A syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-cell mitochondrial dysfunction in Type 2 diabetes

Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.

Estimating the risk of type-2 diabetes using obese-years in a contemporary population of the Framingham Study

BACKGROUND: We have recently demonstrated that an obese-years construct is a better predictor of the risk of diabetes than the severity of body weight alone. However, these risk estimates were derived from a population cohort study initiated in 1948 that might not apply to the current population.

OBJECTIVE: To validate an obese-years construct in estimating the risk of type-2 diabetes in a more contemporary cohort study.

DESIGN: A total of 5,132 participants of the Framingham Offspring Study, initiated in 1972, were followed up for 45 years. Body mass index (BMI) above 29 kg/m(2) was multiplied by the number of years lived with obesity at that BMI to define the number of obese-years. Time-dependent Cox regression was used to explore the association.

RESULTS: The risk of type-2 diabetes increased significantly with increase in obese-years. Adjusted hazard ratios increased by 6% (95% CI: 5-7%) per additional 10 points of obese-years. This ratio was observed to be similar in both men and women, but was 4% higher in current smokers than in never/ex-smokers. The Akaike Information Criterion confirmed that the Cox regression model with the obese-years construct was a stronger predictor of the risk of diabetes than a model including either BMI or the duration of obesity alone.

CONCLUSIONS: In a contemporary cohort population, it was confirmed that the obese-years construct is strongly associated with an increased risk of type-2 diabetes. This suggests that both severity and the duration of obesity should be considered in future estimations of the burden of disease associated with obesity.

Willingness to initiate insulin among adults with type 2 diabetes in Australian primary care: results from the Stepping Up Study

AIMS: To determine 'hypothetical willingness' to initiate insulin, and identify associated factors, among adults with type 2 diabetes (T2DM) in primary care for whom insulin is clinically indicated.

METHODS: Eligible participants were adults with T2DM with an HbA1c ≥7.5% (58mmol/mol) and prescribed maximum oral hypoglycaemic agents. A total of 261 participants were recruited from 74 Victorian general practices: mean age 62±10 years; 39% (n=103) women; diabetes duration 10±6 years; HbA1c 9.0±1.3% (75±14mmol/mol). Data collected by the Stepping Up Study: demographic and clinical characteristics, 'willingness' to initiate insulin, insulin appraisals, depressive symptoms, and diabetes-related distress. A multinomial regression investigated predictors of 'willingness'.

RESULTS: Nineteen percent (n=50) were 'very willing' to initiate insulin, if recommended. The final regression model (R(2)=.44, χ(2)(12) 145.91, p<.001) demonstrated higher socioeconomic status and less negative attitudes to insulin were associated with increased willingness to initiate insulin.

CONCLUSIONS: Among adults with T2DM for whom insulin is clinically indicated, only one in five are 'very willing' to begin insulin therapy. Independent of demographics, clinical factors and emotional wellbeing, insulin appraisals were associated with 'willingness'. This study highlights the importance of addressing attitudinal barriers to insulin therapy among adults with T2DM in primary care to improve insulin receptiveness.

The impact of insulin therapy and attitudes towards insulin intensification among adults with type 2 diabetes: A qualitative study

BACKGROUND: As type 2 diabetes (T2DM) is a progressive chronic condition, regular clinical review and treatment intensification are critical for prevention of long-term complications. Our aim was to explore the personal impact of insulin therapy, both positive and negative consequences, and attitudes towards future insulin intensification. METHODS: Twenty face-to-face interviews were conducted, and transcripts were analysed using thematic inductive analysis. Eligible participants were adults with T2DM, using insulin injections for <4years. Participants were mostly men (n=13, 65%), (median (range)) aged 65 (43-76) years, living with T2DM for 11.5 (2-27) years. RESULTS: Five themes emerged regarding the consequences (positive and negative) of insulin therapy, including: physical impact, personal control, emotional well-being, freedom/flexibility, (concerns about) others' reactions. Increased inconvenience and the perceived seriousness of using fast-acting insulin were both reported as barriers to future insulin intensification, despite most participants being receptive to the idea of administering additional injections. CONCLUSIONS: Positive and negative experiences of insulin therapy were reported by adults with T2DM and most were receptive to insulin intensification despite reported barriers. These findings may inform clinical interactions with people with T2DM and interventions to promote receptiveness to insulin initiation and intensification.

Measuring the stigma surrounding Type 2 diabetes: development and validation of the Type 2 Diabetes Stigma Assessment Scale (DSAS-2)

OBJECTIVE: To develop and validate a self-report measure of perceived and experienced stigma for use with adults with type 2 diabetes: the Type 2 Diabetes Stigma Assessment Scale (DSAS-2). RESEARCH DESIGN AND METHODS: An item pool was drafted based on qualitative data from 25 adults with type 2 diabetes and content from other health-related stigma questionnaires. Thirteen adults with type 2 diabetes completed 57 draft diabetes stigma items and participated in cognitive debriefing interviews. Based on participant feedback, the pool was reduced to 48 items with a 5-point Likert scale (strongly disagree to strongly agree). A total of 1,064 adults with type 2 diabetes completed a survey including these 48 items and other validated measures. Data were subject to principal components analysis and Spearman ρ correlations. RESULTS: The scale was reduced to 19 items, with an unforced three-factor solution indicative of three subscales: Treated Differently (6 items, α = 0.88), Blame and Judgment (7 items, α = 0.90), and Self-stigma (6 items, α = 0.90). A forced one-factor solution supported the calculation of a total score (α = 0.95). Satisfactory concurrent, convergent, and discriminant validity were demonstrated. CONCLUSIONS: The 19-item DSAS-2 is a reliable and valid measure of type 2 diabetes stigma. A rigorous design and validation process has resulted in a relatively brief measure of perceived and experienced stigma in type 2 diabetes. The novel scale has satisfactory psychometric properties and is now available to facilitate much-needed research in this field.

Behavioural innovation is key to improving the health of one million Australians living with type 2 diabetes

Policy, research and clinical practice need a paradigm shift, focused on human behaviour and psychology.

Development and evaluation of a computer-based, self-management tool for people recently diagnosed with type 2 diabetes

Aim. The purpose of this study was to develop and evaluate a computer-based, dietary, and physical activity self-management program for people recently diagnosed with type 2 diabetes. Methods. The computer-based program was developed in conjunction with the target group and evaluated in a 12-week randomised controlled trial (RCT). Participants were randomised to the intervention (computer-program) or control group (usual care). Primary outcomes were diabetes knowledge and goal setting (ADKnowl questionnaire, Diabetes Obstacles Questionnaire (DOQ)) measured at baseline and week 12. User feedback on the program was obtained via a questionnaire and focus groups. Results. Seventy participants completed the 12-week RCT (32 intervention, 38 control, mean age 59 (SD) years). After completion there was a significant between-group difference in the "knowledge and beliefs scale" of the DOQ. Two-thirds of the intervention group rated the program as either good or very good, 92% would recommend the program to others, and 96% agreed that the information within the program was clear and easy to understand. Conclusions. The computer-program resulted in a small but statistically significant improvement in diet-related knowledge and user satisfaction was high. With some further development, this computer-based educational tool may be a useful adjunct to diabetes self-management. This trial is registered with clinicaltrials.gov NCT number NCT00877851.

Age of onset of obesity and risk of type 2 diabetes

OBJECTIVE: To compare a simple measure - age of onset of obesity - to an obese-years construct (a product of duration and magnitude of obesity) as risk factors for type 2 diabetes.

METHOD: Participants from the Framingham Heart Study who were not obese and did not have diabetes at baseline were included (n=4,320). The Akaike Information Criterion (AIC) was computed to compare four Cox proportional hazards models with incident diabetes as the outcome and: (i) obese-years; (ii) age of onset of obesity; (iii) body mass index (BMI); and (iv) age of onset of obesity plus magnitude of BMI combined, as exposures.

RESULTS: AIC indicated that the model with obese-years provided a more effective explanation of incidence of type 2 diabetes compared to the remaining three models. Models including age of onset of obesity plus BMI were not appreciably different from the model with BMI alone, except in those aged ≥60.

CONCLUSIONS: While obese-years was the optimal obesity construct to explain risk of type 2 diabetes, age of onset may be a useful, practical addition to current BMI in the elderly.

IMPLICATIONS: Where computation of obese-years is not possible or impractical, age of onset of obesity combined with BMI may provide a useful alternative.

Sociodemographic correlates of the increasing trend in prevalence of gestational diabetes mellitus in a large population of women between 1995 and 2005

OBJECTIVE—Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for the development of type 2 diabetes in the mother and is  responsible for morbidity in the child. To better identify women at risk of developing GDM we examined sociodemographic correlates and changes in the prevalence of GDM among all births between 1995 and 2005 in Australia's largest state.
RESEARCH DESIGN AND METHODS—A computerized database of all births (n = 956,738) between 1995 and 2005 in New South Wales, Australia, was used in a multivariate logistic regression that examined the association between sociodemographic characteristics and the occurrence of GDM.
RESULTS—Between 1995 and 2005, the prevalence of GDM increased by 45%, from 3.0 to 4.4%. Women born in South Asia had the highest adjusted odds ratio (OR) of any region (4.33 [95% CI 4.12–4.55]) relative to women born in Australia. Women living in the three lowest socioeconomic quartiles had higher adjusted ORs for GDM relative to women in the highest quartile (1.54 [1.50–1.59], 1.74 [1.69–1.8], and 1.65 [1.60–1.70] for decreasing socioeconomic status quartiles). Increasing age was strongly associated with GDM, with women aged >40 years having an adjusted OR of 6.13 (95% CI 5.79–6.49) relative to women in their early 20s. Parity was associated with a small reduced risk. There was no association between smoking and GDM.
CONCLUSIONS—Maternal age, socioeconomic position, and ethnicity are important correlates of GDM. Future culturally specific interventions should target prevention of GDM in these high-risk groups.

Vitamin C and the risk of gestational diabetes mellitus: a case-control study

OBJECTIVE: To examine whether low maternal dietary intake of vitamin C and low maternal plasma ascorbic acid (AA) concentrations are associated with an increased risk of gestational diabetes mellitus (GDM).
METHODS: Cases were 67 women with GDM meeting National Diabetes Data Group criteria. Controls were 260 women without such a diagnosis. Maternal dietary vitamin C consumption during the periconceptional period and during pregnancy was assessed using a 121-item, semiquantitative food frequency questionnaire. Maternal plasma AA concentrations were determined using automated enzymatic procedures on specimens collected during the intrapartum period.
RESULTS: Mean maternal daily consumption of vitamin C and plasma AA concentrations were 10% and 31% lower, respectively, among GDM cases as compared with controls (130.7 +/- 10.2 vs. 145 +/- 4.9 mg/d, P = .190; 36 +/- 2.0 vs. 53 +/- 1.0 micromol/L, P <.001). After controlling for maternal age, race, prepregnancy adiposity, family history of type 2 diabetes, energy intake and income, women reporting low daily vitamin C intake (< 70 mg/d), as compared with the other women, experienced a 3.7-fold increased risk of GDM (odds ratio [OR] = 3.7, 95% confidence interval [CI] 1.7-8.2). There was a linear relation in risk of GDM with decreasing concentrations of plasma AA (P for linear trend <.001). After adjusting for confounders, women in the lowest quartile (< 42.6 micromol/L), as compared with women in the highest quartile (> 63.3 micromol/L), experienced > 12-fold increased risk of GDM (OR = 12.8, 95% CI 3.5-46.2). CONCLUSION: Low maternal dietary vitamin C intake and low plasma AA concentrations are associated with an increased risk of GDM. Large, prospective, cohort studies are needed to further evaluate the potential beneficial role of vitamin C and other antioxidants in the prevention of impaired glucose tolerance in pregnancy.

Maternal plasma ascorbic acid (vitamin C) and risk of gestational diabetes mellitus

Background : Antioxidants, particularly vitamin C (ascorbic acid), have the capacity to influence glucose tolerance. Modification of diet could reduce the likelihood of developing gestational diabetes mellitus.

Methods : In a prospective cohort study of pregnant women, we studied the association of maternal plasma ascorbic acid concentrations, measured at an average of 13 weeks' gestation, with subsequent risk of gestational diabetes. Maternal plasma ascorbic acid concentrations were determined using automated enzymatic procedures. Dietary vitamin C intake during the periconceptional period and early pregnancy was ascertained using a semiquantitative food frequency questionnaire. We fitted generalized linear models to derive estimates of relative risks and 95% confidence intervals (CIs).

Results : Approximately 4% (n = 33) of 755 women who completed pregnancy developed gestational diabetes mellitus. Plasma ascorbic acid concentrations were inversely associated with the risk of gestational diabetes (P for trend = 0.023). After adjusting for maternal age, race, prepregnancy adiposity, parity, family history of type 2 diabetes, and household income, women with plasma ascorbic acid <55.9 micromol/L (lowest quartile) experienced a 3.1-fold increased risk of gestational diabetes (95% CI = 1.0 - 9.7) compared with women whose concentrations were > or = 74.6 micromol/L (upper quartile). Women who consumed <70 mg vitamin C daily experienced a 1.8-fold increased risk of gestational diabetes compared with women who consumed higher amounts (95% CI = 0.8 - 4.4).

Conclusions : If confirmed, our results raise the possibility that current efforts to encourage populations to consume diets rich in antioxidants, including vitamin C, could reduce the occurrence of gestational diabetes mellitus.

Diabetes mellitus in the australian indigenous community

This report aims to investigate the higher prevalence of type 2 diabetes (T2D) among Indigenous Australians, with recommendations to Australians Health Professionals in order to increase awareness of Indigenous health peculiarities related to diabetes mellitus (DM). Diabetes has become one of the most common public health problems of the 21st century. The proportion of Aborigines Australians developing T2D is 5 to 10 times greater than non-Aborigines. Although DM in Aboriginal community is multifactorial, this report shows three perceived causes: (i) obesity and the "Thrifty Gene Hypothesis", (ii) geographical position and (iii) smoking. It concluded that the combination of these causes have increased the incidence of DM among Indigenous Australians. Therefore, the following are recommended: improvement of genetic research, improvement of medical facilities, and increased employment of Indigenous Health Professionals and improvement of anti-smoking policies.

Participation in physical activity : perception of women with a previous history of gestational diabetes

The aim was to explore the perceptions of physical activity among women with previous gestational diabetes mellitus, in the context of preventing Type 2 diabetes mellitus.

Diabetes risk reduction behaviours of rural postpartum women with a recent history of gestational diabetes

Introduction: For most women, gestational diabetes is temporary; however, an episode of gestational diabetes mellitus (GDM) confers an approximately seven-fold increased risk of developing type 2 diabetes mellitus. Objective: To examine readiness to adopt diabetes risk reduction behaviours and the prevalence of these behaviours among rural women with GDM during their last pregnancy.
Methods: The study design was a self-administered mailed questionnaire seeking information about demographics, stage of change, physical activity level and dietary fat intake. Setting: Regional outpatient context. Participants: Women with a single episode of GDM between 1 July 2001 and 31 December 2005 (n = 210). Main outcome measures: Stage of change for physical activity, weight loss and reducing dietary fat behaviour; meeting activity targets, body mass index (BMI) and dietary fat score.
Results: Eighty-four women returned completed questionnaires (40% response rate). Of the 77 women eligible (mean age 35 ± 3.8 years), 58% met recommended activity targets. Sixty-three percent of women were overweight or obese: mean BMI 29.6 kg/m2 (± 7.30). Women reported a high level of preparedness to engage in physical activity, weight loss and reduction of fat intake. Thirty-nine percent of women had not had any postpartum follow-up glucose screening. Women who remembered receiving diabetes prevention information were significantly more likely to meet physical activity targets (p<0.05).
Conclusions: Readiness to engage in behaviour change was high among this group of rural women for all three diabetes risk reduction behaviours measured. However, despite a high proportion of women meeting activity targets and reducing fat intake, the majority of women remained overweight or obese. Postpartum follow-up glucose testing needs to be improved and the impact of diabetes prevention information provided during pregnancy warrants further study.

Diabetes care provision: barriers, enablers and service needs of young adults with Type 1 diabetes from a region of social disadvantage

AIMS:
To determine the barriers to and enablers of engaging with specialist diabetes care and the service requirements of young adults with Type 1 diabetes mellitus from a low socio-economic, multicultural region.

METHODS:
A cross-sectional survey targeted 357 young adults with Type 1 diabetes, aged 18-30 years. Participants completed questions about barriers/enablers to accessing diabetes care and service preferences, self-reported HbA(1c), plus measures of diabetes-related distress (Problem Areas in Diabetes), depression/anxiety (Hospital Anxiety and Depression Scale), and illness perceptions (Brief Illness Perceptions Questionnaire).

RESULTS:
Eighty-six (24%) responses were received [55 (64%) female; mean ± sd age 24 ± 4 years; diabetes duration 12 ± 7 years; HbA(1c) 68 ± 16 mmol/mol (8.4 ± 1.5%)]. Logistical barriers to attending diabetes care were reported; for example, time constraints (30%), transportation (26%) and cost (21%). However, 'a previous unsatisfactory diabetes health experience' was cited as a barrier by 27%. Enablers were largely matched to overcoming these barriers. Over 90% preferred a multidisciplinary team environment, close to home, with after-hours appointment times. Forty per cent reported severe diabetes-related distress, 19% reported moderate-to-severe depressive symptoms and 50% reported moderate-to-severe anxiety.

CONCLUSIONS:
Among these young adults with Type 1 diabetes, glycaemic control was suboptimal and emotional distress common. They had identifiable logistical barriers to accessing and maintaining contact with diabetes care services, which can be addressed with flexible service provision. A substantial minority were discouraged by previous unsatisfactory experiences, suggesting health providers need to improve their interactions with young adults. This research will inform the design of life-stage-appropriate diabetes services targeting optimal engagement, access, attendance and ultimately improved healthcare outcomes in this vulnerable population.