Role of the Insulin-like Growth Factor System in Neurodegenerative Disease.

The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.

Relationship between abdominal adiposity, cardiovascular fitness, and biomarkers of cardiovascular risk in British adolescents.

BACKGROUND: Puberty is a critical time in the development of overweight and obesity. The aim of this study was to examine relationships between measures of adiposity, cardiovascular fitness, and biomarkers of cardiovascular disease risk in adolescents. METHODS: In a cross-sectional study design, 129 girls and 95 boys aged 12.9-14.4 years at various stages of puberty were included, along with their mothers (n = 217) and fathers (n = 207). Anthropometric assessments of adiposity were made, along with cardiovascular physical fitness, using the 20-m shuttle run test, and biomarkers associated with cardiovascular risk, including glucose, insulin, triglyceride, fibrinogen, and C-reactive protein (CRP) concentrations. RESULTS: Waist-to-height ratio values were similar in boys and girls and correlated positively with diastolic blood pressure, insulin, triglyceride, fibrinogen, and CRP concentrations, and inversely with cardiovascular fitness scores. Skinfold thickness measurements were higher in girls. High-molecular-weight adiponectin concentrations were lower in boys than girls, particularly in late puberty, and CRP levels were higher. Cardiovascular fitness, maternal body mass index (BMI), and paternal BMI contributed independently to the variance in waist measurements in girls and boys. Gender, triceps skinfold thickness, and weight-to-height ratio, but not parental BMI, contributed independently to the variance in cardiovascular fitness. CONCLUSION: There is a relationship between measures of adolescent adiposity and parental weight that involves factors other than cardiovascular fitness. Adolescent boys have relatively more abdominal fat than girls and a tendency to have a proinflammatory profile of biomarkers. These observations suggest that family and social environmental interventions are best undertaken earlier in childhood, particularly among boys.

Development of a Pilates Teaching Framework from an international survey of teacher practice.

OBJECTIVE: Pilates is used increasingly in a variety of clinical settings. However, there is lack of clarity in the literature as to what is meant by the term. Teachers incorporating apparatus based on the designs of Joseph Pilates (1883-1967) into their practice refer to themselves as Comprehensive Teachers, and this group divides itself further into Classical and Contemporary practice. The aim of this research was to explore the meanings of these terms with Comprehensive Teachers and to develop a framework that reflects current views and practice. METHOD: Online international survey of Pilates Teachers through closed Facebook forums. Open questions were used to elicit views of the definition and practice of Pilates, and how standards should be set across the sector. RESULTS: Of 109 participants, 35% were based in the UK and 32% in the USA; 48% identified as Classical teachers, 32% as Contemporary, 5% as both and 15% as Matwork instructors. A thematic analysis of the qualitative data revealed agreement on the scope and content of Classical and Contemporary Comprehensive Pilates, however the discourse indicated there might be stereotyping about each other's practice. Classical teachers, for example, spoke of their own practice as authentic while Contemporary teachers used terms such as strict and inflexible for Classical practice. However, members of either group may incorporate both Classical and Contemporary approaches within their practice. We have designed a Pilates Teaching Framework to take into account the types of apparatus, the types of exercises and the order in which the exercises are executed. CONCLUSIONS: A framework that emphasises Pilates teaching rather than teacher practice is proposed for consistency and clarity when describing Pilates in professional and public contexts.

The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor-Binding Proteins in the Nervous System.

The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.

Multi-sector perspectives on learning for interprofessional practice: lessons for higher education and organisational culture.

In order to build the evidence base for interprofessional education and practice, it is important to establish how the concepts and theories are understood by higher education providers, policy-makers, managers, and practitioners. Using an interdisciplinary research approach, and facilitated by the use of visual images, we undertook a discourse analysis of interviews and discussions around definitions, competencies, and cultures of learning for interprofessional practice in the context of child health and social care in Scotland. Challenges to interprofessional practice were seen as generated within professional hierarchies and the complicatedness of working with chronic or multisystem disease. In order to work collaboratively, individual practitioners should understand the boundaries of their own knowledge and skills and demonstrate the capacity for interpersonal communication (within and between professions), as well as problem-solving and dealing with uncertainty. While there was agreement on these as key learning needs for collaborative working, the term interprofessional education was rarely used in practice by the interviewees and there was perception of a gap between university and workplace settings in supporting learning for interprofessional practice. It is recommended that educational frameworks acknowledge that the interprofessional learning journey is influenced by context and organisational culture.

The Role of the Growth Hormone/Insulin-Like Growth Factor System in Visceral Adiposity.

There is substantial evidence that the growth hormone (GH)/insulin-like growth factor (IGF) system is involved in the pathophysiology of obesity. Both GH and IGF-I have direct effects on adipocyte proliferation and differentiation, and this system is involved in the cross-talk between adipose tissue, liver, and pituitary. Transgenic animal models have been of importance in identifying mechanisms underlying these interactions. It emerges that this system has key roles in visceral adiposity, and there is a rationale for targeting this system in the treatment of visceral obesity associated with GH deficiency, metabolic syndrome, and lipodystrophies. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.

An individual approach to feline diabetes care: a case report and literature review.

BACKGROUND: Achieving insulin independence is emerging as a realistic therapeutic goal in the management of feline diabetes mellitus. CASE PRESENTATION: The management of an 11-year-old spayed female Burmese cat presenting with diabetes mellitus after corticosteroid administration is described. Remission was achieved after the frequency of insulin administration was increased to four times a day, and supported by intensive home blood glucose monitoring and a high protein, low carbohydrate diet. CONCLUSION: Owners are important collaborators in feline diabetes care and, with intensive home monitoring, more frequent insulin treatment may lead to remission without hypoglycemia. More frequent insulin injections than recommended in the literature may be necessary to achieve glycemic control and used as an alternative to a longer-acting insulin.

Insulin-like growth factor I in cats: validation of an enzyme-linked immunosorbent assay and determination of biologic variation.

BACKGROUND: Insulin-like growth factor I (IGF-I) measurements are used in veterinary medicine for diagnosing growth hormone disorders. IGF-I assays are subject to interference by IGF-binding proteins (IGFBP) which may not be efficiently removed by standard extraction methods. Adding excess IGF-II during analysis may improve accuracy. OBJECTIVES: The purpose of the study was to validate a commercial human IGF-I ELISA which uses excess IGF-II for feline samples and to evaluate biologic variation. METHODS: Precision was determined by calculating the coefficient of variation (CV). Accuracy was determined by recovery after removal of IGFBP, addition of IGF-I, and linear dilution after the addition of IGFBP. Biologic variation was determined by repeated sampling in 7 cats. RESULTS: There was interference by IGFBP in the high measuring range, resulting in falsely low IGF-I concentrations. This was overcome by the addition of high concentrations of IGF-II. Untreated serum had a measured/expected ratio of 98-115% compared to serum where IGFBP had been removed. Recovery after the addition of IGF-I was 83-112%. Inter- and intra-assay CVs ranged from 2.4% to 5.0% which is within the minimum acceptance criteria based on biologic variation. The reference interval of IGF-I was wide (90-1207 ng/mL) and there was a significant association between body weight and ln IGF-I (P < .000001). CONCLUSIONS: This human ELISA is suitable for feline samples, but interfering IGFBP can cause falsely low concentrations. It is recommended to dilute samples such that IGF-I is < 28 ng/mL on the standard curve to grant for sufficient IGF-II for binding of interferent IGFBP.

The Insulin-Like Growth Factor System in Obesity, Insulin Resistance and Type 2 Diabetes Mellitus.

The insulin-like growth factor (IGF) system, acting in concert with other hormone axes, is important in normal metabolism. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH) secretion, while total IGF-I levels are relatively unchanged due to increased hepatic GH sensitivity. IGF-binding protein (IGFBP)-1 levels are suppressed in relation to the increase in insulin levels in obesity and low levels predict the development of type 2 diabetes several years later. Visceral adiposity and hepatic steatosis, along with a chronic inflammation, contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated. The IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target.

Effect of Ghrelin on Hepatic IGF-Binding Protein-1 Production.

Ghrelin plays key roles in energy homeostasis by central and peripheral actions that include effects on insulin signalling pathways in liver. Insulin is an important inhibitor of production by hepatocytes of insulin-like growth factor-binding protein-1 (IGFBP-1) which has an endocrine role to inhibit IGF availability. The effects of ghrelin, insulin, an AMPK activator, and an AMPK inhibitor on IGFBP-1 secretion were studied in H4-II-E rat liver cells. Ghrelin (100 nM) blocked the inhibitory effect of a maximally effective concentration of insulin (10 ng/mL) on IGFBP-1 secretion during a 5 h incubation period (P < 0.001) in the absence and presence of an AMPK inhibitor. Ghrelin, alone, had no effect on IGFBP-1 production, but enhanced secretion independently of insulin under conditions of AMPK activation (P < 0.001). In conclusion, IGFBP-1 is identified as a novel target of ghrelin action in liver that may contribute to its metabolic effects in obesity.

Pubertal stage and measures of adiposity in British schoolchildren.

BACKGROUND: Puberty is a critical period in the development of obesity. Body mass index (BMI), waist circumference and skin-fold thickness are used generally as estimates of body fat in children and adults. AIM: To identify a marker of adiposity that is independent of pubertal status and determine its relationship to physical fitness in adolescence. SUBJECTS AND METHODS: Girls (n = 147) and boys (n = 100) from year 8 in three Welsh schools self-reported Tanner stages. Anthropometric measurements of adiposity were made and aerobic fitness estimated with a 20-metre shuttle-run test. RESULTS: Children in early and late puberty were of similar chronological age. BMI strongly correlated with height in early puberty in girls (r = 0.366, p < 0.001) and boys (r = 0.594, p < 0.001), but not in late puberty. Waist-to-height ratio adjusted for the effect of height on waist measurements; and correlated with percentage fat mass in early and late puberty in girls (r = 0.865 and r = 0.772, both p < 0.001) and boys (r = 0.868 and r = 0.877, both p < 0.001). Physical fitness score was inversely related to waist-to-height ratio, with similar regression lines in early and late puberty, in girls (r = - 0.545, p < 0.001 and r = - 0.362, p = 0.005) and boys (r = - 0.490, p < 0.001 and r = - 0.400, p = 0.003). CONCLUSION: Pubertal status should be taken into account in adjusting weight for height in adolescents. Waist-to-height ratio is a convenient and appropriate measure of adiposity during puberty.

IGF-binding protein 1 and abdominal obesity in the development of type 2 diabetes in women.

OBJECTIVE: Low levels of IGF-binding protein 1 (IGFBP1) are associated with metabolic syndrome and predict diabetes development in men. The aim of this study was to determine the levels of IGFBP1 in women who later develop diabetes, in relation to abdominal obesity, and to compare these levels with those of men. METHODS: IGFBP1 levels were determined at baseline and after 8 years in a case-control, prospective study of Swedish women aged 35-56 years. Individuals with normal oral glucose tolerance test (OGTT) who developed abnormal glucose regulation (n=240) were pair matched to controls for age and family history of diabetes and also compared to men of the same age (n=355). RESULTS: Low fasting IGFBP1 and increased waist measurement predicted development of diabetes in women (n=60; odds ratio (OR) 70, 95% confidence interval (CI) 8-661, lowest tertile and OR 27, 95% CI 5-141, highest tertile). In women developing diabetes, baseline IGFBP1 levels were lower than expected for fasting insulin values, were associated with impaired suppression after OGTT and increased during 8 years despite an increase in fasting insulin. All individuals in the highest tertile for waist and with

Stereotyping at the undergraduate level revealed during interprofessional learning between future doctors and biomedical scientists.

Interprofessional education (IPE) involving undergraduate health professionals is expected to promote collaboration in their later careers. The role of IPE between doctors and biomedical scientists has not been explored at the undergraduate level. Our aim was to introduce IPE sessions for medical and biomedical students in order to identify the benefits and barriers to these groups learning together. Medical and biomedical students together discussed laboratory results, relevant literature, and ideas for developing new diagnostic tools. The programme was evaluated with questionnaires and interviews. While there was general support for the idea of IPE, medical and biomedical students responded differently. Biomedical students were more critical, wanted more explicit learning objectives and felt that their professional role was often misunderstood. The medical students were more enthusiastic but regarded the way the biomedical students communicated concerns about their perceived role as a barrier to effective interprofessional learning. We conclude that stereotyping, which can impede effective collaborations between doctors and biomedical scientists, is already present at the undergraduate level and may be a barrier to IPE. Effective learning opportunities should be supported at the curriculum level and be designed to specifically enable a broad appreciation of each other's future professional roles.

Diabetic osteopathy and the IGF system in the Goto-Kakizaki rat.

OBJECTIVE: Diabetes mellitus is associated with an increased risk of osteopenia, fracture and Charcot arthropathy. Abnormalities of the IGF system commonly observed in diabetes may underlie this "diabetic osteopathy" as IGF-I and its binding proteins (IGFBPs) have been shown to affect osteoblast and osteoclast activity. DESIGN: In type-2 diabetic and control rats we analyzed IGF-I and IGFBP-1 and -4 levels in serum, and notably, also the IGF-I levels in cortical bone, ankles and vertebrae by immunoassays. Osteopathy was assessed by radiography and dual energy X-ray absorptiometry. RESULTS: In the diabetic rats IGF-I was significantly reduced in serum and diaphyseal bone while IGFBP-1 and IGFBP-4 were increased in serum. The periosteal and endosteal diameters were increased in the diaphysis of humerus and tibia (changes similar to those in elderly humans) while bone mineral density was reduced in long bone metaphyses and vertebrae. CONCLUSIONS: Our study demonstrates both systemic and local disturbances of the IGF-system in rats with type-2 diabetes, consistent with the observed enhanced endosteal erosion in long bone diaphyses, and osteopenia in metaphyses and vertebrae. Whether similar IGF-system changes contribute to osteopathy in patients with diabetes and if treatment of diabetes can reverse the osteopathy has yet to be explored.

Altered response of insulin-like growth factor-binding protein 1 to nutritional deprivation in type 2 diabetes mellitus.

Circulating insulin-like growth factor-binding protein 1 (IGFBP-1) normally has a close inverse relationship to insulin secretion, which results in a characteristic diurnal variation. However, in type 2 diabetes the correlation with insulin may be lost and IGFBP-1 concentrations relatively increased. The aim of this study was to determine the effect of nutritional deprivation on the diurnal patterns of IGFBP-1 regulation in type 2 diabetes mellitus. After a baseline assessment period, food intake was reduced over 48 hours to 627.6 kJ/d (150 kcal/d) for 72 hours and increased again over 24 hours to baseline (refeeding). Blood samples were taken at 2-hour intervals, for 24 hours in the baseline period, 48 hours during nutritional deprivation, and 24 hours during refeeding. Six individuals with type 2 diabetes were compared with 2 groups that were selected for normal fasting glucose and insulin levels and comprised 6 obese and 6 lean subjects. During energy (caloric) restriction, fasting insulin levels decreased to a similar extent in each study group. At baseline, IGFBP-1 concentrations were similar in each of the study groups and at the end of the period of energy (caloric) restriction the 6:00 AM fasting levels had increased by 144% in the obese control group and by 245% in the lean individuals (each P < .001). In the patients with type 2 diabetes there was a blunted increase in IGFBP-1 concentrations with nutritional deprivation by 33% compared with baseline. During refeeding after nutritional deprivation the IGFBP-1 response to insulin was restored in the individuals with diabetes. In conclusion, patients with type 2 diabetes mellitus have altered IGFBP-1 regulation, relating to impaired hepatic insulin sensitivity, which improves after a period of energy (caloric) restriction.

Gender-specific pattern of insulin-like growth factor-binding protein-3 protease activity in mouse thyroid.

There is evidence that the IGF system plays an important role in the growth and function of the thyroid gland. Proteolysis is an important posttranslational process that modulates the affinity of IGF binding proteins (IGFBPs) to IGFs, thus regulating their activity. IGFBP-3 has been shown to be cleaved by members of the kallikrein family, some of which are expressed in human thyroid and are characterized by regulation by steroid hormones. The aim of this study was to determine whether IGFBP-3 protease activity is present in mouse thyroid tissue and to characterize its activity by gender and nutrition. Male and female BALB/c mice, aged 16 wk, were studied in the fasted state, or after 1-h or 4-h refeeding. IGFBP protease activity was present in thyroid tissue and resulted in a decrease in IGFBP-3 affinity for IGF-I. The activity was inhibited by 10 mM ZnCl(2), activated by CaCl(2), and was substantially greater in tissue from male mice compared with that from female animals. These properties and the pattern of effect of a panel of protease inhibitors were consistent with this protease being a member of the tissue kallikrein family. Serum inhibited the proteolytic effect of thyroid extracts. There was no effect of nutrition. In conclusion, the degree of activity of IGFBP-3 protease in mouse thyroid tissue is gender specific and is likely to lead to an increased IGF availability in male mice.

Troglitazone stimulates IGF-binding protein-1 by a PPAR gamma-independent mechanism.

IGFBP-1 modulates IGF availability for glucose homeostasis and it may also play a paracrine role in hepatocyte survival. IGFBP-1 is inhibited transcriptionally by insulin and is also regulated by a number of pathways that influence hepatic insulin sensitivity. The effect of the thiazolidinedione troglitazone on IGFBP-1 production was studied in HepG2 human hepatoma cells, which were found to express PPAR alpha, PPAR gamma, and PXR. Troglitazone stimulated IGFBP-1 mRNA expression 2-fold within 3h of exposure (P<0.001) and stimulated secretion up to 3-fold over a narrow dose range within 24h (P<0.001). This effect was mimicked by the PXR ligands clotrimazole and phenobarbital, but not by Wy14,643 or rosiglitazone, which are ligands for PPAR alpha and -gamma, respectively. We conclude that the effect of troglitazone on IGFBP-1 production by HepG2 cells is independent of PPAR and may involve PXR.

IGF-I in a normal population: relation to psychosocial factors.

OBJECTIVE: IGF-I has important actions on cell division, apoptosis, differentiation and metabolism, as well as on cell proliferation in vascular smooth muscle. Deficiency of GH, an important regulator of IGF-I, is associated with reduced well-being. IGF-I levels have been related to cognitive function in older individuals. The aim of the present study was to investigate the IGF-I concentrations in a normal population of men and women aged 20-74 years and to determine the influence of a variety of behavioural and psychosocial factors as well as metabolic factors on these concentrations. DESIGN: Cross-sectional study. PATIENTS: The study group consisted of 408 randomly selected people who had answered a questionnaire concerning health care utilization and quality of life that was administered to a random sample of 4200 people over age 17 from the northwestern region of greater Stockholm in 1995. Thirty-four men and 34 women were randomly selected from the age group 20-24 and from each 10-year age group between the ages of 25-75 years. Seventy-one per cent of the 408 people invited to come in for an examination agreed to attend, making a total sample size of 288 people. MEASUREMENTS: A medical examination was performed and blood drawn in the morning after subjects had been fasting overnight. Before the examination, they were asked to fill out a questionnaire concerning lifestyle and psychosocial factors. RESULTS: The distribution of IGF-I was positively skewed, but using logarithmically transformed IGF-I, a more symmetrical distribution was obtained. A linear inverse correlation was found between logarithmically transformed IGF-I levels and age which explained more than 40% of the variation in men and women. Linear correlation analysis between IGF-I and different parameters of health and disease, lifestyle and psychosocial factors, resulted in several significant correlations most of which disappeared after controlling for age. In the younger age group (20-44) there were positive correlations between IGF-I and psychosocial factors representing quality of life and psychological well-being. In the middle age group (45-59) higher IGF-I levels were related to better physical health, higher education and higher concentrations of lipoprotein Lp(a). In the older age group (over 59 years) higher levels of low-density lipoprotein-cholesterol (LDL-C) and lower levels of SHBG were associated with higher IGF-I levels. CONCLUSION: In a randomly selected (nondisease) population, IGF-I concentrations show a consistent decrease with age in both men and women, accompanied by different association patterns relevant to disease risk. Levels are related to psychosocial parameters in the younger age group and metabolic impairment associated with increased cardiovascular risk in the older age groups. We speculate on the relative roles of age and cohort differences in rearing conditions in determining these differences.