiating activity, the use of exenatide in the management of hyperglycaemia in AIS may reduce the incidence of hypoglycaemia, thereby conferring a benefit in morbidity and mortality for patients in the long term. Trial registration number ACTRN12614001189617.

Cross-species gene expression analysis identifies a novel set of genes implicated in human insulin sensitivity

Objective:Insulin resistance (IR) is one of the earliest predictors of type 2 diabetes. However, diagnosis of IR is limited. High fat fed mouse models provide key insights into IR. We hypothesized that early features of IR are associated with persistent changes in gene expression (GE) and endeavored to (a) develop novel methods for improving signal:noise in analysis of human GE using mouse models; (b) identify a GE motif that accurately diagnoses IR in humans; and (c) identify novel biology associated with IR in humans.Methods:We integrated human muscle GE data with longitudinal mouse GE data and developed an unbiased three-level cross-species analysis platform (single gene, gene set, and networks) to generate a gene expression motif (GEM) indicative of IR. A logistic regression classification model validated GEM in three independent human data sets (n=115).Results:This GEM of 93 genes substantially improved diagnosis of IR compared with routine clinical measures across multiple independent data sets. Individuals misclassified by GEM possessed other metabolic features raising the possibility that they represent a separate metabolic subclass. The GEM was enriched in pathways previously implicated in insulin action and revealed novel associations between β-catenin and Jak1 and IR. Functional analyses using small molecule inhibitors showed an important role for these proteins in insulin action.Conclusions:This study shows that systems approaches for identifying molecular signatures provides a powerful way to stratify individuals into discrete metabolic groups. Moreover, we speculate that the β-catenin pathway may represent a novel biomarker for IR in humans that warrant future investigation.