Epigenetic markers to predict conversion from gestational diabetes to type 2 diabetes

CONTEXT: Lifestyle factors mediate epigenetic changes that can cause chronic diseases. Although animal and laboratory studies link epigenetic changes to diabetes, epigenetic information in women with gestational diabetes (GDM) and type 2 diabetes is lacking. OBJECTIVE: To measure epigenetic markers across pregnancy and early postpartum and identify markers that could be used as predictors for conversion from GDM to type 2 diabetes. DESIGN: Global histone H3 dimethylation was measured at three time points: 30 weeks gestation, 8-10 weeks postpartum and 20 weeks postpartum, in white blood cells from four groups of women with and without diabetes. SETTING AND PARTICIPANTS: A total of 39 participants (six to nine in each group) were recruited including: non-diabetic women; women with GDM who developed postpartum type 2 diabetes; women with GDM without postpartum type 2 diabetes; and women with type 2 diabetes. MAIN OUTCOME MEASURE: Percentages of dimethylation of H3 histones relative to total H3 histone methylation were compared between diabetic/non-diabetic groups using appropriate comparative statistics. RESULTS: H3K27 dimethylation was 50-60% lower at 8-10 and 20 weeks postpartum in women with GDM who developed type 2 diabetes, compared with non-diabetic women. H3K4 dimethylation was 75% lower at 8-10 weeks postpartum in women with GDM who subsequently developed type 2 diabetes compared with women who had GDM who did not. CONCLUSIONS: The percentage of dimethylation of histones H3K27 and H3K4 varied with diabetic state and has the potential as a predictive tool to identify women who will convert from GDM to type 2 diabetes.

Age-specific trends from 2000-2011 in all-cause and cause-specific mortality in type 1 and type 2 diabetes: a cohort study of more than one million people

OBJECTIVE: To analyze changes by age-group in all-cause and cause-specific mortality rates from 2000-2011 in people with diabetes. RESEARCH DESIGN AND METHODS: A total of 1,189,079 (7.3% with type 1 diabetes) Australians with diabetes registered on the National Diabetes Service Scheme between 2000 and 2011 were linked to the National Death Index. Mortality rates in the total population were age standardized to the 2001 Australian population. Mortality rates were calculated for the following age-groups: 0 to <40 years, ≥ 40 to <60 years, and ≥60 to ≤85 years. Annual mortality rates were fitted using a Poisson regression model including calendar year as a covariate and age and sex where appropriate, with Ptrend reported. RESULTS: For type 1 diabetes, all-cause, cardiovascular disease (CVD), and diabetes age-standardized mortality rates (ASMRs) decreased each year by 0.61, 0.35, and 0.14 per 1,000 person-years (PY), respectively, between 2000 and 2011, Ptrend < 0.05, while cancer mortality remained unchanged. By age, significant decreases in all-cause, CVD, and diabetes mortality rates were observed in all age-groups, excluding diabetes mortality in age-group 0-40 years. For type 2 diabetes, all-cause, CVD, and diabetes ASMRs decreased per year by 0.18, 0.15, and 0.03 per 1,000 PY, respectively, Ptrend < 0.001, while cancer remained unchanged. By age, these decreases were observed in all age-groups, excluding 0-40 years, where significant increases in all-cause and cancer mortality were noted and no change was seen for CVD and diabetes mortality. CONCLUSIONS: All-cause, CVD, and diabetes ASMRs in type 1 and type 2 diabetes decreased between 2000 and 2011, while cancer ASMRs remained unchanged. However, younger populations are not benefiting from the same improvements as older populations. In addition, the absence of a decline in cancer mortality warrants urgent attention.

Can the direct medical cost of chronic disease be transferred across different countries? Using cost-of-illness studies on type 2 diabetes, epilepsy and schizophrenia as examples

OBJECTIVES: To systematically review cost of illness studies for schizophrenia (SC), epilepsy (EP) and type 2 diabetes mellitus (T2DM) and explore the transferability of direct medical cost across countries.

METHODS: A comprehensive literature search was performed to yield studies that estimated direct medical costs. A generalized linear model (GLM) with gamma distribution and log link was utilized to explore the variation in costs that accounted by the included factors. Both parametric (Random-effects model) and non-parametric (Boot-strapping) meta-analyses were performed to pool the converted raw cost data (expressed as percentage of GDP/capita of the country where the study was conducted).

RESULTS: In total, 93 articles were included (40 studies were for T2DM, 34 studies for EP and 19 studies for SC). Significant variances were detected inter- and intra-disease classes for the direct medical costs. Multivariate analysis identified that GDP/capita (p<0.05) was a significant factor contributing to the large variance in the cost results. Bootstrapping meta-analysis generated more conservative estimations with slightly wider 95% confidence intervals (CI) than the parametric meta-analysis, yielding a mean (95%CI) of 16.43% (11.32, 21.54) for T2DM, 36.17% (22.34, 50.00) for SC and 10.49% (7.86, 13.41) for EP.

CONCLUSIONS: Converting the raw cost data into percentage of GDP/capita of individual country was demonstrated to be a feasible approach to transfer the direct medical cost across countries. The approach from our study to obtain an estimated direct cost value along with the size of specific disease population from each jurisdiction could be used for a quick check on the economic burden of particular disease for countries without such data.

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.

'Are you sure you're going to have another one of those?': a qualitative analysis of the social control and social support models in type 2 diabetes

While there is evidence that spouses can impact the self-management of adults with type 2 diabetes mellitus, less is known about the influence of the wider social network. This qualitative study explored the perceived impact of the family as well as friends and work colleagues on type 2 diabetes mellitus self-management. A total of 25 adults with type 2 diabetes mellitus participated in semi-structured interviews regarding their social experiences of living with diabetes. Deductive thematic analysis was applied to the data. Pre-existing themes of health-related social control and social support were identified in the wider social network, with additional themes of non-involvement and unintentional undermining also emerging.

An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus.

Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.

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.

Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy:a multicenter prospective 8 years follow up study

Background: Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention. Methods: We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B). Results: Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan-Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041-1.387, p 0.012). Conclusions: These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy.

The impact of bariatric surgery on estimated glomerular filtration rate in patients with type 2 diabetes:a retrospective cohort study

Background: Diabetes mellitus is the most common cause of end-stage renal disease, which is associated with increased morbidity and mortality. The impact of bariatric surgery on chronic kidney disease is unclear. Objectives: Our primary aim was to assess the impact of bariatric surgery on estimated glomerular filtration rate (eGFR) in type 2 diabetes (T2D) patients. Our secondary aim was to compare the impact of bariatric surgery versus routine care on eGFR in patients with T2D. Setting: University Hospital, United Kingdom. Methods: A retrospective cohort analysis of adults with T2D who underwent bariatric surgery at a single center between January 2005 and December 2012. Data regarding eGFR were obtained from electronic patients records. eGFR was calculated using the Modification of Diet in Renal Disease formula. Data regarding patients with T2D who did not undergo bariatric surgery ("routine care") were obtained from patients attending the diabetes clinic at the same center from 2009 to 2011. Results: One hundred sixty-three patients were included (mean age 48.5±8.8 yr; baseline body mass index 50.8±9.1 kg/m2) and were followed for 3.0±2.3 years. Bariatric surgery resulted in an improvement in eGFR (median [interquartile range] 86.0 [73.0-100.0] versus 92.0 [77.0-101.0] mL/min/1.73 m2 for baseline versus follow-up, respectively; P = .003), particularly in patients with baseline eGFR≤60 mL/min/1.73 m2 (48.0 [42.0-57.0] versus 61.0 [55.0-63.0] mL/min/1.73 m2; P = .004). After adjusting for baseline eGFR, glycated hemoglobin (HbA1C), body mass index, age, and gender, bariatric surgery was associated with higher study-end eGFR compared with routine care (B = 7.787; P< .001). Conclusion: Bariatric surgery results in significant improvements in eGFR in T2D patients, particularly those with an eGFR≤60 mL/min/1.73 m2, while routine care was associated with a decline in eGFR.

Sustained efficacy of dapagliflozin when added to metformin in type 2 diabetes inadequately controlled by metformin monotherapy

Background and aims: The selective SGLT2 inhibitor dapagliflozin (DAPA) reduces hyperglycaemia independently of insulin secretion or action by inhibiting renal glucose reabsorption. This study (MB102014) is a randomised double-blind, placebo (PBO)-controlled trial of DAPA added to metformin (MET) in T2DM (n=546) inadequately controlled with MET alone. Previously reported short-term data at week 24 showed significant mean reductions in the primary [HbA1c] and secondary [fasting plasma glucose (FPG) and weight] endpoints with DAPA compared to PBO. Here we report efficacy and safety results at week 102 of the long-term extension. Materials and methods: Patients aged 18-77 years with HbA1c 7-10% received DAPA 2.5 mg, 5 mg, 10 mg or PBO, plus open-label MET (≥1500mg/d). Exploratory endpoints at week 102 included changes from baseline in HbA1c, FPG and weight, and were analyzed by longitudinal repeated measures analysis. Results: Overall 71.2% of patients completed 102 weeks of the study; fewer on PBO (63.5%) than on DAPA 2.5 mg, 5 mg, and 10 mg (68.3%, 73.0%, 79.8%), due mainly to more patients on PBO discontinuing for lack of efficacy. At week 102, all DAPA groups showed greater mean reductions from baseline in HbA1c, FPG and weight compared to PBO (table), effects that were similar to those observed at week 24 and maintained throughout the trial. More patients at week 102 also achieved a therapeutic response of HbA1c<7% with DAPA 2.5 mg, 5 mg, and 10 mg (20.7%, 26.4%, 31.5%) than with PBO (15.4%). Adverse events (AEs), serious AEs and AEs leading to discontinuation were balanced across all groups. Signs and symptoms suggestive of genital infection (GenInf) were reported in 11.7%, 14.6%, 12.6% (DAPA 2.5 mg, 5 mg, 10 mg) and 5.1% (PBO) of patients, with 1 discontinuation due to GenInf. Signs and symptoms suggestive of urinary tract infection (UTI) were reported in 8.0%, 8.8%, 13.3% (DAPA 2.5 mg, 5 mg, 10 mg) and 8.0% (PBO), with 1 discontinuation due to UTI. No event of pyelonephritis was reported. Conclusion: In comparison to PBO, DAPA added to MET over 102 weeks demonstrated greater and sustained improvements in glycaemic control, clinically meaningful reduction in weight, and no increased risk of hypoglycaemia in patients with T2DM inadequately controlled with MET alone.