The Transatlantic HbA1c gap: differences in glycaemic control across the lifespan between people included in the US T1D Exchange Registry and those included in the German/Austrian DPV registry.

AIM: To compare HbA1c levels across the lifespan in people with type 1 diabetes in the USA with those in Germany/Austria, and to examine potential differences in HbA1c levels between sexes, insulin delivery methods and minority status. METHODS: Data were extracted from the US T1D Exchange Registry (n=18 381 participants from 73 sites) and from the German/Austrian Prospective Diabetes Follow-up Registry, the DPV (n=32 643 participants from 362 sites). Mean HbA1c was calculated for each year of age for individuals aged ≤25 years, and at 2-year age intervals for individuals aged >25 years. Curves for mean HbA1c by age were estimated using locally weighted scatterplot smoothing. HbA1c differences between registries, sexes, insulin delivery methods, and minority status were assessed by age group using multiple linear regression. RESULTS: In both registries, mean HbA1c increased by ~11 mmol/mol (1.0%) between the ages of 9 and 18 years, although at quite different absolute levels: from 66 mmol/mol (8.2%) to 77 mmol/mol (9.2%) in the T1D Exchange Registry, and from 56 mmol/mol (7.3%) to 66 mmol/mol (8.2%) in the DPV. Sex differences were observed in the DPV only. In the T1D Exchange Registry, injection users had higher mean HbA1c than pump users across the lifespan, whereas in the DPV higher HbA1c levels in injection users were observed in the age groups 6 to <12 years, 12 to <18 years, and 30 to <50 years (P < 0.001). Minority status was significantly associated with higher HbA1c in most age groups in both registries. CONCLUSIONS: Significant differences in HbA1c were noted between the USA and Germany/Austria, with disparities more pronounced in early childhood through to young adulthood. Further studies should identify causes for these disparities.

Understanding adolescent and parent acceptability and feasibility experience in a large Type 1 diabetes mellitus behavioural trial.

AIMS: Using an 18-month, multisite randomized control trial as an exemplar, the aim of this study was to identify themes related to adolescent and parental feasibility and acceptability for participation in large behavioural trials designed to improve adolescents' Type 1 diabetes self-management. METHODS: Thematic analysis methodology was used to develop themes describing factors related to acceptability and feasibility. RESULTS: Based on a sample of interviews (N = 72), factors contributing to intervention acceptability and feasibility were identified. Aspects of acceptability included: a framework for goal-setting, the coach as a non-judgemental listener, perception of an ongoing benefit to participation and the delivery mode. Aspects of feasibility included: participants' altruism to help adolescents with Type 1 diabetes; pre-enrolment preparation for intervention content and duration; and the option of remote intervention delivery via telephone or video, which minimized travel time and costs. In addition, participants described positive outcomes including improvements in behaviour, Type 1 diabetes self-management behaviours and parent-adolescent communication, and emotion-attitude changes. Participants also described potential revisions that may inform future trials. CONCLUSIONS: Acceptability and feasibility of behavioural interventions with adolescents with chronic illness have multifactorial dimensions. While empowering adolescent self-management, parental support is also an under-appreciated aspect to consider. Potential revisions were identified for subsequent behavioural trials.

Diabetes technology: improving care, improving patient-reported outcomes and preventing complications in young people with Type 1 diabetes.

With the evolution of diabetes technology, those living with Type 1 diabetes are given a wider arsenal of tools with which to achieve glycaemic control and improve patient-reported outcomes. Furthermore, the use of these technologies may help reduce the risk of acute complications, such as severe hypoglycaemia and diabetic ketoacidosis, as well as long-term macro- and microvascular complications. In addition, diabetes technology can have a beneficial impact on psychosocial health by reducing the burden of diabetes. Unfortunately, diabetes goals are often unmet and people with Type 1 diabetes too frequently experience acute and long-term complications of this condition, in addition to often having less than ideal psychosocial outcomes. Increasing realization of the importance of patient-reported outcomes is leading to diabetes care delivery becoming more patient-centred. Diabetes technology in the form of medical devices, digital health and big data analytics have the potential to improve clinical care and psychosocial support, resulting in lower rates of acute and chronic complications, decreased burden of diabetes care, and improved quality of life.

Predictors of early renal function decline in adults with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes and the Pittsburgh Epidemiology of Diabetes Complications studies.

AIM: Diabetic kidney disease is one of the leading complications of Type 1 diabetes, but its prediction remains a challenge. We examined predictors of rapid decline in estimated GFR (eGFR) in two Type 1 diabetes cohorts: the Coronary Artery Calcification in Type 1 Diabetes (CACTI) and the Pittsburgh Epidemiology of Diabetes Complications (EDC). METHODS: A select subset of participants (CACTI: n = 210 and EDC: n = 98) diagnosed before 17 years of age with Type 1 diabetes duration ≥ 7 years, and follow-up data on eGFR by CKD-EPI creatinine for up to 8 years were included in the analyses. Early renal function decline was defined as annual decline in eGFR ≥ 3 ml/min/1.73 m2 , and normal age-related decline as eGFR ≤ 1 ml/min/1.73 m2 . Parallel logistic regression models were constructed in the two cohorts. RESULTS: Early renal function decline incidence was 36% in CACTI and 41% in EDC. In both cohorts, greater baseline eGFR (CACTI: OR 3.12, 95% CI 1.97-5.05; EDC: OR 1.92, 95% CI 1.17-3.15 per 10 ml/min/1.73 m2 ) and log albumin-to-creatinine (ACR) (CACTI: OR 3.24, 95% CI 1.80-5.83; EDC: OR 1.87, 95% CI 1.18-2.96 per 1 unit) predicted greater odds of early renal function decline in fully adjusted models. Conversely, ACE inhibition predicted lower odds of early renal function decline in women in CACTI, but similar relationships were not observed in women in EDC. CONCLUSIONS: A substantial proportion of people with Type 1 diabetes in the EDC and CACTI cohorts experienced early renal function decline over time. ACE inhibition appeared to be protective only in women in CACTI where the prevalence of its use was twofold higher compared with the EDC.

Behavioural implications of traditional treatment and closed-loop automated insulin delivery systems in Type 1 diabetes: applying a cognitive restraint theory framework.

As the prevalence of obesity in Type 1 diabetes rises, the effects of emerging therapy options should be considered in the context of both weight and glycaemic control outcomes. Artificial pancreas device systems will 'close the loop' between blood glucose monitoring and automated insulin delivery and may transform day-to-day dietary management for people with Type 1 diabetes in multiple ways. In the present review, we draw directly from cognitive restraint theory to consider unintended impacts that closed-loop systems may have on ingestive behaviour and food intake. We provide a brief overview of dietary restraint theory and its relation to weight status in the general population, discuss the role of restraint in traditional Type 1 diabetes treatment, and lastly, use this restraint framework to discuss the possible behavioural implications and opportunities of closed-loop systems in the treatment of Type 1 diabetes. We hypothesize that adopting closed-loop systems will lift the diligence and restriction that characterizes Type 1 diabetes today, thus requiring a transition from a restrained eating behaviour to a non-restrained eating behaviour. Furthermore, we suggest this transition be leveraged as an opportunity to teach people lifelong eating behaviour to promote healthy weight status by incorporating education and cognitive reappraisal. Our aim was to use a transdisciplinary approach to highlight critical aspects of the emerging closed-loop technologies relating to eating behaviour and weight effects and to promote discussion of strategies to optimize long-term health in Type 1 diabetes via two key outcomes: glycaemic control and weight management.

Flexible Lifestyles for Youth (FL3X) behavioural intervention for at-risk adolescents with Type 1 diabetes: a randomized pilot and feasibility trial.

AIM: To determine the potential effect sizes for the Flexible Lifestyle for Youth (FL3X) behavioural intervention to improve glycaemic control (HbA(1c)) and quality of life for at-risk adolescents with Type 1 diabetes. METHODS: Participants [n = 61; age 12-16 years, HbA(1c) 64-119 mmol/mol (8-13%)] were randomized to FL3X (minimum three sessions) or usual care. Effect sizes (Cohen's d), comparing the mean difference between the groups, were calculated. RESULTS: Study retention (95%), attendance at intervention sessions (87% attended all three sessions) and acceptability were high (100% of the adolescents and 91% of parents would recommend the programme to others). Overall, 41% of participants in the intervention group and 24% of participants in the control group were 'responders' [HbA(1c) decreased by > 6 mmol/mol (0.5%); d = 0.37]. HbA(1c) levels decreased (d = -0.18), diabetes-specific quality of life increased (d = 0.29), but generic quality of life decreased (d = -0.23) in the intervention compared with the control group. CONCLUSIONS: The FL3X programme merits further study for improving HbA(1c) and diabetes-specific quality of life in adolescents with Type 1 diabetes. (Clinical trials registry no.: NCT01286350).

Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes.

AIM: To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. METHOD: We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥ 20 µg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 µg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. RESULTS: Estimated insulin sensitivity was significantly higher at both baseline (4.6 ± 1.2 vs 3.4 ± 1.7; P = 0.002) and follow-up (5.2 ± 1.9 vs. 3.5 ± 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. CONCLUSIONS: In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.

A practical method to measure GFR in people with type 1 diabetes.

AIMS: Improved early diagnostic methods are needed to identify risk for kidney disease in people with type 1 diabetes. We hypothesized that glomerular filtration rate (GFR) measured by iohexol clearance in dried blood spots (DBS) on filter paper would be comparable to plasma (gold-standard) and superior to estimated GFR (eGFR) and, second, that adjustment for ambient blood glucose would improve accuracy and precision of GFR measurement. METHODS: GFR was measured by iohexol clearance in plasma, DBS, and as estimated by the CKD-Epidemiology Collaboration equations in 15 adults with type 1 diabetes at two visits, one euglycemic and one hyperglycemic. RESULTS: GFR measured by DBS was more comparable and less biased than GFR cystatin C, serum creatinine, and both combined. GFR was higher during hyperglycemia. Correction for between visit glycemia statistically significantly reduced bias and mean squared error for GFR measured by DBS as compared to gold-standard during euglycemia. CONCLUSIONS: Iohexol clearance measured with DBS performed better than eGFR methods. Correction for ambient blood glucose improved precision and accuracy of GFR measurement. This method is more convenient than the gold-standard GFR method and may improve screening and diagnostic capabilities in people with type 1 diabetes, especially when GFR is >60ml/min/1.73m(2).

Association of insulin sensitivity to lipids across the lifespan in people with Type 1 diabetes.

AIMS: Insulin resistance and dyslipidaemia both increase cardiovascular risk in Type 1 diabetes. However, little data exist on the associations of insulin resistance to lipids in Type 1 diabetes. Our objective was to explore the associations between insulin resistance (assessed by glucose infusion rate) and lipids in people with Type 1 diabetes and determine whether adiposity and/or average glycaemia influence these associations. METHODS: Hyperinsulinaemic-euglycaemic clamp studies were performed in 60 subjects with Type 1 diabetes aged 12-19 years (age 15±2 years, 57% female, duration of diabetes 6.3±3.8 years, HbA(1c) 8.6±1.5%, IFCC=70 mmol/mol) and 40 subjects with Type 1 diabetes aged 27-61 years (age 45±9 years, 53% female, duration of diabetes 23±8 years, HbA(1c) 7.5±0.9%, IFCC=58 mmol/mol). Multiple linear regression models were fit to examine the association between glucose infusion rate and fasting lipid levels with adjustment for possible confounders. RESULTS: Lower glucose infusion rate was significantly associated with lower levels of HDL cholesterol in youths with Type 1 diabetes and with higher levels of triglycerides and higher triglyceride/HDL ratio in both youths and adults. The magnitude of the associations between glucose infusion rate and lipid levels translate into interquartile differences of 0.098 mmol/l for HDL cholesterol, 0.17 mmol/l for triglycerides and 1.06 for triglycerides/HDL in the adolescents and 0.20 mmol/l for triglycerides and 1.01 for triglycerides/HDL in the adults. The associations were attenuated and no longer statistically significant by adjustment for adiposity among adults, while adjustment for HbA(1c) had a small effect in youths and adults. CONCLUSIONS: Lower insulin sensitivity is associated with a more atherogenic lipid profile in both youths and adults with Type 1 diabetes.

Glycaemic variability is associated with coronary artery calcium in men with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study.

AIMS: We investigated coronary artery calcium in association with glucose levels and variability measured using continuous glucose monitoring in adults with Type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes study. METHODS: Coronary artery calcium was measured by electron beam tomography. The presence of any coronary artery calcium was analysed with respect to glucose levels [mean(T) (mean glucose), % of values < 3.9 mmol/l, > 10 mmol/l and either < 3.9 or > 10 mmol/l] and glycaemic variability [sd(T) (sd of all glucose values); sd(dm) (sd of the daily mean glucose levels) and sd(hh:mm) (glucose sd for a specified time of day, over all days)] using 3-5 days of continuous glucose monitoring from 75 subjects (45 women, 30 men), age 42 ± 9 years (mean ± sd) and diabetes duration of 29 ± 8 years using logistic regression. RESULTS: We observed significant associations between coronary artery calcium and mean(T) (OR = 4.4, 95% CI 1.1-18.6), % of values > 10 mmol/l (OR = 5.5, 95% CI 1.3-22.6), % of measures < 3.9 or > 10 mmol/l (OR = 5.7, 95% CI 1.3-24.9), sd(T) (OR = 4.7, 95% CI 1.1-19.7), sd(dm) (OR = 6.0, 95% CI 1.2-30.4) and sd(hh:mm) (OR = 4.0, 95% CI 1.1-15.4), among men, but none of these variables were associated with the presence of coronary artery calcium in women. CONCLUSIONS: We report the novel finding that subclinical atherosclerosis is associated with glucose levels and variability in men with Type 1 diabetes. The relationship of coronary artery calcium and glucose variability in Type 1 diabetes, and potential gender differences in this association, deserve further study.

Association of glycaemia with lipids in adults with type 1 diabetes: modification by dyslipidaemia medication.

AIMS/HYPOTHESIS: Hyperglycaemia and dyslipidaemia are common metabolic abnormalities in adults with type 1 diabetes and both increase cardiovascular disease (CVD) risk. The hypothesis of this study was that change in HbA(1c) over 6 years would be associated with change in fasting lipids in adults with type 1 diabetes. METHODS: The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study examined 652 patients with type 1 diabetes (54% female); 559 and 543 had follow-up visits at 3 and 6 years. Baseline age (mean ± SD) was 37 ± 9 years, diabetes duration 23 ± 9 years, and HbA(1c) 8.0 ± 1.3%. Use of dyslipidaemia medication was 17%, 32%, and 46% at the three visits. Separate longitudinal mixed models were fitted to examine the relationship between change in HbA(1c) and change in fasting total cholesterol (TC), HDL-cholesterol (HDL-c), LDL-cholesterol (LDL-c), log triacylglycerols (TG), and non-HDL-cholesterol (non-HDL-c). Because of an interaction between dyslipidaemia medication use and association of HbA(1c) with lipids, results were stratified by dyslipidaemia medication use. RESULTS: Among patients not using dyslipidaemia medication, a higher HbA(1c) was associated with significantly worse levels of the lipids TC, LDL-c, TG and non-HDL-c (per 1% change in HbA1c, TC 0.101 mmol/l, 95% CI 0.050, 0.152; LDL-c 0.103 mmol/l, 95% CI 0.058, 0.148; TG 0.052 mmol/l, 95% CI 0.024, 0.081; and non-HDL-c 0.129 mmol/l, 95% CI 0.078, 0.180) but not HDL-c (-0.20 mmol/l, 95% CI -0.047, 0.007). The associations between HbA(1c) and any lipid outcome among those on dyslipidaemia medication were in the same direction, but attenuated compared with persons not on medication. CONCLUSIONS/INTERPRETATION: Change in HbA(1c) is significantly associated with change in fasting lipids, but dyslipidaemia medications may be required to optimise lipid and cardiovascular health.

Higher fibrinogen levels predict progression of coronary artery calcification in adults with type 1 diabetes.

AIM: To determine whether fibrinogen levels predict independently progression of coronary artery calcification (CAC) in adults with type 1 diabetes. METHODS: Data from a prospective cohort--the Coronary Artery Calcification in Type 1 Diabetes Study--were evaluated. Fibrinogen levels at baseline were separated into quartiles. CAC was measured twice and averaged at baseline and at follow-up 2.4+/-0.4 years later. CAC progressors were defined as participants whose square-root transformed CAC volume increased by >or=2.5 mm3 or development of clinical coronary artery disease during the follow-up period. RESULTS: Fibrinogen levels were higher in progressors than in non-progressors (276+/-61 mg/dl versus 259+/-61 mg/dl, p=0.0003). CAC progression, adjusted for known cardiovascular risk factors, increased in the highest quartile. CONCLUSIONS: Higher fibrinogen levels predict CAC progression in type 1 diabetes subjects, independent of standard cardiovascular risk factors.

Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule.

AIMS/HYPOTHESIS: Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria. METHODS: Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study). RESULTS: Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively). CONCLUSIONS/INTERPRETATION: We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications.

Adults with type 1 diabetes eat a high-fat atherogenic diet that is associated with coronary artery calcium.

AIMS/HYPOTHESIS: Coronary heart disease is the leading cause of mortality among people with type 1 diabetes. Diet is an important lifestyle factor that relates to risk of CHD. The aim of this study was to examine how diet and adherence to dietary guidelines differ between adults with and without type 1 diabetes, and their correlation with CHD risk factors and coronary artery calcium (CAC). METHODS: The study involved 571 people with type 1 diabetes and 696 controls, aged 19 to 56 years, who were asymptomatic for CHD. CAC was measured by electron-beam computed tomography. RESULTS: Compared with the controls, adults with type 1 diabetes reported a diet higher in fat, saturated fat and protein but lower in carbohydrates. Fewer than half of those with type 1 diabetes met dietary guidelines for fat and carbohydrate intake, and only 16% restricted saturated fat to less than 10% of daily energy intake. Adults with type 1 diabetes were significantly less likely to meet dietary guidelines than controls. Fat and saturated fat intakes were positively correlated, but carbohydrate intake was negatively correlated with CHD risk factors and HbA(1c). A high-fat diet and higher intake of protein were associated with greater odds of CAC, while higher carbohydrate intake was associated with reduced odds of CAC. CONCLUSIONS/INTERPRETATION: Adults with type 1 diabetes reported consuming higher than recommended levels of fat and saturated fat. High fat intake was associated with increased CHD risk factors, worse glycaemic control and CAC. An atherogenic diet may contribute to the risk of CHD in adults with type 1 diabetes.

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Individuals with type 1 diabetes have an increased incidence of coronary artery disease (CAD) and a higher risk of cardiovascular death compared with individuals of the same age in the general population. While chronic hyperglycaemia and insulin resistance partially explain excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes. The aim of the present study was to evaluate the association of apolipoprotein A-IV (APOA4) polymorphisms with coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis. SUBJECTS AND METHODS: Two previously well-studied functional APOA4 polymorphisms resulting in the substitution of the amino acid Thr for Ser at codon 347 and Gln for His at codon 360 were genotyped in 634 subjects with type 1 diabetes and 739 non-diabetic control subjects, the participants of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. RESULTS: The His360 allele was associated with a significantly higher risk of CAC progression among patients with type 1 diabetes (33.7 vs 21.2%, p=0.014), but not in the control subjects (14.1 vs 11.1%, p=0.42). Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk). CONCLUSIONS /INTERPRETATION: This is the first report suggesting an association between the APOA4 Gln360His polymorphism and risk of CAC progression in subjects with type 1 diabetes. Additional studies are needed to explore potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis.