Aims

Hepatocyte nuclear factor-1α (HNF-1α) regulates the expression of genes encoding proteins involved in glucose metabolism and insulin secretion. Mutations in the HNF-1α gene cause maturity-onset diabetes of the young Type 3. However, the mechanism leading to this disease has not been completely ascertained. Previously, we found a novel mutation in the regulatory element of the human HNF-1α gene in two Chinese diabetes pedigrees. The nucleotide at position -128 T was substituted by G (nt-128 T→G). In this study, we analysed the functional defect of nt-128 T→G in HNF-1α transcription activity.

Methods

Luciferase reporter gene assays were carried out to examine the functional characteristics of this mutant. Electrophoretic mobility shift assays and chromatin immunoprecipitation were performed to confirm the binding of nuclear proteins to oligonucleotides.

Results

The variant construct (nt-128 T→G) had a 1.65-fold increase in promoter activity compared with that of the wild-type construct in HepG2 cells and a 1.33-fold increase in MIN6 cells, respectively. The variant resided at a FOXA/ HNF-3 binding site identified by a series of competitive electrophoretic mobility shift assays and antibody supershift analyses. The assays showed a differential binding affinity in the wild-type and the nt-128 T→G mutant fragments by FOXA/ HNF-3. Chromatin immunoprecipitation indicated that FOXA/ HNF-3 bound to this region in vivo. One nucleotide substitution in the FOXA/ HNF-3 site in the human HNF-1α regulatory element caused an increase of HNF-1α transcriptional activity.

Conclusions

Our data suggested that this substitution in the promoter region affects DNA–protein interaction and HNF-1α gene transcription. The mutant may contribute to the development of diabetes in these two nt-128 T→G pedigrees of Chinese.

Aims

Thiazolidinediones (TZD) have been associated with an expansion in plasma volume and the development of peripheral oedema. A recent study reported an association between the use of TZDs and development of congestive heart failure (CHF). The objective of this study was to determine if short-term use of pioglitazone, a TZD, is associated with increased risk of CHF hospitalisation in a well-characterised, community-based cohort of type 2 diabetic patients without prevalent CHF.

Methods

A cohort study of all patients in the Kaiser Permanente Medical Care Program with type 2 diabetes (Kaiser Permanente Northern California Diabetes Registry) who initiated any diabetes pharmacotherapy (n=23,440) between October, 1999 and November, 2001. Only patients initiating single new therapies (“new users”) were included to reduce confounding and create mutually-exclusive exposure groups. We constructed Cox proportional hazards models (with sulfonylureas initiators specified as the reference group) to evaluate the impact of initiating new diabetes therapies on time to incident CHF hospitalisation, defined by primary hospital discharge diagnosis.

Results

Patients initiated pioglitazone (15.2%), sulfonylureas (25.3%), metformin (50.9%), and insulin (8.6%) alone or as additions to pre-existing or maintained therapies. Three hundred and twenty CHF hospitalisations were observed during the follow-up (10.2 months on average) after initiation. Relative to sulfonylurea initiators, there were no significant increases in the incidence of CHF hospitalisation among those initiating pioglitazone (hazard ratio (HR) = 1.28; 95% confidence interval (CI): 0.85 – 1.92) after adjusting for demographic, behavioural, and clinical factors. There was a significantly higher incidence among those initiating insulin (HR = 1.56; 95% CI: 1.00 – 2.45) and lower incidence among those initiating metformin, (HR = 0.70; 95% CI: 0.49 – 0.99).

Conclusions

This study of patients with type 2 diabetes failed to find evidence that short-term pioglitazone use was associated with an elevated risk of CHF hospitalisation relative to the standard, first line diabetes therapy.

Aims

To examine the relationship between physical function limitations and diabetes self-management, processes of care, and intermediate outcomes in adults ≥65 years of age with type 2 diabetes.

Methods

We studied 1,796 participants 65 years of age and older in managed care health plans enrolled in Translating Research into Action for Diabetes (TRIAD). Physical functioning was assessed at baseline with the Physical Component Summary of the Short Form-12 (SF-12) Health Survey. Diabetes self-management was assessed with follow-up surveys, and processes of care (eye exams, urine microalbumin testing, foot exams, etc.) and intermediate health outcomes (HbA1c, blood pressure, LDL-c) were assessed with medical chart reviews. Multivariate regression models were constructed to examine the associations between physical function limitations and outcomes.

Results

Frequency of eye exams (OR 0.69, 95% CI 0.49 - 0.99) was the only process of care that was worse for participants with physical function limitations (n=573) compared to those without limitations (n=618). Neither self-management nor intermediate outcomes differed by whether patients had or did not have physical function limitations.

Conclusion

Limitations in physical functioning as assessed by the SF-12 were not associated with substantial difference in diabetes care in adults ≥65 years of age enrolled in managed care health plans.

Aims

To evaluate the association between vitamin D insufficiency and peripheral neuropathy in a nationally representative sample of adults with diagnosed diabetes.

Methods

Vitamin D concentrations, medical examination variables and questionnaire results from the 2001–2004 National Health and Nutrition Examination Survey were analysed for adults ≥ 40 years old with diagnosed diabetes (unweighted n = 591, weighted n = 8.82 million). Neuropathy was defined as self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling in hands or feet. Additionally, Semmes–Weinstein monofilament test results were used as an indicator of neuropathy. Insufficient vitamin D was characterized as < 30 ng/ml.

Results

In the weighted population, 81% of adults with diabetes had vitamin D insufficiency. Vitamin D insufficiency was more common among Hispanics (92%) and non-Hispanic black people (98%) than among non-Hispanic white people (76%). Within the 3 months preceding the questionnaire, 50% reported experiencing pain or numbness (paresthesia) in their hands or feet; 37% reported pain or tingling in hands or feet; and 38% reported numbness or loss of feeling in hands or feet. Eight per cent had 4–6 insensate areas on their feet as determined by the Semmes– Weinstein monofilament test. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95% CI 1.17–3.85) and the adjusted numbness measure (odds ratio 2.04; 95% CI 1.18–3.52).

Conclusions

Vitamin D insufficiency is associated with self-reported peripheral neuropathy symptoms even after adjusting for demographic factors, obesity, co-morbidities, use of medications for neuropathy and diabetes duration and control.

Aims

Point-of-care HbA1c is routine in clinical practice. Comparison of point-of-care HbA1c against laboratory measurements across sites and over time is warranted.

Methods

One hundred and twenty-one young persons with Type 1 diabetes from four centres provided 450 paired samples collected over 10 months for point-of-care HbA1c and central laboratory-based high-performance liquid chromatography (HPLC) HbA1c determinations. Change in HbA1c over time was assessed by difference from initial to final HbA1c and by growth modelling with annualized slope calculation. Change in HbA1c was categorized as improved (decrease of ≥ 0.5% or negative slope), no change (± 0.4% of initial HbA1c or slope = 0) or worsened (increase of ≥ 0.5% or positive slope).

Results

The 450 paired samples (median of four pairs/patient) were highly correlated (r = 0.97, P < 0.0001), as were time-specific and site-specific pairs (r = 0.94 to 0.98, P < 0.0001). Initial-to-final point-of-care HbA1c and HPLC HbA1c changes were 0.3 ± 1.1% (range −2.7 to 4.1) and 0.4 ± 1.2% (–3.9 to 4.5), respectively, with 21% of patients (n = 26) discordant for change categories. ΔHbA1c by point-of-care HbA1c vs. HPLC HbA1c differed across the HbA1c range and by ≥ 0.5% absolute difference in ΔHbA1c in 14 (54%) of the 26 patients discordant for HbA1c change categories. Mean annual HbA1c slope was 0.4 ± 1.5% (−5.4 to 4.8) for point-of-care HbA1c and 0.4 ± 1.6% (−6.9 to 5.2) for HPLC HbA1c, with 18% (n = 22 pairs) discordant for change categories.

Conclusions

Assessment of absolute HbA1c change may not be different for point-of-care HbA1c compared with HPLC HbA1c; however, misclassification of patients by discrete cut-off values may occur with point-of-care HbA1c compared with HPLC HbA1c determinations.

Aims

In a pediatric patients, the burden of diabetes lies within the family. In the current era of intensive insulin therapy, perceived parental burden may affect the family’s efforts at effective diabetes management. The aims of this study were to re-examine and revise a measure of perceived parental burden associated with caring for a child with diabetes in the current era.

Methods

A geographically diverse population of young people (N = 376) with Type 1 diabetes and their parents included participants in the Juvenile Diabetes Research Foundation continuous glucose monitoring study and patients from the Joslin Diabetes Center. Participants provided data on demographics, diabetes management, diabetes-specific family conflict, and quality of life at baseline and after 6 months of follow-up.

Results

Young people were 12.9 ± 2.7 years old with diabetes duration of 6.3 ± 3.5 years. Mean HbA1C was 8.0 ± 1.2%(64 mmol/mol), 58% received insulin pump therapy, and young people monitored blood glucose 5.2 ± 2.3 times/day. Factor analysis yielded two factors, ‘Immediate Burden’ and ’Theoretical Burden’. The Problem Areas in Diabetes Survey – Parent Revised version (PAID-PR) demonstrated excellent internal consistency (Cronbach’s α = 0.87; factor 1 α = 0.78; factor 2 α = 0.83). Greater parental burden was associated with more frequent blood glucose monitoring, higher HbA1C levels, greater diabetes-specific family conflict, and lower quality of life. Test-retest analysis was acceptable (r = 0.62).

Conclusions

The PAID-PR demonstrated excellent internal consistency, good test-retest reliability, and associations with diabetes-specific family conflict and quality of life. This brief measure may have both clinical and research utility in the management of young people with Type 1 diabetes.

Aims

Young adulthood is a challenging period for patients with Type 1 diabetes as developmental changes complicate Type 1 diabetes management and gaps in care may arise as patients transition from paediatric to adult providers. This period has been associated with worsening diabetes outcomes. One approach to aid young adults during this transition period could entail professionally led support groups to enhance self-motivation and facilitate peer-to-peer interactions. We implemented and evaluated a support group for young adults with Type 1 diabetes as a pilot project.

Methods

Young adults with Type 1 diabetes (18–30 years) participated in monthly, professionally led support groups for 5 months. Questionnaires were completed pre- and post-group and chart review data were collected regarding glycaemic control and visit frequency in the year before and after group participation.

Results

Participation in the group was associated with improvement in HbA1c and decreased self-reported diabetes burden, along with a trend for an increase in diabetes-related self-care behaviours. Frequency of visits did not vary from pre- to post-group. Discussion topics identified by participants included managing diabetes in day-to-day life, experiences and interactions with others who do not have diabetes and emotions related to diabetes. Participants identified that they sought a diabetes care team that offers knowledge, support and a multidisciplinary team.

Conclusions

Professionally led support groups may have utility for increasing social support and optimizing diabetes outcomes in young adults with Type 1 diabetes.

Aim

We have assessed whether corneal confocal microscopy can be used to detect alterations in nerve morphology following an improvement in risk factors associated with diabetic neuropathy.

Methods

Twenty-five patients with diabetes with mild to moderate neuropathy and 18 control subjects underwent corneal confocal microscopy to quantify corneal nerve fibre density, branch density, length) and tortuosity at baseline and after 24 months from first visit. This was not planned as an intervention trial and was simply an observational follow-up.

Results

At baseline, nerve fibre density (18.8 ± 2.1 vs. 46.0 ± 3.8 number/mm2, P = 0.001), nerve branch density (6.9 ± 1.5 vs. 35.6 ± 6.7 number/mm2, P < 0.0001), nerve fibre length (8.3 ± 0.9 vs. 13.5 ± 0.8 mm/mm2, P < 0.0001) and nerve fibre tortuosity (19.8 ± 1.6 vs. 22.7 ± 2.2, P < 0.05) were significantly lower in patients with diabetes than in control subjects. At follow-up, glycaemic control (HbA1c 64 ± 3 to 58 ± 2 mmol/mol, P = 0.08), total cholesterol (4.9 ± 0.2 to 4.2 ± 0.2 mmol/l, P = 0.01), systolic blood pressure (145.8 ± 4.9 to 135.9 ± 3.7 mmHg, P = 0.09) and diastolic blood pressure (77.8 ± 2.7 to 70.8 ± 2.5, P = 0.03) improved. Nerve fibre density (24.1 ± 2.0, P = 0.05), nerve branch density (11.1 ± 1.3, P = 0.01) and nerve fibre tortuosity (22.6 ± 1.5, p=0.05) increased significantly, with no change in nerve fibre length (8.4 ± 0.5). Improvement in nerve fibre density correlated significantly with the improvement in HbA1c (r = −0.51, P = 0.008). Via four multifactorial regressions, this confirms the negative association between HbA1c and nerve fibre density (P = 0.02).

Conclusions

This study shows that corneal confocal microscopy may be employed in longitudinal studies to assess progression of human diabetic neuropathy and also supports the hypothesis that improvements in risk factors for diabetic neuropathy, in particular HbA1c, may lead to morphological repair of nerve fibres.

Aims

To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth.

Methods

We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin.

Results

The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010).

Conclusions

The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden.

Aims

Adherence to diabetes-related tasks is an important construct. The Diabetes Self-Management Profile is a validated, semi-structured interview assessing adherence in paediatric patients with Type 1 diabetes. We created and validated a brief questionnaire version of the Diabetes Self-Management Profile called the Diabetes Self-Management Questionnaire.

Methods

Young people with Type 1 diabetes, ages 9–15 years (n = 338) and their parents provided data from chart review, interview and questionnaires.

Results

Diabetes Self-Management Questionnaire scores correlated significantly with Diabetes Self-Management Profile scores, HbA1c, blood glucose monitoring frequency and other measures associated with adherence and/or glycaemic control (P ≤ 0.01 for all). Young people and parent scores were correlated (r = 0.55, P < 0.0001). The Diabetes Self-Management Questionnaire demonstrated modest internal consistency (Cronbach’s α = 0.59), adequate for a brief measure of multidimensional adherence. In addition, factor analysis confirmed one factor.

Conclusions

This brief adherence questionnaire demonstrated construct validity in young people 9–15 years old and their parents and may have utility in clinical and research settings.

Aims

One of the factors influencing the cost-effectiveness of population screening for type 2 diabetes may be uptake. We examined attendance and practice- and individual-level factors influencing uptake at each stage of a diabetes screening programme in general practice.

Methods

A stepwise screening programme was undertaken among 135,825 people aged 40-69 years without known diabetes in 49 general practices in East England. The programme included a score based on routinely available data (age, sex, BMI and prescribed medication) to identify those at high risk who were offered random capillary blood glucose (RBG) and glycosylated haemoglobin tests. Those screening positive were offered fasting capillary blood glucose (FBG) and confirmatory oral glucose tolerance tests (OGTT).

Results

33,539 high risk individuals were invited for a RBG screening test; 24,654 (74%) attended. 94% attended the follow-up FBG test and 82% the diagnostic OGTT. 70% of individuals completed the screening programme. Practices with higher GP staff complements and those located in more deprived areas had lower uptake for RBG and FBG tests. Male sex and a higher BMI were associated with lower attendance for RBG testing. Older age, prescription of antihypertensive medication and a higher risk score were associated with higher attendance for FBG and RBG tests.

Conclusions

High attendance rates can be achieved by targeted stepwise screening of individuals assessed as high risk by data routinely available in general practice. Different strategies may be required to increase initial attendance, ensure completion of the screening programme, and reduce the risk that screening increases health inequalities.

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, HbA1c 8.6 ± 1.5%) and 40 subjects with Type 1 diabetes aged 27–61 years (age 45 ± 9 years, 53% female, duration of diabetes 23 ± 8 years, HbA1c 7.5 ± 0.9%). 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 HbA1c 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.

Aims

A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians.

Methods

We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥ 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case–control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies.

Results

In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24–0.67) kg/m2 per A-allele (P = 3.0× 10−5) and with waist circumference was 0.88 (95% CI 0.36–1.41) cm per A-allele (P = 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07–1.30); P = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14–1.31); P = 1.07× 10−8] even after adjusting for BMI [1.18 (95% CI 1.10–1.27); P = 1.02× 10−5] or waist circumference [1.18 (95% CI 1.10–1.27); P = 3.97× 10−5].

Conclusions

The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Aims

To compare obstetric and perinatal outcomes in women with Type 1 and Type 2 diabetes and relate these to maternal risk factors.

Methods

Prospective cohort study of 682 consecutive diabetic pregnancies in East Anglia during 2006–2009. Relationships between congenital malformation, perinatal mortality and perinatal morbidity (large for gestational age, preterm delivery, neonatal care) with maternal age, parity, ethnicity, glycaemic control, obesity and social disadvantage were examined using bivariable and multivariate models.

Results

There were 408 (59.8%) Type 1 and 274 (40.2%) Type 2 diabetes pregnancies. Women with Type 2 diabetes were older(P < 0.001), heavier (P < 0.0001), more frequently multiparous (P < 0.001), more ethnically diverse (p < 0.0001) and more socially disadvantaged (P = 0.0004). Although women with Type 2 diabetes had shorter duration of diabetes (P < 0.0001) and better pre-conception glycaemic control [HbA1c 52 mmol/mol (6.9%) Type 2 diabetes vs. 63 mmol/l (7.9%) Type 1 diabetes; p < 0.0001), rates of congenital malformation and perinatal mortality were comparable. Women with Type 2 diabetes had fewer large-for-gestational-age infants (37.6 vs. 52.9%, P < 0.0008), fewer preterm deliveries (17.5 vs. 37.1%, P < 0.0001) and their offspring had fewer neonatal care admissions (29.8 vs. 43.2%, P = 0.001). Third trimester HbA1c (OR 1.35,95% CI 1.09–1.67, P = 0.006) and social disadvantage (OR 0.80, 95% CI 0.67–0.98; P = 0.03) were risk factors for large for gestational age.

Conclusions

Despite increased age, parity, obesity and social disadvantage, women with Type 2 diabetes had better glycaemic control, fewer large-for-gestational-age infants, fewer preterm deliveries and fewer neonatal care admissions. Better tools are needed to improve glycaemic control and reduce the rates of large for gestational age, particularly in Type 1 diabetes.

Aims

Type 1 diabetes mellitus increases the risk for sudden unexplained death (SUD), generating concern that diabetes processes and/or treatments underlie these deaths. Young (<50 yrs) and otherwise healthy patients who are found dead in bed have been classified as experiencing “dead in bed” (DIB) syndrome.

Methods

We thus identified all un-witnessed deaths in two related registries (Children’s Hospital of Pittsburgh and Allegheny County) yielding 1,319 persons with childhood-onset (age<18 yrs) Type 1 DM diagnosed between 1965 and 1979. Cause of death was determined by a mortality classification committee (MCC) of at least 2 physician epidemiologists, based on the death certificate and additional records surrounding the death.

Results

Of the 329 participants who had died, the MCC has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were SUDs (13 male), and 7 met DIB criteria. The MCC adjudicated cause of death in the 7 DIB persons as: diabetic coma (n=4), unknown (n=2), and cardiomyopathy (n=1, found on autopsy). The 3 DIB individuals who participated in a clinical study had higher HbA1c, lower BMI, and higher daily insulin dose compared to both those dying from other causes and those surviving.

Conclusions

SUD in Type 1 DM seems to be increased 10-fold and associated with male sex, while DIB individuals have a high HbA1c and insulin dose, and low BMI. Though sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to SUD and DIB.

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 [meanT (mean glucose), % of values < 3.9 mmol/l, > 10 mmol/l and either < 3.9 or > 10 mmol/l] and glycaemic variability [sdT (sd of all glucose values); sddm (sd of the daily mean glucose levels) and sdhh: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 meanT (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), sdT (OR = 4.7, 95% CI 1.1–19.7), sddm (OR = 6.0, 95% CI 1.2–30.4) and sdhh: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.

Aims

Diabetes mellitus may be associated with excessive lean mass loss. Other diabetes-related conditions may also play a role. We assessed body composition changes associated with diabetes in older adults with adjustment for diabetes-related co-morbidities.

Methods

Three thousand, one hundred and fifty-three community-living adults aged ≥ 65 years were examined for lifestyle factors, diabetes-related medical conditions and body composition by dual energy X-ray absorptiometry at baseline and 4 years later. Body composition changes were compared between participants with diabetes and those without diabetes. Multivariate linear regression was used to examine the relationship between appendicular lean mass loss and confounders.

Results

Appendicular lean mass loss in men with diabetes was two times that of men without diabetes (−1.5% in ‘no diabetes’ vs. −3.0% in ‘diabetes’) and in women with diabetes was 1.8 times that of those without diabetes (−1.9% in ‘no diabetes’ vs. −3.4% in ‘diabetes’) over 4 years. Men with diabetes also had higher total body mass loss and higher total body fat loss than men without diabetes. Women with diabetes had higher total body mass loss but total body fat loss was similar. After adjusting for age, body mass index, diabetes-related conditions, lifestyle factors and total body mass loss, diabetes remained an independent predictor of appendicular lean mass loss in both men and women.

Conclusion

Diabetes was associated with higher bodymass loss and higher appendicular lean mass loss in older adults. In men, diabetes was also associated with total body fat loss.

Aims

Electrocardiographic ventricular repolarization QT parameters are independent risk factors for cardiovascular events and sudden cardiac death in diabetic patients. The aim of the study was to investigate the association of polymorphisms of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene with QT interval in Chinese subjects with or without Type 2 diabetes.

Methods

Three single nucleotide polymorphisms (SNPs) (rs10494366, rs12143842 and rs12029454) were genotyped in 1240 Type 2 diabetic patients (631 men and 609 women) and 1196 normal controls (433 men and 763 women). Individuals with overt diseases other than diabetes were excluded. Heart-rate corrected QT interval (QTc) was determined by standard 12-lead ECG and Bazett formula. Sex-pooled analysis and sex-specific analysis for genotype–phenotype association were both conducted.

Results

In the diabetic group, the rs12143842 T allele was associated with a 3.87-ms (P = 0.014, empirical P = 0.039) increase in QTc duration for each additional allele copy, while rs10494366 and rs12029454 exhibited no significant association with QTc. We found no evidence of association for the three SNPs in subjects with normal glucose regulation. No significant SNP-gender and -diabetes affection interaction was observed.

Conclusions

The genetic variant rs12143842 in NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes. Future studies in different populations are needed to validate this finding and to evaluate the impact of NOS1AP variants on cardiovascular events and sudden cardiac death in diabetic patients.

Background

Time trends in overweight and obesity in the general population have been well documented; however, temporal patterns in type 1 diabetes (T1D) have not been thoroughly investigated. We therefore assessed temporal patterns in overweight and obesity and predictors of weight change in 589 individuals from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, a cohort of childhood onset T1D.

Methods

Participants were first seen in 1986–1988, when mean age and diabetes duration were 29 and 20 years, respectively, and biennially thereafter for 18 years. Overweight was defined as 25≤BMI<30 kg/m2. Obese was defined as a BMI≥30 kg/m2.

Results

At baseline, the prevalence of overweight and obesity were 28.6% and 3.4%, respectively. After 18 years of follow-up, the prevalence of overweight increased by 47% while the prevalence of obesity increased 7-fold. Seven percent were on intensive insulin therapy (≥3 insulin injections per day or on insulin pump) at baseline; by 2004–2007, this was 82%. Predictors of weight change were a higher baseline HbA1c, symptomatic autonomic neuropathy (inversely), overt nephropathy (inversely), and going onto intensive insulin therapy during follow-up.

Conclusion

These data demonstrate dramatic weight gain in T1D and underscore the complexity of weight change in this disease.

Aims

To examine the relationship between depressive symptomatology, diabetes-related distress and aspects of diabetes self-care in a cohort of individuals with Type 1 diabetes.

Methods

Individuals with Type 1 diabetes taking part in the Pittsburgh Epidemiology of Diabetes Complications Study completed the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression (CES-D) Scale and the Problem Areas in Diabetes (PAID) scale. Self-care was measured by physical activity in the past week and over the previous year, frequency of blood glucose/urine testing, smoking status and alcohol intake.

Results

Clinically significant levels of depressive symptomatology (i.e. scores ≥ 16) were reported by 14% of the study population on the BDI and by 18% on the CES-D. There were strong correlations between depressive symptoms and diabetes-related distress (PAID scores) and physical activity. Multivariate analyses indicated that depression was independently associated with diabetes-related distress scores and with physical activity, but not with frequency of blood glucose testing.

Conclusions

These findings have implications for clinical practice and treatment of both psychological morbidity and diabetes. There may be significant effects of depression on aspects of diabetes self-care. Further prospective studies are required to confirm these findings.

Aims

Little is known about the association between a lifetime history of major depressive disorder (L-MDD) and diabetes self-management, particularly when depression is remitted. We examined the association between L-MDD, and diabetes self-management in women with type 2 diabetes who were not depressed at the time of assessment.

Methods

L-MDD was assessed with structured psychiatric interview. Participants completed paper-and-pencil measures of demographics, diabetes-related distress, self-care behaviors, healthcare utilization, and diabetes self-efficacy.

Results

One-hundred fifty three women participated; 41% had L-MDD. Compared to their never-depressed counterparts, women with L-MDD had more diabetes distress, reported lower overall rates of self-monitoring of blood glucose (SMBG) and greater tendency to skip SMBG, had lower diet adherence, and were less likely to have seen a primary care provider in the past year. Diabetes self-efficacy mediated the relationship between L-MDD and self-management.

Conclusions

Interventions to promote self-management for patients with L-MDD may be warranted.

Aims

Specific polymorphisms of the apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) genes appear to increase risk for Alzheimer’s disease and cognitive dysfunction in the general population, yet little research has examined whether genetic factors influence risk of cognitive dysfunction in patients with Type 1 diabetes. The long-term follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) population provides an opportunity to examine if specific genetic variations in APOE and ACE alter risk for cognitive decline.

Methods

Neurocognitive function in Type 1 diabetic subjects from the DCCT/EDIC study was assessed at DCCT entry and re-assessed approximately 18 years later, using a comprehensive cognitive test battery. Glycated haemoglobin (HbA1c) and the frequency of severe hypoglycaemic events leading to coma or seizures were measured over the 18-year follow-up. We determined whether the APO εs4 and ACE intron 16 indel genotypes were associated with baseline cognitive function and with change over time, and whether they conferred added risk in those subjects experiencing severe hypoglycaemic events or greater glycaemic exposure.

Results

None of the APOE or ACE polymorphisms were associated with either baseline cognitive performance or change in cognition over the 18-year follow-up. Moreover, none of the genotype variations altered the risk of cognitive dysfunction in those subjects with severe hypoglycaemic episodes or high HbA1c.

Conclusions

In this sample of young and middle-aged adults with Type 1 diabetes, APOε4 and ACED alleles do not appear to increase risk of cognitive dysfunction.

Aims

To determine the occurrence of microalbuminuria in young people with Type 1 diabetes mellitus followed prospectively for 2 years and to relate the presence of persistent elevations in urinary albumin excretion (UAE) to age, diabetes duration, puberty and other factors.

Methods

During a 2 year period, random urine samples were obtained from 471 patients, aged 8–18 years (mean ± SD 12.9 ± 2.3 years) with Type 1 diabetes duration 5.6 ± 3.0 years, as part of routine clinical care. Urine albumin and creatinine concentrations were measured in 1310 samples (median, 3 samples per patient) and the albumin:creatinine ratio was calculated (in micrograms albumin per milligram creatinine). Height, weight, blood pressure (BP), glycated haemoglobin (HbA1c), blood glucose monitoring frequency and Tanner staging were collected from patients’ medical records.

Results

Twenty-three per cent of patients had one or more sample with elevated UAE (≥20 μg/mg) and 9.3% had persistent elevations (≥2 samples ≥20 μg/mg). Those with and without persistent microalbuminuria did not differ significantly in age, diabetes duration, z–score for body mass index, pubertal status or BP percentile. Ten per cent of children <13 years old and 9% of children ≥13 years old had persistent microalbuminuria. Persistent microalbuminuria was significantly associated with diabetes duration only in older children (duration 0.5–3 years, 4%; 4–6 years, 8%; ≥7 years, 14%; P = 0.02, trend test). Mean HbA1c over the 2 years was 8.7 ± 1.2%. In a logistic regression model, mean HbA1c was the only significant predictor of persistent microalbuminuria (odds ratio 1.3, 95% confidence interval 1.0–1.6, P = 0.05).

Conclusions

Microalbuminuria in older children with Type 1 diabetes is likely to be clinically significant. In younger children, it may reflect functional, reversible renal changes. Longitudinal analysis is needed to confirm the probable transient nature of microalbuminuria in young patients with Type 1 diabetes.

Aims

Increased body weight and disordered eating attitudes/behaviours are common in adolescent girls with Type 1 diabetes (T1D). Disordered eating increases risks for diabetes-related complications. This study aimed to identify a rapid screening approach for disordered eating attitudes and behaviours in adolescent girls with T1D and to examine the relationship between disordered eating and body weight in this population.

Methods

Ninety adolescent girls, aged 12–19 years, provided a self-assessment of weight status. Participants also completed questionnaires to assess attitudes/behaviours toward food and eating, appetitive responsiveness to the food environment, disinhibition in eating and weight history.

Results

Forty-three per cent of participants reported a history of overweight. Compared with participants who reported never being overweight, those who reported ever being overweight were significantly older, scored significantly higher on all measures of disordered eating attitudes/behaviours (P ≤ 0.009) and were 4.8 times more likely to be currently overweight or obese (P < 0.001). Glycated haemoglobin (HbA1c) was similar between those who did and did not report ever being overweight.

Conclusions

Because of the ill-health effects of disordered eating and the higher rate of overweight in adolescent girls with T1D, effective screening tools are warranted. The single question ‘Have you ever been overweight?’ may be sufficient as a first question to screen for those at high risk for disordered eating attitudes/behaviours and to provide early intervention and prevention.

Aims

Prospective studies have identified chronic inflammation as a risk factor for type 2 diabetes. However, it is not known whether infection by specific pathogens or having a greater “pathogen burden” is associated with diabetes. The aim of this study was to examine the cross-sectional relation of seropositivity to five pathogens (C. pneumoniae, cytomegalovirus, H. pylori, hepatitis A virus, herpes simplex virus) and prevalent diabetes.

Methods

Baseline data from a random sample of MultiEthnic Study of Atherosclerosis (MESA) participants (n=1,000; age: 45-84) were used. Diabetes was defined by ADA 2003 criteria, and “pathogen burden” by the number of pathogens (0–5) for which an individual was seropositive. Logistic regression was used to test differences in diabetes prevalence by seropositivity. Linear regression was used to explore associations between pathogen seropositivity and the inflammation markers CRP, IL-6, and fibrinogen.

Results

Diabetes prevalence was 12.7%, while seropositivity for C. pnuemoniae was 76%, cytomegalovirus 77%, H. pylori 45%, hepatitis A 58%, and herpes simplex virus 85%. 72% were seropositive for ≥3 pathogens. In crude analyses, the prevalence of diabetes was higher among those with a pathogen burden ≥3, and with seropositivity to cytomegalovirus, H. pylori, hepatitis A, and herpes simplex virus. After adjustment for demographic covariates (particularly race) all associations became nonsignificant. Pathogen seropositivity was also not related to inflammation marker levels.

Conclusions

Following demographic adjustments, no associations were observed between infection by several pathogens and diabetes status, suggesting no etiologic role for them in the occurrence of diabetes.