Role of leptin receptors in the development of obesity

The focus of this dissertation was leptin and the leptin receptor, and the role of these genes (OB and OB-R) in the development of obesity and type 2 diabetes in humans and Psammomys obesus, a polygenic rodent model of obesity and type 2 diabetes. Studies in humans showed that circulating leptin concentrations were positively associated with adiposity, and independently associated with circulating insulin and triglyceride concentrations. Analysis of two leptin receptor sequence polymorphisms in a Caucasian Australian population and a population of Nauruan males, with very high prevalence rates of obesity, showed no associations between sequence variation within the OB-R gene and obesity- or diabetes-related phenotypic measures. In addition, these two OB-R polymorphisms were not associated with longitudinal changes in body mass or composition in either of the populations examined. A unique analysis of the effects of multiple gene defects in the Nauruan population, demonstrated that the presence of sequence alterations in both the OB and OB-R genes were associated with insulin resistance. Psammomys obesus is regarded as an excellent rodent model in which to study the development of obesity and type 2 diabetes in humans. Examination of circulating leptin concentrations in Psammomys revealed that, as in humans, leptin concentrations were associated with adiposity, and independently associated with circulating insulin concentrations. This animal model was utilised to examine expression of OB-R, and the regulation of expression of this gene after dietary manipulation. OB-R is known to have several isoforms, and in particular, OB-RA and OB-RB gene expression were examined. OB-RB is the main signalling isoform of the leptin receptors. It has a long intracellular domain and has previously been shown to play an important role in energy balance and body weight regulation in rodents and humans. OB-RA is a much shorter isoform of OB-R, and although it lacks the long intracellular domain necessary to activate the JAK/STAT pathway, OB-RA is also capable of signalling, although to a lesser degree than OB-RB. OB-RA is found to be expressed almost ubiquitously throughout the body, and this isoform may be involved in transport of leptin into the cell, although its role remains unclear. OB-RA and OB-RB were both found to be expressed in a large number of tissues in Psammomys obesus. Interestingly, obese Psammomys were found to have lower levels of expression of OB-RA and OB-RB in the hypothalamus, compared to lean animals. This finding raises the possibility that decreased leptin signalling in the brain of obese, hyperleptinemic Psammomys obesus may contribute to the leptin resistance previously described in this animal model. However, the primary defect is unclear, as alternatively, increased circulating leptin concentrations may lead to down-regulation of leptin receptors. The effect of fasting on leptin concentrations and gene expression of OB-RA and OB-RB was also examined. A 24-hour fast resulted in no change in body weight, but a reduction in circulating leptin concentrations, and an increase in hypothalamic OB-RB gene expression in lean Psammomys. In obese animals, fasting again did not alter body weight, but resulted in an increase in both circulating leptin concentrations and hypothalamic OB-RB gene expression. In the liver, fasting resulted in a large increase in OB-RA gene expression in both lean and obese animals. These results highlighted the fact that regulation of leptin receptor gene expression in polygenic models of obesity and type 2 diabetes is complex, and not solely under the control of circulating leptin concentrations. Sucrose-feeding is an established method of inducing obesity and type 2 diabetes in rodents, and this experimental paradigm was utilised to examine the effects of longer term perturbations of energy balance on the leptin signalling pathway in Psammomys obesus. Addition of a 5% sucrose solution to the diet of lean and obese Psammomys resulted in increased body weight in both groups of animals, however only obese Psammomys showed increased fat mass and the development of type 2 diabetes. The changes in body mass and composition with sucrose-feeding were accompanied by decreased circulating leptin concentrations in both groups of animals, as well as a range of changes in leptin receptor gene expression. Sucrose-feeding increased hypothalamic OB-RB gene expression in obese Psammomys only, while in the liver there was evidence of a reduction in OB-RA and OB-RB gene expression in both lean and obese animals. The direct effects of sucrose on the leptin signalling pathway are unclear, however it is possible to speculate that the effect of sucrose to decrease leptin concentrations may have been involved in the exacerbation of obesity and the development of type 2 diabetes in obese Psammomys, From these studies, it appears that sequence variation in the OB and OB-R genes is unlikely to be a major factor in the etiology of obesity in human populations. The ability to examine regulation of expression of these genes in Psammomys obesus, however, has demonstrated that the effects of nutritional modifications on leptin receptor gene expression need closer attention. The role of the OB and OB-R genes in metabolism and the development of type 2 diabetes also warrants further examination, with particular attention on the differential effects of dietary modifications on leptin receptor gene expression across a range of tissues.

Cut-points for waist circumference in Europids and South Asians

There is little strong evidence that currently recommended higher waist circumference cut-points for Europids compared with South Asians are associated with similar risk for type 2 diabetes. This study was designed to provide such evidence. Longitudinal studies over 5 years were conducted among 5,515 Europid and 2,214 ethnically South Asian participants. Age-standardized diabetes incidence at different levels of waist circumference and incidence difference relative to a reference value were calculated. The Youden Index was used to determine waist circumference cut-points. At currently recommended cut-points, estimated annual diabetes incidence for a 50-year-old Europid was <0.6% for both sexes, and for a 50-year-old South Asian, 5.8% for men and 2.1% for women. Annual diabetes incidence of 1% was observed for a 50 year old at a waist circumference 35–40 cm greater in Europid compared to South Asian men and women. Incidence difference between recommended cut-points and a reference value (80 cm in men, 70 cm in women) was 0.3 and 4.4% per year for Europid and South Asian men, and 0.2 and 0.8% per year for Europid and South Asian women, respectively. Waist circumference cut-points chosen using the Youden Index were shown to be dependent on obesity levels in the population. The much higher observed risk of diabetes in South Asians compared to Europids at the respective recommended waist circumference cut-points suggests that differences between them should be greater. Approaches that use the Youden Index to select waist circumference cut-points are inappropriate and should not be used for this purpose.

A prospective study of factors that lead to body dissatisfaction during pregnancy

This study examined changes in body image and predictors of body dissatisfaction during pregnancy. It was expected that higher levels of depression, social comparison tendencies, teasing, societal pressure to be thin and public self-consciousness would predict body dissatisfaction prospectively. Healthy pregnant women (n = 128) completed questionnaires on three occasions during their pregnancies reporting on a total of four time points: 3 months prior to pregnancy (retrospectively reported), in the early to mid-second trimester, the late-second/early-third trimester, and the latter part of the third trimester. For the most part women reported adapting to the changes that occurred in their body; however, women were most likely to experience higher levels of body dissatisfaction in early to mid-second trimester. Findings related to predictors of body dissatisfaction revealed that both social and psychological factors contributed to body image changes in pregnancy. Implications of the findings are discussed.

Differential gene expression in the skeletal muscle of Psammomys obesis

Focuses on discovering and investigating altered gene expression in the skeletal muscle of Psammomys obesus which is a unique model of obesity and Type II diabetes in which its development is similar to that of the human population. Defects in the skeletal muscle are pivotal to the development of Type II diabetes. Using the latest techniques in molecular biology the regulation of a number of genes was confirmed to be altered in obese or diabetic animals compared to lean. This indicates that changes to gene expression contribute to the metabolic disturbances associated with obesity and Type II diabetes.

Turning points and transitions : experiences of young women with Type 1 diabetes

This research explores young women with Type 1 diabetes' perspectives of the problems and how they manage them when facing turning points and making life transitions. The study presents a substantive theory of how the women tried to minimise the grip of blood glucose levels felt during transitions by creating stability in their lives.

Implementation of clinical practice guidelines using simulation in education

Background: Underpinning the Department of Human Services (DHS) “Future directions for Victoria’s maternity services” strategy in Victoria, are the principles of achieving the right balance between primary level care and access to appropriate levels of medical care by making the best use of the complementary skills of midwives, GPs and obstetricians. Planning new models of care have exposed a need to upskill many clinicians in providing evidence based pregnancy care. A statewide education program conducts 1 day workshops to multidisciplinary forums in Victoria. The program content is developed with each service and simulation activities are incorporated in the workshop to provide a realistic environment for practising skills related to the implementation of clinical practice guidelines.

Method: Post workshop surveys are completed anonymously by participants using a five point Likert scale to evaluate their experiences in peer learning, the use of simulation, reflective practice and communication skills training. Open ended responses were analysed thematically.

Results: In 2007, 14 workshops were conducted with 254 clinicians attending. The survey response rate was 80%. Participants responded ‘strongly agree’ or ‘agree’ that the workshop: enhanced their ability to access current pregnancy care research and information 193/ 204(95%), challenged them to think more broadly 192/204(94%), provided an opportunity to reflect on their communication skills during the simulation actives 197/201 (96%) and provided a valuable opportunity for observing the communication skills of their peers 197/ 201(98%).

Conclusion: Providing opportunities for peer learning in pregnancy education is valuable and the use of simulation can play an important role in overcoming barriers to implementing guidelines.

Depression and anxiety through pregnancy and the early postpartum : an examination of prospective relationships

Background: The aim of this study was to explore the prospective relationship between depressive symptoms and anxiety across pregnancy and the early postpartum.
Methods: Participants (N=207) completed the State–Trait Anxiety Inventory Trait subscale, Beck Depression Inventory, and social support and sleep quality measures at two time points during pregnancy and once in the early postpartum period.
Results: After accounting for the relative stability of anxiety and depression over time, depressive symptoms earlier in pregnancy predicted higher levels of anxiety in late pregnancy and anxiety in late pregnancy predicted higher depressive symptomatology in the early postpartum. A bi-directional model of depression and anxiety in pregnancy was supported.
Limitations: Data were based on self-reports and participating women were predominantly tertiary educated with high family incomes.
Conclusion: Our findings suggest that depressive symptoms precede the development of higher levels of anxiety and that anxiety, even at non-clinical levels, can predict higher depressive symptoms. Clinicians are advised to screen for anxiety and depression concurrently during pregnancy.

Neonatal growth outcomes at birth and one month postpartum following in utero exposure to antidepressant medication

Objective: There is evidence of increasing prescription of antidepressant medication in pregnant women. This has arisen from the recognition of the importance of treating maternal depression. This must be balanced, however, with information on outcomes for infants and children exposed to antidepressants in pregnancy. The aim of the present study was to examine whether neonatal outcomes including gestational age at birth, neonatal growth outcomes at birth and then at 1 month postpartum were altered by in utero exposure to antidepressant medication using a prospective and controlled design.

Method: A prospective case–control study recruited 27 pregnant women taking antidepressant medication and 27 matched controls who were not taking antidepressant medication in pregnancy at an obstetric hospital in Melbourne, Australia. Of the 27 women taking medication, 25 remained on medication in the third trimester. A purpose-designed self-report questionnaire and the Beck Depression Inventory-II were completed in pregnancy, after birth and at one month postpartum. In addition information was collected on exposed and non-exposed infants including Apgar scores, birthweight/length/head circumference and gestational age at birth. Weight/length/head circumference was again collected at 1 month of age.

Results: Infants exposed to antidepressants in utero were eightfold more likely to be born at a premature gestational age, had significantly lower birthweight and were smaller in length and head circumference than non-exposed infants. There was no association between birth outcomes and maternal depression. At 1 month, the difference in weight in the exposed group became significantly greater than the control group.

Conclusion: Antidepressant exposure in utero may affect gestational age at birth and neonatal outcomes independently of antenatal maternal depression. Further studies are needed to examine whether these findings vary according to the type of antidepressant prescribed and follow up growth and development in exposed infants beyond 1 month.

Continuity of midwifery care and gestational weight gain in obese women : a randomised controlled trial

Background: The increased prevalence of obesity in pregnant women in Australia and other developed countries is a significant public health concern. Obese women are at increased risk of serious perinatal complications and guidelines recommend weight gain restriction and additional care. There is limited evidence to support the effectiveness of dietary and physical activity lifestyle interventions in preventing adverse perinatal outcomes and new strategies need to be evaluated. The primary aim of this project is to evaluate the effect of continuity of midwifery care on restricting gestational weight gain in obese women to the recommended range. The secondary aims of the study are to assess the impact of continuity of midwifery care on: women’s experience of pregnancy care; women’s satisfaction with care and a range of psychological factors.
Methods/Design: A two arm randomised controlled trial (RCT) will be conducted with primigravid women recruited from maternity services in Victoria, Australia. Participants will be primigravid women, with a BMI≥30 who are less than 17 weeks gestation. Women allocated to the intervention arm will be cared for in a midwifery continuity of care model and receive an informational leaflet on managing weight gain in pregnancy. Women allocated to the control group will receive routine care in addition to the same informational leaflet. Weight gain during pregnancy, standards of care, medical and obstetric information will be extracted from medical records. Data collected at recruitment (self administered survey) and at 36 weeks by postal survey will include sociodemographic information and the use of validated scales to measure secondary outcomes.
Discussion: Continuity of midwifery care models are well aligned with current Victorian, Australian and many international government policies on maternity care. Increasingly, midwifery continuity models of care are being introduced in low risk maternity care, and information on their application in high risk populations is required. There is an identified need to trial alternative antenatal interventions to reduce perinatal risk factors for women who are obese and the findings from this project may have application in other maternity services. In addition this study will inform a larger trial that will focus on birth and postnatal outcomes.

Serum 25-Hydroxyvitamin D, calcium intake and risk of type 2 diabetes after 5 years : results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)

OBJECTIVE To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity.

RESEARCH DESIGN AND METHODS A total of 6,537 of the 11,247 adults evaluated in 1999–2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004–2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG).

RESULTS During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P < 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63–0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years.

CONCLUSIONS Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.

Cluster randomized controlled trial of a peer support program for people with diabetes: study protocol for the Australasian peers for progress study

Background
Well managed diabetes requires active self-management in order to ensure optimal glycaemic control and appropriate use of available clinical services and other supports. Peer supporters can assist people with their daily diabetes self-management activities, provide emotional and social support, assist and encourage clinical care and be available when needed.
Methods
A national database of Australians diagnosed with type 2 diabetes is being used to invite people in pre-determined locations to participate in community-based peer support groups. Peer supporters are self-identified from these communities. All consenting participants receive diabetes self-management education and education manual prior to randomization by community to a peer support intervention or usual care. This multi-faceted intervention comprises four interconnected components for delivering support to the participants. (1) Trained supporters lead 12 monthly group meetings. Participants are assisted to set goals to improve diabetes self-management, discuss with and encourage each other to strengthen linkages with local clinical services (including allied health services) as well as provide social and emotional support. (2) Support through regular supporter-participant or participant-participant contact, between monthly sessions, is also promoted in order to maintain motivation and encourage self-improvement and confidence in diabetes self-management. (3) Participants receive a workbook containing diabetes information, resources and community support services, key diabetes management behaviors and monthly goal setting activity sheets. (4) Finally, a password protected website contains further resources for the participants. Supporters are mentored and assisted throughout the intervention by other supporters and the research team through attendance at a weekly teleconference. Data, including a self-administered lifestyle survey, anthropometric and biomedical measures are collected on all participants at baseline, 6 and 12 months. The primary outcome is change in cardiovascular disease risk using the UKPDS risk equation. Secondary outcomes include biomedical, quality of life, psychosocial functioning, and other lifestyle measures. An economic evaluation will determine whether the program is cost effective.
Discussion
This manuscript presents the protocol for a cluster randomized controlled trial of group-based peer support for people with type 2 diabetes in a community setting. Results from this trial will contribute evidence about the effectiveness of peer support in achieving effective self-management of diabetes.

Maternal dietary intake during pregnancy has longstanding consequences for the health of her offspring

Over the past 100 years, advances in pharmaceutical and medical technology have reduced the burden of communicable disease, and our appreciation of the mechanisms underlying the development of noncommunicable disease has broadened. During this time, a number of studies, both in humans and animal models, have highlighted the importance of maintaining an optimal diet during pregnancy. In particular, a number of studies support the hypothesis that suboptimal maternal protein and fat intake during pregnancy can have long-term effects on the growing fetus, and increase the likelihood of these offspring developing cardiovascular, renal, or metabolic diseases in adulthood. More recently, it has been shown that dietary intake of a number of micronutrients may offset or reverse the deleterious effects of macronutrient imbalance. Furthermore, maternal fat intake has also been identified as a major contributor to a healthy fetal environment, with a beneficial role for unsaturated fats during development as well as a beneficial impact on cell membrane physiology. Together these studies indicate that attempts to optimise maternal nutrition may prove to be an efficient and cost-effective strategy for preventing the development of cardiovascular, renal, or metabolic diseases.

IDF Diabetes Atlas : sixth edition

This 6th edition of the IDF Diabetes Atlas once again sets the standard for evidence on the global epidemiology of diabetes. The new estimates build on the groundwork laid by previous editions, and confirm the precipitous rise in diabetes over the last few years. An astounding 382 million people are estimated to have diabetes, with dramatic increases seen in countries all over the world. The overwhelming burden of the disease continues to be shouldered by low- and middleincome countries, where four out of five people with diabetes are living. Socially and economically disadvantaged people in every country carry the greatest burden of diabetes and are often the most affected financially.

Managing older people with type 2 diabetes

The Guideline for Managing Older People with Type 2 Diabetes was considered a necessary development following the launch of the IDF 2012 Global Guideline for Type 2 Diabetes. In the latter, recommendations for managing diabetes in older people were included for the first time by the IDF but the review group felt that there were many areas where specific advice was still needed and indeed would offer the clinician extra value in decision making. It was also felt that the format of recommendation in the 2012 Guideline did not offer the flexibility required to address the special issues of older people and their varied physical, cognitive, and social needs.

An international group of diabetes experts was assembled to consider the key issues that require attention in supporting the highest quality of diabetes care for older people on a global scale. This Guideline is unique as it has been developed to provide the clinician with recommendation that assist in clinical management of a wide range of older adults such as those who are not only relatively well and active but those who are functionally dependent. This latter group has been categorised as those with frailty, or dementia, or those at the end of life. We have included practical advice on assessment measures that enable the clinician to categorise all older adults with diabetes and allow the appropriate and relevant recommendations to be applied.

The Guideline has been structured into main chapter headings dealing with expected areas such as cardiovascular risk, education, renal impairment, diabetic foot disease and so on, but also includes commonly addressed areas such as seen such as sexual health. Also included is a section of 'special consideration' where areas such as pain and end of life care are addressed.