Janine Cusumano

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 HbA1c 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]), HbA1c (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]), HbA1c (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]), HbA1c (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.

Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes.

OBJECTIVE To examine the hypothesis that vitamin D deficiency (VDD) is associated with an increased prevalence of microvascular complications in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS In a cross-sectional study of 517 patients, 25-hydroxyvitamin D was measured. Retinopathy was assessed by 7-field stereoscopic retinal photography, peripheral neuropathy by thermal and vibration threshold testing, and microalbuminuria by albumin excretion rate or albumin-to-creatinine ratio. RESULTS Retinopathy prevalence was higher in cases with VDD versus sufficiency (18 vs. 9%, P = 0.02); deficiency was not associated with microalbuminuria or neuropathy. In logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03–4.33]), diabetes duration (1.13, 1.05–1.23), and HbA1c (1.24, 1.02–1.50). CONCLUSIONS VDD is associated with an increased prevalence of retinopathy in young people with type 1 diabetes. The inflammatory and angiogenic effects of VDD may contribute to early retinal vascular damage; however, further investigations are warranted.

Prevalence of diabetes complications 6 years after diagnosis in an incident cohort of childhood diabetes

Aims  To examine the prevalence of early diabetes complications 6 years after diagnosis of diabetes. The hypothesis that initial contact with a multidisciplinary team would be associated with a reduced risk of microvascular complications was tested in this cohort.

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 HbA1c 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.

Retinal Vascular Geometry Predicts Incident Renal Dysfunction in Young People With Type 1 Diabetes

OBJECTIVE To examine the relationship between retinal vascular geometry parameters and development of incident renal dysfunction in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS This was a prospective cohort study of 511 adolescents with type 1 diabetes of at least 2 years duration, with normal albumin excretion rate (AER) and no retinopathy at baseline while attending an Australian tertiary-care hospital. AER was quantified using three overnight, timed urine specimen collections and early renal dysfunction was defined as AER >7.5 μg/min. Retinal vascular geometry (including length-to-diameter ratio [LDR] and simple tortuosity [ST]) was quantified from baseline retinal photographs. Generalized estimating equations were used to examine the relationship between incident renal dysfunction and baseline venular LDR and ST, adjusting for age, diabetes duration, glycated hemoglobin (A1C), blood pressure (BP), BMI, and cholesterol. RESULTS Diabetes duration at baseline was 4.8 (IQR 3.3–7.5) years. After a median 3.7 (2.3–5.7) years follow-up, 34% of participants developed incident renal dysfunction. In multivariate analysis, higher retinal venular LDR (odds ratio 1.7, 95% CI 1.2–2.4; quartile 4 vs. 1–3) and lower venular ST (1.6, 1.1–2.2; quartile 1 vs. 2–4) predicted incident renal dysfunction. CONCLUSIONS Retinal venular geometry independently predicted incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may help to elucidate early mechanistic pathways for microvascular complications. Retinal venular geometry may be a useful tool to identify individuals at high risk of renal disease early in the course of diabetes.

Early elevation of albumin excretion rate is associated with poor gluten-free diet adherence in young people with coeliac disease and diabetes

There are conflicting data on microvascular complications in coexisting Type 1 diabetes and coeliac disease. We compared complications rates in youth with or without coeliac disease and examined the association between gluten‐free diet adherence and complications.

Sex Differences in Retinal Microvasculature Through Puberty In Type 1 Diabetes: Are Girls at Greater Risk of Diabetic Microvascular Complications?

PURPOSE Adolescent females with type 1 diabetes (T1D) are reported to have greater risk of early microvascular complications than males. We hypothesize sex differences in retinal vascular geometry (RVG) through puberty are associated with earlier-onset microvascular complications. METHODS Prepubertal patients (n = 64, 35 male) with T1D, complication-free at baseline, were followed through to sexual maturity with detailed Tanner-staging and repeated diabetes complications assessments. Retinal vascular geometry from digitized retinal photographs at each visit was assessed using a semiautomated computer program. Determinants of RVG measurements (pre-, during, and post puberty) were explored using generalized estimating equations (GEE). Factors associated with time to onset of retinopathy and albumin excretion rate (AER) were examined using multivariable Cox regression. RESULTS Median follow-up was 7.2 years. Retinopathy developed in 69% and elevated albumin excretion in 56%. In multivariable GEE, female sex was associated with wider venular caliber (prepuberty: lowest-quartile, odds ratio 0.40 [95% confidence interval: 0.17, 0.96]); P = 0.04) and lower arteriolar length-to-diameter-ratio (LDRa) (during puberty: lowest-quartile 2.87 [1.01, 8.13]; P = 0.047 and post puberty: 2.93 [0.96, 8.64]; P = 0.06). In Cox-regression, females developed retinopathy earlier than males (8.1 vs. 9.6 years; P = 0.002). Female sex (hazard ratio [HR] 3.8 [1.6-8.6]; P = 0.002) and growth velocity (1.3 [1.1-1.5]; P = 0.001) were associated with earlier retinopathy. CONCLUSIONS This is the first longitudinal study to repeatedly examine RVG through puberty in youth with T1D. Sex dimorphism was observed. Female sex was associated with lower LDRa, wider venules, and earlier onset of retinopathy. These RVG patterns have been associated with incident microvascular complications but did not reach statistical significance in this study. Larger studies are needed to investigate the RVG, microvascular complications, and sex associations early in the course of T1D.

Plantar fascia thickness is longitudinally associated with retinopathy and renal dysfunction: a prospective study from adolescence to adulthood

Aim: The aim was to study the longitudinal relationship between plantar fascia thickness (PFT) as a measure of tissue glycation and microvascular (MV) complications in young persons with type 1 diabetes (T1DM). Methods: We conducted a prospective longitudinal cohort study of 152 (69 male) adolescents with T1DM who underwent repeated MV complications assessments and ultrasound measurements of PFT from baseline (1997–2002) until 2008. Retinopathy was assessed by 7-field stereoscopic fundal photography and nephropathy by albumin excretion rate (AER) from three timed overnight urine specimens. Longitudinal analysis was performed using generalized estimating equations (GEE). Results: Median (interquartile range) age at baseline was 15.1 (13.4–16.8) years, and median follow-up was 8.3 (7.0–9.5) years, with 4 (3–6) visits per patient. Glycemic control improved from baseline to final visit [glycated hemoglobin (HbA1c) 8.5% to 8.0%, respectively; p = .004]. Prevalence of retinopathy increased from 20% to 51% (p < .001) and early elevation of AER (>7.5 μg/min) increased from 26% to 29% (p = .2). A greater increase in PFT (mm/year) was associated with retinopathy at the final assessment (ΔPFT 1st vs. 2nd-4th quartiles, χ2 = 9.87, p = .02). In multivariate GEE, greater PFT was longitudinally associated with retinopathy [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.0–10.3] and early renal dysfunction (OR 3.2, CI 1.3–8.0) after adjusting for gender, blood pressure standard deviation scores, HbA1c, and total cholesterol. Conclusions: In young people with T1DM, PFT was longitudinally associated with retinopathy and early renal dysfunction, highlighting the importance of early glyccmic control and supporting the role of metabolic memory in MV complications. Measurement of PFT by ultrasound offers a noninvasive estimate of glyccmic burden and tissue glycation.

Vitamin D deficiency is not associated with changes in retinal geometric parameters in young people with type 1 diabetes.

Changes in retinal geometric parameters predict risk and progression of diabetic retinopathy (DR). We have shown that vitamin D deficiency (VDD) is associated with DR. We hypothesized that VDD mediates changes in retinal geometric parameters. Retinal vascular geometric parameters were assessed using a semiautomated computer program in photographs from young people with type 1 diabetes (T1D) (n = 481) and summarized as central retinal arteriolar and venular equivalents (CRAE, CRVE), fractal dimension, length-diameter ratio, branching angle and curvature tortuosity. Parameters were compared between those with and without DR and VDD (25-hydroxyvitamin D concentration ≤ 50 nmol/L). Retinal vascular geometric parameters were also compared across quartiles of vitamin D levels. Median CRVE was higher in patients with DR compared with those without (median (IQR) CRVE 247.3 μm (31.3) versus 238.8 μm (23.5), P = 0.01). Fractal dimension was marginally greater in patients without VDD (1.49 (0.06) versus 1.47 (0.07) P = 0.03). There was no difference in CRAE, CRVE, length-diameter ratio, branching angle, and curvature tortuosity between those with and without VDD and across quartiles of 25OHD. In conclusion, DR is associated with higher CRVE in young people with T1D; however, VDD is not associated with changes in retinal vascular geometric measures, suggesting an earlier role in the time course of DR pathogenesis.