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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. [ABSTRACT FROM AUTHOR]

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.

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.

Objective: This study was designed to explore the timeline of protection against complications in prepubertal children with diabetes, in particular the effects of diabetes duration before age 5 years., Research Design and Methods: In this study, 193 adolescents with prepubertal diabetes onset were followed longitudinally for retinopathy (early background and clinical) and microalbuminuria (albumin excretion rate >7.5 micro g/min and >20 micro g/min). Multiple logistic regression analysis was used to compare the effect of pre- and postpubertal diabetes duration on the risk of each complication in 90 subjects reassessed as young adults. For the entire cohort, Kaplan-Meier estimates were used to determine time free of each complication, and survival was compared in those diagnosed before and after age 5 years. Accelerated failure time modeling was used to estimate the effect of covariates, including diabetes duration before puberty, on the risk of complications., Results: Prepubertal duration improved the prediction for retinopathy over postpubertal duration alone in the young adults. The survival-free period of retinopathy and microalbuminuria was significantly longer (2-4 years) for those diagnosed before age 5 years compared with those diagnosed after age 5 years. Time to onset of all complications increased progressively with longer diabetes duration before gonadarche. Higher HbA(1c) during adolescence had an independent effect on the risk of retinopathy and microalbuminuria., Conclusions: Prepubertal diabetes duration remains a significant predictor of retinopathy in young adults. The effect of time on the risk of retinopathy and microalbuminuria is nonuniform, with an increasing delay in the onset of complications in those with longer prepubertal duration. These findings are of major clinical importance when setting targets of glycemic control in young children who are at greatest risk of hypoglycemia.

Objective: To identify environmental factors involved in the etiology of insulin-dependent diabetes mellitus (IDDM)., Research Design and Methods: An estimated 90% of all incident cases of IDDM in patients 0-14 years of age in New South Wales, Australia, were ascertained over 18 months. For each IDDM patient, two age- and sex-matched control subjects were randomly selected from the population. Past environmental exposures were determined with a questionnaire completed by the parents. Response rates were 92% for the IDDM patients (217 of 235) and 55% for the control subjects (258 of 470). The relative risk associated with each exposure was estimated with the odds ratio (OR) adjusted for confounding factors using multiple logistic regression., Results: The introduction of cow's milk-based infant formula into the diet before 3 months of age was associated with an increased risk (OR 1.52, 95% confidence interval [CI] 1.04-2.24). Exclusive breast-feeding for > or = 3 months was associated with a protective effect (OR 0.66, 95% CI 0.45-0.97). High dietary intake of cow's milk protein in the 12 months before the onset of diabetic symptoms was also associated with an increased risk (OR 1.84, 95% CI 1.12-3.00). A recent infection (during the 3 months before onset of diabetic symptoms) was more common in the patients than the control subjects (OR 2.92, 95% CI 1.96-4.35), as was day care attendance before the age of 3 (OR 1.73, 95% CI 1.00-3.00). When two age-groups, defined by the median age at onset of diabetes, were compared, the associations with early infant-feeding were stronger among the younger group (< 9.2 years), and associations with recent diet and recent infection were stronger among the older group (> or = 9.2 years)., Conclusions: These results indicate an increased risk of IDDM associated with early dietary exposure to cow's milk-containing formula, short duration of exclusive breast-feeding, high intake of cow's milk protein in the recent diet, recent infection, and early attendance at day care.

Objective: To determine the incidence of insulin-dependent diabetes mellitus (IDDM) in children 0-14 years of age in the state of New South Wales, Australia, which has a total population of 5.73 million., Research Design and Methods: We established a prospective register, identifying 361 incident cases over a 2-year period (1990-1991) with two independent sources of case ascertainment. The primary source was the reporting of newly diagnosed patients by physicians and diabetes educators. The secondary source was a subsidized syringe scheme., Results: Using the capture-recapture method, ascertainment was estimated to be 99.4% complete. The age-standardized incidence rate was 14.5 per 100,000 person-years (95% confidence interval: 13.0-16.0). No significant differences were found when comparing the first and second years of the register, boys and girls, geographical areas, or Aboriginal and non-Aboriginal children. There was seasonal variation in the onset (with more cases in winter), which was evident in the 10- to 14-year age-group (P = 0.01), but not in younger age-groups. A first-degree relative was already affected in 6.9% of the cases. No significant difference was noted in the age at onset when comparing cases with and without an affected first-degree relative., Conclusions: The incidence of childhood IDDM in New South Wales is similar to rates found in other predominantly Anglo-Saxon populations. IDDM occurs in Aboriginal children with a frequency comparable to that in the rest of the population.

Objective: To evaluate computerized infrared pupillometry for the assessment of autonomic neuropathy in adolescents with type I diabetes., Research Design and Methods: We measured resting pupil diameters and pupillary light reflexes in 142 adolescents with type I diabetes (72 boys and 70 girls, 10.4-19.8 yr of age, duration of diabetes 0.7-18.3 yr) and in 75 nondiabetic control subjects (29 boys, 46 girls, 11.3-19.8 yr of age). All study participants were assessed using four standard cardiovascular tests: maximum-minimum heart rate during deep breathing (mean of three cycles); heart-rate change during a Valsalva maneuver (Valsalva ratio, mean of three maneuvers); lying-to-standing heart-rate change (30:15 ratio); and lying-to-standing BP change., Results: Mean resting pupil diameters were significantly smaller in the diabetic group: 6.28 +/- 0.06 vs. 6.77 +/- 0.11 mm, P < 0.0001); and significantly smaller with greater duration of diabetes (r = -0.29, P = 0.0006) and higher levels of GHb (r = -0.24, P = 0.004). Patients with retinopathy grade 30 or more (Wisconsin 191 grading) had significantly smaller resting pupil diameters: 5.9 +/- 0.16 vs. 6.4 +/- 0.12 mm, P = 0.008). The phasic light reflex as determined by reflex amplitude and maximum constriction velocity was significantly reduced in the diabetic group: 2.27 +/- 0.03 vs. 2.44 +/- 0.04 mm, P = 0.0009; and 6.68 +/- 0.12 vs. 7.24 +/- 0.16 mm/s, P = 0.007). Reduced reflex amplitude was related to a longer postpubertal duration of diabetes (r = -0.18, P = 0.04). We found no association between pupillary and cardiovascular tests., Conclusions: Infrared computerized pupillometry demonstrates subclinical diabetic autonomic neuropathy as early as adolescence. Its presence seems to be related to longer duration of diabetes and unfavorable metabolic control.