Autonomic nerve testing predicts the development of complications: a 12-year follow-up study.

OBJECTIVE: Cardiac autonomic nerve tests have predicted increased mortality in adults with diabetes, predominantly due to nephropathy, cardiac disease, and hypoglycemia. The significance of subclinical autonomic nerve test abnormalities has not been systematically studied in adolescents. We aimed to reassess an adolescent cohort, whose autonomic nervous system had been tested 12 years earlier by both pupillometry and cardiovascular tests. RESEARCH DESIGN AND METHODS: From 1990 to 1993, adolescents with type 1 diabetes (n = 335) were assessed for autonomic neuropathy (median age 14.7 years [interquartile range 13.0-16.8], duration of diabetes 6.3 years [4.0-9.6], and A1C 8.3% [7.5-9.4]). Between 2003 and 2005, contact was made with 59% of the original group. Individual assessment 12 years later included completion of a validated hypoglycemia unawareness questionnaire (n = 123) and urinary albumin-to-creatinine ratio (n = 99) and retinal (n = 102) screening, as well as analysis of reports from external doctors (n = 35). RESULTS: At baseline, there was no difference in age, duration of diabetes, or complications between those who participated in the follow-up phase (n = 137) and those who did not participate (n = 196). However, baseline A1C was lower in the follow-up participants (8.2 vs. 8.5% for participants vs. nonparticipants, respectively, P = 0.031). At 12 years of follow-up, 93% were aware and 7% were unaware that they had hypoglycemia; 32 (31%) had no retinopathy, but 10% required laser therapy, and 80 (81%) had no microalbuminuria. Small pupil size at baseline was independently associated with the development of microalbuminuria (odds ratio 4.36 [95% CI 1.32-14.42], P = 0.016) and retinopathy (4.83 [1.3-17.98], P = 0.019) but not with the development of hypoglycemia unawareness. There was no association with baseline cardiovascular tests and the development of complications 12 years later. CONCLUSIONS: In this study, we found an association between baseline pupillometry tests and the presence of microalbuminuria and retinopathy at 12 years of follow-up. This suggests that pupillometry abnormalities may be early indicators of patients who are at high risk of future microvascular disease.

Decline in neurophysiological function after 7 years in an adolescent diabetic cohort and the role of aldose reductase gene polymorphisms.

OBJECTIVE: This 7-year longitudinal study examines the potential impact of aldose reductase gene (AKR1B1) polymorphisms on the decline of nerve function in an adolescent diabetic cohort. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (n = 262) were assessed with three cardiovascular autonomic tests (heart rate variation during deep breathing, Valsalva maneuver, and during standing from a lying position) and pupillometry (resting pupil diameter, constriction velocity, and reflex amplitude), thermal, and vibration thresholds on the foot. Genotyping was performed for promoters (C-106T and C-12G), (CA)(n) dinucleotide repeats, and intragenic BamH1 polymorphism. RESULTS: Median time between first and last assessment was 7.0 years (interquartile range 5.1-11.1), with a median of five assessments (four to seven) per individual. At first assessment, median age was 12.7 years (11.7-13.9), median duration was 5.3 years (3.4-8.0), and median HbA(1c) was 8.5% (7.8-9.3). All tests declined over time except for two cardiovascular autonomic tests and vibration discrimination. Faster decline in maximum constriction velocity was found to associate with the Z-2 allele (P = 0.045), Z-2/Z-2 (P = 0.026). Slower decline in hot thermal threshold discrimination associated with Z+2 (P = 0.044), Z+2/Z+2 (P < 0.0005), Z+2/T (P = 0.038), and bb (P = 0.0001). CONCLUSIONS: Most autonomic and quantitative sensory nerve testings declined over time. AKR1B1 polymorphisms were strongly associated with the rate of decline of these complications.

Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes.

OBJECTIVE: To compare the prevalence of diabetes complications and their risk factors in youth with type 1 versus type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a comparative clinic-based study of 1,433 patients with type 1 diabetes and 68 patients with type 2 diabetes aged <18 years from New South Wales, Australia. Retinopathy was assessed by seven-field stereoscopic retinal photography; albumin excretion rate from three consecutive, timed, overnight urine collections; peripheral neuropathy by thermal and vibration threshold; and autonomic neuropathy by pupillometry. HbA(1c) (A1C) and lipids were measured in all patients and C-peptide in patients with type 2 diabetes. RESULTS: In patients with type 1 versus type 2 diabetes, median (interquartile range) age was 15.7 years (13.9-17.0) and 15.3 years (13.6-16.4), respectively (P = 0.2), whereas median diabetes duration was 6.8 years (4.7-9.6) and 1.3 years (0.6-3.1), respectively (P < 0.0001). Retinopathy was significantly more common in patients with type 1 diabetes (20 vs. 4%, P = 0.04), while microalbuminuria and hypertension were significantly less common (6 and 16% in type 1 diabetes vs. 28 and 36% in type 2 diabetes). Rates of peripheral and autonomic neuropathy were similar (27 and 61% in type 1 diabetes vs. 21 and 57% in type 2 diabetes). In multivariate analyses, microalbuminuria was significantly associated with older age (odds ratio 1.3 [95% CI 1.2-1.5], P < 0.001) and systolic hypertension (3.63 [2.0-6.3], P < 0.001) in type 1 diabetes, while only higher A1C (1.7 [1.3-2.9], P = 0.002) was significant in patients with type 2 diabetes. CONCLUSIONS: Youth with type 2 diabetes have significantly higher rates of microalbuminuria and hypertension than their peers with type 1 diabetes, despite shorter diabetes duration and lower A1C. The results of this study support recommendations for early complications screening and aggressive targeting of glycemic control in patients with type 2 diabetes.

Discordant trends in microvascular complications in adolescents with type 1 diabetes from 1990 to 2002.

OBJECTIVE: Since the Diabetes Control and Complications Trial, diabetes management goals have changed. The aims of the present study were to assess complication rates, including nerve abnormalities, in adolescents from 1990 to 2002 and to investigate associated risk factors. RESEARCH DESIGN AND METHODS: Cross-sectional analysis of complications was assessed in three study periods (1990-1994 [T1], 1995-1998 [T2], and 1999-2002 [T3]) in adolescents matched for age and diabetes duration (n = 878, median age 14.6 years, median duration 7.5 years). Retinopathy was assessed by seven-field stereoscopic fundal photography, albumin excretion rate (AER) from three consecutive timed overnight urine collections, peripheral nerve function by thermal and vibration thresholds, and autonomic nerve function by cardiovascular reflexes. RESULTS: Retinopathy declined significantly (T1, 49%; T2, 31%; and T3, 24%; P < 0.0001), early elevation of AER (> or = 7.5 microg/min) declined (38, 30, and 25%, respectively, P = 0.022), and microalbuminuria (AER > or = 20 microg/min) declined (7, 3, and 3%, respectively; P = 0.017, T1 vs. T2 and T3). Autonomic nerve abnormalities were unchanged (18, 21, and 18%, respectively; P = 0.60), but peripheral nerve abnormalities increased (12, 19, and 24%, respectively; P = 0.0017). More patients were treated with three or more injections per day (12, 46, and 67%, respectively; P < 0.0001) and insulin dose increased (1.08, 1.17, and 1.22 units x kg(-1) x day(-1), respectively; P < 0.0001), but median HbA(1c) (A1C) was unchanged (8.5, 8.5, and 8.4%, respectively). BMI and height SD score increased: BMI 0.46, 0.67, and 0.79, respectively (P < 0.0001), and height -0.09, 0.05, and 0.27, respectively (P < 0.0001). CONCLUSIONS: Retinopathy and microalbuminuria declined over time in this cohort, but the increased rate of peripheral nerve abnormalities is of concern. Despite intensified management (higher insulin dose and more injections), A1C has not changed and remains well above the recommended targets for adolescents.

Insulin Pump Therapy Is Associated with Lower Rates of Retinopathy and Peripheral Nerve Abnormality.

OBJECTIVE: To compare rates of microvascular complications in adolescents with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). RESEARCH DESIGN AND METHODS: Prospective cohort of 989 patients (aged 12-20 years; diabetes duration >5 years) treated with CSII or MDI for >12 months. Microvascular complications were assessed from 2000-14: early retinopathy (seven-field fundal photography), peripheral nerve function (thermal and vibration threshold testing), autonomic nerve abnormality (heart rate variability analysis of electrocardiogram recordings) and albuminuria (albumin creatinine ratio/timed overnight albumin excretion). Generalized estimating equations (GEE) were used to examine the relationship between treatment and complications rates, adjusting for socio-economic status (SES) and known risk factors including HbA1c and diabetes duration. RESULTS: Comparing CSII with MDI: HbA1C was 8.6% [70mmol/mol] vs. 8.7% [72 mmol/mol]) (p = 0.7), retinopathy 17% vs. 22% (p = 0.06); microalbuminuria 1% vs. 4% (p = 0.07), peripheral nerve abnormality 27% vs. 33% (p = 0.108) and autonomic nerve abnormality 24% vs. 28% (p = 0.401). In multivariable GEE, CSII use was associated with lower rates of retinopathy (OR 0.66, 95% CI 0.45-0.95, p = 0.029) and peripheral nerve abnormality (OR 0.63, 95% CI 0.42-0.95, p = 0.026), but not albuminuria (OR 0.46, 95% CI 0.10-2.17, p = 0.33). SES was not associated with any of the complication outcomes. CONCLUSIONS: In adolescents, CSII use is associated with lower rates of retinopathy and peripheral nerve abnormality, suggesting an apparent benefit of CSII over MDI independent of glycemic control or SES.

A flexible diet using an insulin to carbohydrate ratio for adolescents with type 1 diabetes - a pilot study.

BACKGROUND & AIMS: There is significant interest in the utility of flexible meal plans for individuals with type 1 diabetes. However, there is a paucity of data examining this approach in adolescents. The aim of this study was to assess glycemic control, weight status and quality of life over 12 months in adolescents with type 1 diabetes, who were commenced on a flexible meal plan using an insulin to carbohydrate ratio. METHODS: 38 adolescents with type 1 diabetes were recruited and 28 completed the study. Glyceamic control, weight status and quality of life were measured using haemoglobin A1c, BMI and the Diabetes Quality of Life -Youth questionnaire. RESULTS: Nine months after the adolescents were transitioned to a flexible meal and insulin plan, mean BMI SDS decreased (by 0.15 ± 0.20; P < 0.001) and haemoglobin A1c increased (by 0.7 ± 0.83%; P = 0.001). Adolescents reported no change in the impact or concerns about diabetes. However, mean life satisfaction scores increased (5.5 ± 9.5; P = 0.008). CONCLUSIONS: On a flexible meal and insulin plan glycemic control deteriorated although weight status and life satisfaction, two outcomes which may be important to the adolescents, improved. A flexible meal and insulin plan warrants further investigation as a management option.

Continued reduction in the prevalence of retinopathy in adolescents with type 1 diabetes: role of insulin therapy and glycemic control.

OBJECTIVE: To examine trends in microvascular complications in adolescents with type 1 diabetes between 1990 and 2009 in Sydney, Australia. RESEARCH DESIGN AND METHODS: We used analysis of complications in 1,604 adolescents (54% female, aged 12-20 years, median duration 8.6 years), stratified by four time periods using Generalized Estimation Equations as follows: T1 (1990-1994), T2 (1995-1999), T3 (2000-2004), and T4 (2005-2009). Early retinopathy was detected using seven-field fundal photography, albumin excretion rate (AER) using timed overnight urine collections, and albumin-to-creatinine ratio (ACR) and peripheral nerve function using thermal and vibration threshold. RESULTS: Retinopathy declined (53, 38, 23, and 12%; P < 0.001), as did borderline elevation of AER/ACR (45, 30, 26, and 30%; P < 0.001) and microalbuminuria (8, 4, 3, and 3%; P = 0.006). Multiple daily injections (MDI)/continuous subcutaneous insulin infusion (CSII) use increased (17, 54, 75, and 88%; P < 0.001), median HbA(1c) decreased (9.1, 8.9, 8.5, and 8.5%; P < 0.001), and severe hypoglycemia was unchanged (6, 8, 10, and 7%; P = 0.272). Retinopathy was associated with diabetes duration (odds ratio [OR] 1.12 [95% CI 1.08-1.17]), age (1.13 [1.06-1.20]), HbA(1c) (1.16 [1.08-1.25]), systolic blood pressure (BP) SDS (1.31 [1.16-1.48]), socioeconomic disadvantage (1.42 [1.04-1.95]), and 1 to 2 injections per day (vs. MDI/CSII; 1.35 [1.05-1.73]); borderline AER/ACR with male sex (1.32 [1.02-1.70]), age (1.19 [1.12-1.26]), HbA(1c) (1.18 [1.08-1.29]), weight SDS (1.31 [1.21-1.53]), insulin dose per kilograms (1.64 [1.13-2.39]), 1 to 2 injections per day (1.41 [1.08-1.84]), and socioeconomic disadvantage (1.68 [1.23-2.31]); and microalbuminuria with age (1.14 [1.01-1.29]), HbA(1c) (1.20 [1.05-1.37]), diastolic BP SDS (1.76 [1.26-2.46]), and 1 to 2 injections per day (1.95 [1.11-3.41]). CONCLUSIONS: The decline in retinopathy supports contemporary guidelines that recommend lower glycemic targets and use of MDI/CSII in children and adolescents with type 1 diabetes.