Rachel T. McGrath

Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity

Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring.

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.

Is there a role for an ultrasensitive thyroglobulin assay in patients with serum antithyroglobulin antibodies? A large (Australian) cohort study in differentiated thyroid cancer

Serum thyroglobulin (Tg) is a marker of residual differentiated thyroid cancer (DTC) after total thyroidectomy; however, circulating antithyroglobulin antibodies (TgAb) may interfere with the immunoassay for Tg. Ultrasensitive assays may have a more significant role in detecting circulating Tg in the context of samples containing TgAb. The aim of this study was to evaluate the utility of ultrasensitive thyroglobulin (US‐Tg) measurement compared to standard Tg measurement and to assess the influence of serum TgAb positivity on Tg detection in a large tertiary referral centre cohort in Australia.

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.

Maternal Obesity Promotes Diabetic Nephropathy in Rodent Offspring.

Maternal obesity is known to increase the risk of obesity and diabetes in offspring. Though diabetes is a key risk factor for the development of chronic kidney disease (CKD), the relationship between maternal obesity and CKD has not been clearly defined. In this study, a mouse model of maternal obesity was employed to determine the impact of maternal obesity on development of diabetic nephropathy in offspring. Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow diet. At postnatal Week 8, offspring were randomly administered low dose streptozotocin (STZ, 55 mg/kg/day for five days) to induce diabetes. Assessment of renal damage took place at postnatal Week 32. We found that offspring of obese mothers had increased renal fibrosis, inflammation and oxidative stress. Importantly, offspring exposed to maternal obesity had increased susceptibility to renal damage when an additional insult, such as STZ-induced diabetes, was imposed. Specifically, renal inflammation and oxidative stress induced by diabetes was augmented by maternal obesity. Our findings suggest that developmental programming induced by maternal obesity has implications for renal health in offspring. Maternal obesity should be considered a risk factor for CKD.

The renal consequences of maternal obesity in offspring are overwhelmed by postnatal high fat diet

Aims/Hypothesis Developmental programming induced by maternal obesity influences the development of chronic disease in offspring. In the present study, we aimed to determine whether maternal obesity exaggerates obesity-related kidney disease. Methods Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow or HFD. At postnatal Week 8, HFD-fed offspring were administered one dose streptozotocin (STZ, 100 mg/kg i.p.) or vehicle control. Metabolic parameters and renal functional and structural changes were observed at postnatal Week 32. Results HFD-fed offspring had increased adiposity, glucose intolerance and hyperlipidaemia, associated with increased albuminuria and serum creatinine levels. Their kidneys displayed structural changes with increased levels of fibrotic, inflammatory and oxidative stress markers. STZ administration did not potentiate the renal effects of HFD. Though maternal obesity had a sustained effect on serum creatinine and oxidative stress markers in lean offspring, the renal consequences of maternal obesity were overwhelmed by the powerful effect of diet-induced obesity. Conclusion Maternal obesity portends significant risks for metabolic and renal health in adult offspring. However, diet-induced obesity is an overwhelming and potent stimulus for the development of CKD that is not potentiated by maternal obesity.

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.