Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Is liraglutide or exenatide better in type 2 diabetes?

Background: Subjects with type 2 diabetes have high circulating levels of glucose. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that has a major role in glucose homeostasis. Exenatide and liraglutide are both agonists at the GLP-1 receptor, and are effective at reducing circulating glucose levels (measured as HbA1c levels), but they have not been compared. Objectives/methods: This evaluation is of a clinical trial comparing liraglutide once a day with exenatide twice a day in subjects with type 2 diabetes. Results: In the Liraglutide Effect and Action in Diabetes (LEAD)-6 trial, subcutaneous liraglutide 1.8 mg once a day was compared with exenatide 10 μg twice a day. The primary efficacy outcome was change in HbA1c levels, and this was significantly greater with liraglutide (1.12%) than with exenatide (0.79%). Liraglutide and exenatide had similar small abilities to reduce body weight, blood pressure and LDL-cholesterol. Conclusions: Liraglutide was more effective than exenatide for overall glycaemic control in subjects with type 2 diabetes. However, this is only true for the preparations and doses tested, that is liraglutide 1.8 mg once weekly and exenatide 10 μg b.i.d., and may not apply when the comparison is undertaken with the new longer-lasting preparation of exenatide once weekly.

Clinical utility of mental state screening as a predictor of intellectual outcomes 6 months after diagnosis of type 1 diabetes

Background Screening tests of basic cognitive status or ‘mental state’ have been shown to predict mortality and functional outcomes in adults. This study examined the relationship between mental state and outcomes in children with type 1 diabetes. Objective We aimed to determine whether mental state at diagnosis predicts longer term cognitive function of children with a new diagnosis of type 1 diabetes. Methods Mental state of 87 patients presenting with newly diagnosed type 1 diabetes was assessed using the School-Years Screening Test for the Evaluation of Mental Status. Cognitive abilities were assessed 1 wk and 6 months postdiagnosis using standardized tests of attention, memory, and intelligence. Results Thirty-seven children (42.5%) had reduced mental state at diagnosis. Children with impaired mental state had poorer attention and memory in the week following diagnosis, and, after controlling for possible confounding factors, significantly lower IQ at 6 months compared to those with unimpaired mental state (p < 0.05). Conclusions Cognition is impaired acutely in a significant number of children presenting with newly diagnosed type 1 diabetes. Mental state screening is an effective method of identifying children at risk of ongoing cognitive difficulties in the days and months following diagnosis. Clinicians may consider mental state screening for all newly diagnosed diabetic children to identify those at risk of cognitive sequelae.

An innovative approach to the assessment of nutrient intake in adults with type 2 diabetes : the development, trial and evaluation of a mobile phone photo/voice dietary record

Nutrition interventions in the form of both self-management education and individualised diet therapy are considered essential for the long-term management of type 2 diabetes mellitus (T2DM). The measurement of diet is essential to inform, support and evaluate nutrition interventions in the management of T2DM. Barriers inherent within health care settings and systems limit ongoing access to personnel and resources, while traditional prospective methods of assessing diet are burdensome for the individual and often result in changes in typical intake to facilitate recording. This thesis investigated the inclusion of information and communication technologies (ICT) to overcome limitations to current approaches in the nutritional management of T2DM, in particular the development, trial and evaluation of the Nutricam dietary assessment method (NuDAM) consisting of a mobile phone photo/voice application to assess nutrient intake in a free-living environment with older adults with T2DM. Study 1: Effectiveness of an automated telephone system in promoting change in dietary intake among adults with T2DM The effectiveness of an automated telephone system, Telephone-Linked Care (TLC) Diabetes, designed to deliver self-management education was evaluated in terms of promoting dietary change in adults with T2DM and sub-optimal glycaemic control. In this secondary data analysis independent of the larger randomised controlled trial, complete data was available for 95 adults (59 male; mean age(±SD)=56.8±8.1 years; mean(±SD)BMI=34.2±7.0kg/m2). The treatment effect showed a reduction in total fat of 1.4% and saturated fat of 0.9% energy intake, body weight of 0.7 kg and waist circumference of 2.0 cm. In addition, a significant increase in the nutrition self-efficacy score of 1.3 (p<0.05) was observed in the TLC group compared to the control group. The modest trends observed in this study indicate that the TLC Diabetes system does support the adoption of positive nutrition behaviours as a result of diabetes self-management education, however caution must be applied in the interpretation of results due to the inherent limitations of the dietary assessment method used. The decision to use a close-list FFQ with known bias may have influenced the accuracy of reporting dietary intake in this instance. This study provided an example of the methodological challenges experienced with measuring changes in absolute diet using a FFQ, and reaffirmed the need for novel prospective assessment methods capable of capturing natural variance in usual intakes. Study 2: The development and trial of NuDAM recording protocol The feasibility of the Nutricam mobile phone photo/voice dietary record was evaluated in 10 adults with T2DM (6 Male; age=64.7±3.8 years; BMI=33.9±7.0 kg/m2). Intake was recorded over a 3-day period using both Nutricam and a written estimated food record (EFR). Compared to the EFR, the Nutricam device was found to be acceptable among subjects, however, energy intake was under-recorded using Nutricam (-0.6±0.8 MJ/day; p<0.05). Beverages and snacks were the items most frequently not recorded using Nutricam; however forgotten meals contributed to the greatest difference in energy intake between records. In addition, the quality of dietary data recorded using Nutricam was unacceptable for just under one-third of entries. It was concluded that an additional mechanism was necessary to complement dietary information collected via Nutricam. Modifications to the method were made to allow for clarification of Nutricam entries and probing forgotten foods during a brief phone call to the subject the following morning. The revised recording protocol was evaluated in Study 4. Study 3: The development and trial of the NuDAM analysis protocol Part A explored the effect of the type of portion size estimation aid (PSEA) on the error associated with quantifying four portions of 15 single foods items contained in photographs. Seventeen dietetic students (1 male; age=24.7±9.1 years; BMI=21.1±1.9 kg/m2) estimated all food portions on two occasions: without aids and with aids (food models or reference food photographs). Overall, the use of a PSEA significantly reduced mean (±SD) group error between estimates compared to no aid (-2.5±11.5% vs. 19.0±28.8%; p<0.05). The type of PSEA (i.e. food models vs. reference food photograph) did not have a notable effect on the group estimation error (-6.7±14.9% vs. 1.4±5.9%, respectively; p=0.321). This exploratory study provided evidence that the use of aids in general, rather than the type, was more effective in reducing estimation error. Findings guided the development of the Dietary Estimation and Assessment Tool (DEAT) for use in the analysis of the Nutricam dietary record. Part B evaluated the effect of the DEAT on the error associated with the quantification of two 3-day Nutricam dietary records in a sample of 29 dietetic students (2 males; age=23.3±5.1 years; BMI=20.6±1.9 kg/m2). Subjects were randomised into two groups: Group A and Group B. For Record 1, the use of the DEAT (Group A) resulted in a smaller error compared to estimations made without the tool (Group B) (17.7±15.8%/day vs. 34.0±22.6%/day, p=0.331; respectively). In comparison, all subjects used the DEAT to estimate Record 2, with resultant error similar between Group A and B (21.2±19.2%/day vs. 25.8±13.6%/day; p=0.377 respectively). In general, the moderate estimation error associated with quantifying food items did not translate into clinically significant differences in the nutrient profile of the Nutricam dietary records, only amorphous foods were notably over-estimated in energy content without the use of the DEAT (57kJ/day vs. 274kJ/day; p<0.001). A large proportion (89.6%) of the group found the DEAT helpful when quantifying food items contained in the Nutricam dietary records. The use of the DEAT reduced quantification error, minimising any potential effect on the estimation of energy and macronutrient intake. Study 4: Evaluation of the NuDAM The accuracy and inter-rater reliability of the NuDAM to assess energy and macronutrient intake was evaluated in a sample of 10 adults (6 males; age=61.2±6.9 years; BMI=31.0±4.5 kg/m2). Intake recorded using both the NuDAM and a weighed food record (WFR) was coded by three dietitians and compared with an objective measure of total energy expenditure (TEE) obtained using the doubly labelled water technique. At the group level, energy intake (EI) was under-reported to a similar extent using both methods, with the ratio of EI:TEE was 0.76±0.20 for the NuDAM and 0.76±0.17 for the WFR. At the individual level, four subjects reported implausible levels of energy intake using the WFR method, compared to three using the NuDAM. Overall, moderate to high correlation coefficients (r=0.57-0.85) were found across energy and macronutrients except fat (r=0.24) between the two dietary measures. High agreement was observed between dietitians for estimates of energy and macronutrient derived for both the NuDAM (ICC=0.77-0.99; p<0.001) and WFR (ICC=0.82-0.99; p<0.001). All subjects preferred using the NuDAM over the WFR to record intake and were willing to use the novel method again over longer recording periods. This research program explored two novel approaches which utilised distinct technologies to aid in the nutritional management of adults with T2DM. In particular, this thesis makes a significant contribution to the evidence base surrounding the use of PhRs through the development, trial and evaluation of a novel mobile phone photo/voice dietary record. The NuDAM is an extremely promising advancement in the nutritional management of individuals with diabetes and other chronic conditions. Future applications lie in integrating the NuDAM with other technologies to facilitate practice across the remaining stages of the nutrition care process.

Longitudinal assessment of neuropathy in type 1 diabetes using novel ophthalmic markers (LANDMark) : study design and baseline characteristics

Aims Corneal nerve morphology and corneal sensation threshold have recently been explored as potential surrogate markers for the evaluation of diabetic neuropathy. We present the baseline findings of the ‘Longitudinal Assessment of Neuropathy in type 1 Diabetes using novel ophthalmic Markers’(LANDMark) study. Methods The LANDMark study is a 4-year, two-site, natural history study of three participant groups: type 1 diabetes with neuropathy (T1W), type 1 diabetes without neuropathy (T1WO) and control participants without diabetes or neuropathy. All participants undergo a detailed annual assessment of neuropathy including corneal nerve parameters measured using corneal confocal microscopy and corneal sensitivity measured using non-contact corneal aesthesiometry. Results 76 T1W, 166 T1WO and 154 control participants were enrolled into the study. Corneal sensation threshold (mbars) was significantly higher (i.e. sensitivity was lower) in T1W (1.0 ± 1.1) than T1WO (0.7 ± 0.7) and controls (0.6 ± 0.4) (p < 0.001), with no difference between T1WO and controls. Corneal nerve fibre length was lower in T1W (14.0 ± 6.4 mm/mm2) compared to T1WO (19.1 ± 5.8 mm/mm2) and controls (23.2 ± 6.3 mm/mm2) (p < 0.001). Corneal nerve fibre length was lower in T1WO compared to controls. Conclusions The LANDMark baseline findings confirm a reduction in corneal sensitivity only in Type 1 patients with neuropathy. However, corneal nerve fibre length is reduced even in Type 1 patients without neuropathy with an even greater deficit in Type 1 patients with neuropathy.

The impact of diabetic ketoacidosis and age on behavior six months post-diagnosis in children with type 1 diabetes

Objectives: Children with type 1 diabetes mellitus (DM1) may be at increased risk of psychosocial and adjustment difficulties. We examined behavioral outcomes six months post-diagnosis in a group of children with newly diagnosed DM1. Methods: This study formed part of a larger longitudinal project examining pathophysiology and neuropsychological outcomes in diabetic patients with or without diabetic ketoacidosis (DKA). Participants were 61 children (mean age 11.8 years, SD 2.7 years) who presented with a new diagnosis of DM1 at the Royal Children’s Hospital, Melbourne. Twenty-three (11 female) presented in DKA and 38 (14 female) without DKA. Parents completed the behavior assessment system for children, second edition six months post-diagnosis. Results: There was a non-linear relationship between age and behavior. Internalising problems (i.e. anxiety depression, withdrawal) peaked in the transition from childhood to adolescence; children aged 10–13 years had elevated rates relative to the normal population (t = 2.55, P = 0.018). There was a non-significant trend for children under 10 to display internalising problems (P = 0.052), but rates were not elevated in children over 13 (P = 0.538). Externalising problems were not significantly elevated in any age group. Interestingly, children who presented in DKA were at lower risk of internalising problems than children without DKA (t = 3.83, P < 0.001). There was no effect of DKA on externalising behaviors. Conclusions: Children transitioning from childhood to adolescence are at significant risk for developing internalising problems such as anxiety and lowered mood after diagnosis of DM1. Somewhat counter-intuitively, parents of children presenting in DKA reported fewer internalising symptoms than parents of children without DKA. These results highlight the importance of monitoring and supporting psychosocial adjustment in newly diagnosed children even when they seem physically well.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. © 2011 Nature America, Inc. All rights reserved.

Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control

Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 × 10−28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 × 10−14). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 × 10−9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.

Self-efficacy, outcome expectations and self-care behaviour in people with type 2 diabetes in Taiwan

Aims. To explore differences in self-care behaviour according to demographic and illness characteristics; and relationships among self-care behaviour and demographic and illness characteristics, efficacy expectations and outcome expectations of people with type 2 diabetes in Taiwan. Background. Most people with diabetes do not control their disease appropriately in Taiwan. Enhanced self-efficacy towards managing diseases can be an effective way of improving disease control as proposed by the self-efficacy model which provides a useful framework for understanding adherence to self-care behaviours. Design and methods. The sample comprised 145 patients with type 2 diabetes aged 30 years or more from diabetes outpatient clinics in Taipei. Data were collected using a self-administered questionnaire for this study. One-way anova, t-tests, Pearson product moment correlation and hierarchical regression were analysed for the study. Results. Significant differences were found: between self-care behaviour and complications (t = −2·52, p < 0·01) and patient education (t = −1·96, p < 0·05). Self-care behaviour was significantly and positively correlated with duration of diabetes (r = 0·36, p < 0·01), efficacy expectations (r = 0·54, p < 0·01) and outcome expectations (r = 0·44, p < 0·01). A total of 39·1% of variance in self-care behaviour can be explained by duration of diabetes, efficacy expectations and outcome expectations. Conclusions. Findings support the use of the self-efficacy model as a framework for understanding adherence to self-care behaviour. Relevance to clinical practice. Using self-efficacy theory when designing patient education interventions for people with type 2 diabetes will enhance self-management routines and assist in reducing major complications in the future.

Factors that affect health outcomes in adults with type 2 diabetes : a cross-sectional study

Background: Factors that individually influence blood sugar control, health-related quality of life, and diabetes self-care behaviors have been widely investigated; however, most previous diabetes studies have not tested an integrated association between a series of factors and multiple health outcomes. ---------- Objectives: The purposes of this study are to identify risk factors and protective factors and to examine the impact of risk factors and protective factors on adaptive outcomes in people with type 2 diabetes.---------- Design: A descriptive correlational design was used to examine a theoretical model of risk factors, protective factors, and adaptive outcomes.---------- Settings: This study was conducted at the endocrine outpatient departments of three hospitals in Taiwan. Participants A convenience sample of 334 adults with type 2 diabetes aged 40 and over.---------- Methods: Data were collected by a self-reported questionnaire and physiological examination. Using the structural equation modeling technique, measurement and structural regression models were tested.---------- Results: Age and life events reflected the construct of risk factors. The construct of protective factors was explained by diabetes symptoms, coping strategy, and social support. The construct of adaptive outcomes comprised HbA1c, health-related quality of life, and self-care behaviors. Protective factors had a significant direct effect on adaptive outcomes (β = 0.68, p < 0.001); however, risk factors did not predict adaptive outcomes (β = − 0.48, p = 0.118).---------- Conclusions: Identifying and managing risk factors and protective factors are an integral part of diabetes care. This theoretical model provides a better understanding of how risk factors and protective factors work together to influence multiple adaptive outcomes in people living with type 2 diabetes.

Repeatability of measuring corneal subbasal nerve fiber length in individuals with Type 2 Diabetes

Purpose: To analyze the repeatability of measuring nerve fiber length (NFL) from images of the human corneal subbasal nerve plexus using semiautomated software. Methods: Images were captured from the corneas of 50 subjects with type 2 diabetes mellitus who showed varying severity of neuropathy, using the Heidelberg Retina Tomograph 3 with Rostock Corneal Module. Semiautomated nerve analysis software was independently used by two observers to determine NFL from images of the subbasal nerve plexus. This procedure was undertaken on two occasions, 3 days apart. Results: The intraclass correlation coefficient values were 0.95 (95% confidence intervals: 0.92–0.97) for individual subjects and 0.95 (95% confidence intervals: 0.74–1.00) for observer. Bland-Altman plots of the NFL values indicated a reduced spread of data with lower NFL values. The overall spread of data was less for (a) the observer who was more experienced at analyzing nerve fiber images and (b) the second measurement occasion. Conclusions: Semiautomated measurement of NFL in the subbasal nerve fiber layer is highly repeatable. Repeatability can be enhanced by using more experienced observers. It may be possible to markedly improve repeatability when measuring this anatomic structure using fully automated image analysis software.

Predicting the consumption of foods low in saturated fats among people diagnosed with Type 2 diabetes and cardiovascular disease. The role of planning in the theory of planned behaviour

The present study tested the utility of an extended version of the theory of planned behaviour that included a measure of planning, in the prediction of eating foods low in saturated fats among adults diagnosed with Type 2 diabetes and/or cardiovascular disease. Participants (N = 184) completed questionnaires assessing standard theory of planned behaviour measures (attitude, subjective norm, and perceived behavioural control) and the additional volitional variable of planning in relation to eating foods low in saturated fats. Self-report consumption of foods low insaturated fats was assessed 1 month later. In partial support of the theory of planned behaviour, results indicated that attitude and subjective norm predicted intentions to eat foods low in saturated fats and intentions and perceived behavioural control predicted the consumption of foods low in saturated fats. As an additional variable, planning predicted the consumption of foods low in saturated fats directly and also mediated the intention–behaviour and perceived behavioural control–behaviour relationships, suggesting an important role for planning as a post-intentional construct determining healthy eating choices. Suggestions are offered for interventions designed to improve adherence to healthy eating recommendations for people diagnosed with these chronic conditions with a specific emphasis on the steps and activities that are required to promote a healthier lifestyle.

Randomised controlled trial of an automated, interactive telephone intervention to improve type 2 diabetes self-management (Telephone-Linked Care Diabetes Project) : study protocol

Background: An estimated 285 million people worldwide have diabetes and its prevalence is predicted to increase to 439 million by 2030. For the year 2010, it is estimated that 3.96 million excess deaths in the age group 20-79 years are attributable to diabetes around the world. Self-management is recognised as an integral part of diabetes care. This paper describes the protocol of a randomised controlled trial of an automated interactive telephone system aiming to improve the uptake and maintenance of essential diabetes self-management behaviours. ---------- Methods/Design: A total of 340 individuals with type 2 diabetes will be randomised, either to the routine care arm, or to the intervention arm in which participants receive the Telephone-Linked Care (TLC) Diabetes program in addition to their routine care. The intervention requires the participants to telephone the TLC Diabetes phone system weekly for 6 months. They receive the study handbook and a glucose meter linked to a data uploading device. The TLC system consists of a computer with software designed to provide monitoring, tailored feedback and education on key aspects of diabetes self-management, based on answers voiced or entered during the current or previous conversations. Data collection is conducted at baseline (Time 1), 6-month follow-up (Time 2), and 12-month follow-up (Time 3). The primary outcomes are glycaemic control (HbA1c) and quality of life (Short Form-36 Health Survey version 2). Secondary outcomes include anthropometric measures, blood pressure, blood lipid profile, psychosocial measures as well as measures of diet, physical activity, blood glucose monitoring, foot care and medication taking. Information on utilisation of healthcare services including hospital admissions, medication use and costs is collected. An economic evaluation is also planned.---------- Discussion: Outcomes will provide evidence concerning the efficacy of a telephone-linked care intervention for self-management of diabetes. Furthermore, the study will provide insight into the potential for more widespread uptake of automated telehealth interventions, globally.