Predictors of change in the neuropsychological profiles of children with type 1 diabetes 2 years after disease onset.

OBJECTIVE: To identify type 1 diabetes-related predictors of change in the neuropsychological profiles of children over the first 2 years of the illness. RESEARCH DESIGN AND METHODS: Children (n = 116) aged 3-14 years were assessed soon after diagnosis and re-evaluated 2 years later to examine relationships between illness variables, such as age of onset and metabolic control history, and changes in neuropsychological status over the first 2 years of type 1 diabetes. RESULTS: Illness variables were significant predictors of change in neuropsychological test scores within 2 years of onset of type 1 diabetes. Age of onset of type 1 diabetes predicted negative change on Performance Intelligence Quotient, whereas both recurrent severe hypoglycemia and chronic hyperglycemia were associated with reduced memory and learning capacity. CONCLUSIONS: These results suggest that the relationship between metabolic control and neuropsychological risk is nonlinear in that children with either recurrent severe hypoglycemia or chronically elevated blood sugars exhibit negative changes in their neuropsychological profiles. Onset of type 1 diabetes very early in life adds another dimension of risk, particularly affecting the acquisition of visuospatial skills.     

Factors associated with academic achievement in children with type 1 diabetes

OBJECTIVE: To examine academic achievement in children with diabetes and to identify predictors of achievement. RESEARCH DESIGN AND METHODS: Participants were 244 children, ages 8-18 years, with type 1 diabetes. Measures included school-administered standardized achievement tests (Iowa Tests of Basic Skills and Iowa Tests of Educational Development [ITBS/ITED]), grade point averages (GPAs), school absences, behavioral assessment, age at disease onset, hospitalizations, and HbA(1c). Statistical differences between subgroups of children were evaluated using t test and ANOVA, statistically controlling for socioeconomic status. Regression analyses were carried out to examine predictors of academic performance. RESULTS: Reading scores and GPA were lower for children with poor metabolic control than for children with average control. Children with hospitalizations for hyperglycemia had lower overall achievement scores than children with better metabolic control and fewer hospitalizations for hyperglycemia. The small group of children with tight metabolic control and hypoglycemic hospitalizations scored particularly low on the ITBS/ITED. Other variables had less clear relationships with academic achievement. Neither early onset of diabetes nor frequent school absence was associated with lower scores on the ITBS/ITED. Sex comparisons found that boys performed better than girls only in math. Socioeconomic status and parent ratings of behavior problems were significantly correlated with academic achievement, but medical variables added only slightly to predictive precision. CONCLUSIONS: For most children with diabetes, medical variables are not as strongly associated with academic achievement as are factors such as socioeconomic status and behavioral factors. Poor metabolic control and serious hypoglycemia, however, are a potential concern for a subset of these children.     

Cognitive function in children with type 1 diabetes: a meta-analysis

OBJECTIVE—To quantify the magnitude and pattern of cognitive difficulties in pediatric type 1 diabetes as well as the effects associated with earlier disease onset and severe hypoglycemia.RESEARCH DESIGN AND METHODS—Pediatric studies of cognitive function since 1985 were identified for study inclusion using MEDLINE and PsycInfo. Effect size (ES, Cohen''s d) between the diabetic and control groups, expressed in SD units, were calculated within cognitive domains to standardize meta-analysis test performance.RESULTS—The meta-analysis sample of 2,144 children consisted of 1,393 study subjects with type 1 diabetes and 751 control subjects from 19 studies. Overall, type 1 diabetes was associated with slightly lower overall cognition (ES −0.13), with small differences compared with control subjects across a broad range of domains, excluding learning and memory, which were similar for both groups. Learning and memory skills, both verbal and visual (−0.28 and −0.25), were more affected for children with early-onset diabetes (EOD) than late-onset diabetes (LOD), along with attention/executive function skills (−0.27). Compared with nondiabetic control subjects, EOD effects were larger, up to one-half SD lower, particularly for learning and memory (−0.49). Generally, seizures were associated with a negligible overall cognition ES of −0.06, with slight and inconsistent cognitive effects found on some measures, possibly reflecting the opposing effects of poorer versus better metabolic control.CONCLUSIONS—Pediatric diabetes generally relates to mildly lower cognitive scores across most cognitive domains. Cognitive effects are most pronounced and pervasive for EOD, with moderately lower performance compared with control subjects. Seizures are generally related to nominal, inconsistent performance differences.Type 1 diabetes affects ∼1 in 500 children. Growing consensus indicates that children with type 1 diabetes, compared with control subjects, are at risk of developing cognitive difficulties (1). However, research results are inconsistent regarding the magnitude and pattern of cognitive difficulties due to heterogeneous samples, sampling procedures, cognitive abilities assessed, and study designs (1,2). Debate remains over the extent and type of pediatric diabetes cognitive difficulties—general cognitive or specific neuropsychological—and their associated risk factors.Using meta-analysis to synthesize data across studies, this article aims to determine whether there is evidence of cognitive dysfunction in children with type 1 diabetes compared with demographically similar children without diabetes. Examination of effect size (ES, Cohen''s d) highlights differences across various cognitive domains and the magnitude of those differences. A second aim of the current study is to determine whether some children with type 1 diabetes have an elevated risk of cognitive dysfunction. Earlier age of diabetes onset is identified in the literature as one of the strongest risk factors associated with disrupted cognitive functioning (3,4,5,6). To examine the impact of early-onset diabetes (EOD) on cognitive abilities, a second meta-analysis is conducted to compare children classified by authors as having earlier age at onset, which may range anywhere from 4 to 7 years depending on the author, to later age at onset (late-onset diabetes [LOD]). Examination of ES determines the scope and magnitude of differences, if any, across cognitive domains. After the relative comparison of EOD and LOD, each group is compared separately with children without diabetes to better assess the true magnitude of cognitive effects for each group compared with children without a chronic disease.A clear picture of EOD effects is obscured because EOD may be a surrogate for recurrent severe hypoglycemia; young children with diabetes have a greater risk of severe hypoglycemia (7). Like EOD, severe hypoglycemia is also associated with poorer performance on measures of cognitive function, particularly memory (8), although these findings have not been consistent across studies (9,10). Therefore, ancillary analyses will be conducted to further explore the possible effects of severe hypoglycemia on cognitive function. Finally, EOD may be a surrogate for longer disease duration, since children with earlier onset correspondingly have longer disease duration than age-matched children diagnosed later. However, there are a limited number of studies available that specifically examine the impact of disease duration on cognitive function, such that these effects are not examined in the present study.     

Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes

OBJECTIVE: Repeated severe hypoglycemia has been reported to reduce long-term spatial memory in children with type 1 diabetes. Early exposure to hypoglycemia may be more damaging to cognitive function than later exposure. Our goal was to determine whether the age at which severe hypoglycemia occurs modulates the impact of severe hypoglycemia frequency on long-term spatial memory. RESEARCH DESIGN AND METHODS: We combined data from three independent studies to obtain a sample of children aged 6-18 years with type 1 diabetes (n = 103) and nondiabetic control subjects (n = 60). Each study evaluated previous severe hypoglycemia and tested short (5 s)- and long (60 s)-delay spatial memory with the spatial delayed response task. Type 1 diabetic participants were categorized as having zero, one to two, or three or more severe hypoglycemic episodes and as having their first severe hypoglycemic episode before or after 5 years of age. Information on chronic hyperglycemia (HbA1c values) was also collected. RESULTS: We found that repeated severe hypoglycemia (more than three episodes) reduced long-delay spatial delayed response performance, particularly when severe hypoglycemic episodes began before the age of 5 years. Age of type 1 diabetes onset and estimates of chronic hyperglycemia did not influence performance. CONCLUSIONS: High frequency of and early exposure to severe hypoglycemia during development negatively affects spatial long-term memory performance.     

Conventional versus intensive diabetes therapy in children with type 1 diabetes: effects on memory and motor speed.

OBJECTIVE: Severe hypoglycemia may impair medial temporal-mediated cognitive skills, such as the ability to recall past events explicitly (delayed declarative memory). The objective of this study was to determine whether delayed declarative memory deficits are present in a group of diabetic children with an increased risk of severe hypoglycemia. RESEARCH DESIGN AND METHODS: Nondiabetic children (n = 16) and children with type 1 diabetes who had been randomly assigned to either intensive (IT) (n = 13) or conventional (CT) (n = 12) diabetes therapy at the time of diagnosis participated in the study. All episodes of severe hypoglycemia were prospectively ascertained. All children were tested on memory tasks that have been closely linked to medial temporal functioning and on reaction time measures. RESULTS: Our results demonstrated that the IT group had a threefold higher rate of severe hypoglycemia, performed less accurately on a spatial declarative memory task, and performed more slowly, but not less accurately, on a pattern recognition task than did the CT group or control subjects. In addition, both groups of type 1 diabetic children were significantly impaired on a motor speed task compared with their nondiabetic peers. CONCLUSIONS: These results indicate a selective relative memory impairment associated with IT that is consistent with the effects of severe hypoglycemia and medial temporal damage or dysfunction. If larger prospective studies determine that severe hypoglycemia is the mediating factor for this memory impairment, extreme caution in imposing overly strict standards for glucose control in young patients with type 1 diabetes would be indicated because of the increased risk of hypoglycemia associated with IT regimens.     

A two-center randomized controlled feasibility trial of insulin pump therapy in young children with diabetes

OBJECTIVE: Our goals were to determine if continuous subcutaneous insulin infusion (CSII), compared with those continuing multiple daily injections (MDIs), can be safely used in young children, if those on CSII will have superior glycemic control, if subjects using CSII will have less hypoglycemia for their level of control, and if families using CSII will report an improved quality of life. RESEARCH DESIGN AND METHODS: We conducted a randomized 1-year feasibility trial comparing CSII with continuing MDIs in preschool children with a history of type 1 diabetes for at least 6 months' duration. Prospective outcomes included measures of overall glycemic control (HbA1c and continuous glucose monitoring system), the incidence of severe hypoglycemia and diabetic ketoacidosis, the percent of glucose values below 3.9 mmol/l, and the parents' report of quality of life. RESULTS: The 19 subjects' ages ranged from 1.7 to 6.1 (mean 3.6) years, duration of diabetes ranged from 0.6 to 2.6 (mean 1.4) years, and baseline HbA1c ranged from 6.7 to 9.6% (mean 7.9%). Seven subjects were male. Nine subjects were randomized to start CSII and 10 to continue on MDI. All baseline characteristics were well balanced. Overall metabolic control, diabetes quality of life, and the incidence of hypoglycemia were similar in the two groups. No subject had diabetic ketoacidosis, while one subject in each group had an episode of severe hypoglycemia. No CSII subject discontinued using the pump during or after the study. CONCLUSIONS: CSII can be a safe and effective method to deliver insulin in young children.     

Impaired Awareness of Hypoglycemia in a Population-Based Sample of Children and Adolescents With Type 1 Diabetes

OBJECTIVE

To determine the prevalence and clinical associations of impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A validated questionnaire was administered to 656 patients with type 1 diabetes over a 6-month period to determine hypoglycemia awareness status. Case ascertainment was 79% of the clinic population. The rate of severe hypoglycemia was determined by data collected prospectively in the preceding year.

RESULTS

Impaired awareness of hypoglycemia was present in 29% of patients. Patients with impaired awareness of hypoglycemia had an earlier onset of diabetes (P < 0.001), were younger (P < 0.001), and had lower mean levels of A1C since diabetes onset (P = 0.006) and at their last visit (P = 0.001). The overall rate of severe hypoglycemia was 24.5 episodes per 100 patient-years in the preceding year. The severe hypoglycemia rate was higher in those with impaired awareness of hypoglycemia (37.1 vs. 19.3 episodes per 100 patient-years, P < 0.001). Among patients aged <6 years (n = 46), 59% of care providers reported impaired awareness of hypoglycemia, and the rate of severe hypoglycemia was significantly higher in those reporting impaired awareness (33.3 vs. 52 episodes per 100 patient-years, P = 0.02). More patients with recurrent hypoglycemia reported impaired awareness of hypoglycemia (47 vs. 28%, P = 0.03).

CONCLUSIONS

A significant proportion of children and adolescents with type 1 diabetes have impaired awareness of hypoglycemia. Screening for impaired awareness is an important component of routine diabetes care and can identify patients at increased risk of a severe hypoglycemic event.Hypoglycemia is a well-known complication of insulin therapy in children and adolescents with diabetes. The risk of recurrent and severe hypoglycemia causes significant anxiety and emotional morbidity for patients and their families and is a limiting factor in the achievement of tight glycemic control.Hypoglycemia unawareness is defined as the onset of neuroglycopenia before autonomic activation (1). Patients have defective symptomatic and counterregulatory hormone responses to hypoglycemia and are unable to initiate self-treatment. This impaired awareness has been associated with severe hypoglycemia, accounting for 36% of the hypoglycemia that occurred while subjects were awake during the Diabetes Control and Complications Trial (2).The neurological consequences of severe hypoglycemia are particularly important in the young child with type 1 diabetes. Hypoglycemia has been associated with a decrease in neurocognitive function in children with type 1 diabetes, particularly those in whom diabetes is diagnosed before the age of 5–6 years (3–5). Repeated hypoglycemic seizures in young children may also cause structural brain changes, as suggested by the prevalence of mesial temporal sclerosis in 16% of a cohort of children with early-onset type 1 diabetes (6). Severe hypoglycemia adds to the considerable burden of disease in families through increased anxiety, poor sleep, increased hospitalizations, excessive lowering of insulin dose, and worsening of glycemic control (7).For clinical and research purposes, determining the presence of hypoglycemia unawareness in children and adolescents with diabetes is important. Various methods have been applied, including the use of self-reporting symptom questionnaires and inducing experimental hypoglycemia in the laboratory to determine the symptom response threshold and counterregulatory hormone response. The aim of this study was to determine the prevalence of impaired awareness of hypoglycemia in a large, population-based cohort with childhood-onset type 1 diabetes, assessed with a self-reporting questionnaire, and to study the relationship between impaired hypoglycemia awareness and severe hypoglycemia.     

Urinary excretion of albumin in adolescents with type 1 diabetes: persistent versus intermittent microalbuminuria and relationship to duration of diabetes, sex, and metabolic control.

OBJECTIVE: Urinary excretion of albumin is a marker for incipient diabetic nephropathy in adults. The intra-individual variability, as well as the relationship to duration of diabetes, onset of the disease, and long-term metabolic control, have not been evaluated in a large sample of pediatric patients. RESEARCH DESIGN AND METHODS: A total of 5,722 nocturnal urinary albumin excretion rates were determined in 447 children, adolescents, and young adults with type 1 diabetes, comprising 1,821 years of observation. Excretion rates were related to duration of diabetes, age at onset of diabetes, sex, blood pressure, and metabolic control. RESULTS: Based on repeated measurements in individual patients, the positive predictive value of one sample was 76%, the negative 99.5%. After a duration of diabetes of 11 years, 5% of patients displayed persistent microalbuminuria (10% after 13 years). The duration of diabetes until persistent microalbuminuria was identical for patients with prepubertal or pubertal onset of diabetes. In addition to duration, female sex (P < 0.03) and insufficient long-term metabolic control (P < 0.03) contributed significantly and independently to urinary albumin excretion. CONCLUSIONS: Determination of urinary albumin excretion rate is useful in pediatric patients. Female subjects with a long duration of diabetes and insufficient metabolic control are especially at risk for microalbuminuria. Even if persistent microalbuminuria usually becomes evident in patients aged > 11 years, the prepubertal duration of diabetes contributes equally to this risk. Good metabolic control therefore should be aspired to from the onset of diabetes.     

The effects of type 1 diabetes on cognitive performance: a meta-analysis

OBJECTIVE: To investigate the exact nature and magnitude of cognitive impairments in patients with type 1 diabetes and the possible association with other disease variables, such as recurrent episodes of hypoglycemia and metabolic control. RESEARCH DESIGN AND METHODS: MedLine and PsycLit search engines were used to identify studies on cognitive performance in patients with type 1 diabetes. Effect sizes (Cohen's d), which are the standardized differences between the experimental and the control group, were calculated. In the meta-analysis, a combined d value was calculated, expressing the magnitude of associations across studies. RESULTS: A total of 33 studies were identified that met the inclusion criteria. Compared with nondiabetic control subjects, the type 1 diabetic group demonstrated a significantly lowered performance on the following cognitive domains: intelligence (d = -0.7), speed of information processing (d = -0.3), psychomotor efficiency (d = -0.6), visual (d = -0.4) and sustained attention (d = -0.3), cognitive flexibility (d = -0.5), and visual perception (d = -0.4). Lowered cognitive performance in diabetic patients appeared to be associated with the presence of microvascular complications but not with the occurrence of severe hypoglycemic episodes or with poor metabolic control. CONCLUSIONS: In patients with type 1 diabetes, cognitive dysfunction is characterized by a slowing of mental speed and a diminished mental flexibility, whereas learning and memory are spared.The magnitude of the cognitive deficits is mild to moderate, but even mild forms of cognitive dysfunction might hamper everyday activities since they can be expected to present problems in more demanding situations.     

A randomized controlled trial of insulin pump therapy in young children with type 1 diabetes

OBJECTIVE: This study assesses the effects of insulin pump therapy on diabetes control and family life in children 1-6 years old with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-six children with type 1 diabetes for >/=6 months were randomly assigned to current therapy (two or three shots per day using NPH insulin and rapid-acting analog) or continuous subcutaneous insulin infusion (CSII) for 6 months. After 6 months, current therapy subjects were offered CSII. Changes in HbA(1c), mean blood glucose (MBG), hypoglycemia frequency, diabetes-related quality of life (QOL), and parental adjustment were recorded. RESULTS: Eleven subjects from each group completed the trial (age 46.3 +/- 3.2 months [means +/- SE]). At baseline, there were no differences between groups in HbA(1c), MBG, age, sex, diabetes duration, or parental QOL. Mean HbA(1c), MBG, and parental QOL were similar between groups at 6 months. Mean HbA(1c) and MBG did not change from baseline to 6 months in either group. The frequency of severe hypoglycemia, ketoacidosis, or hospitalization was similar between groups at any time period. Subjects on CSII had more fasting and predinner mild/moderate hypoglycemia at 1 and 6 months. Diabetes-related QOL improved in CSII fathers from baseline to 6 months. Psychological distress increased in current therapy mothers from baseline to 6 months. All subjects continued CSII after study completion. CONCLUSIONS: CSII is safe and well tolerated in young children with diabetes and may have positive effects on QOL. CSII did not improve diabetes control when compared with injections, despite more mild/moderate hypoglycemia. The benefits and realistic expectations of CSII should be thoroughly examined before starting this therapy in very young children.     

Residual β-Cell Function 3–6 Years After Onset of Type 1 Diabetes Reduces Risk of Severe Hypoglycemia in Children and Adolescents

OBJECTIVE

To determine the prevalence of residual β-cell function (RBF) in children after 3–6 years of type 1 diabetes, and to examine the association between RBF and incidence of severe hypoglycemia, glycemic control, and insulin requirements.

RESEARCH DESIGN AND METHODS

A total of 342 children (173 boys) 4.8–18.9 years of age with type 1 diabetes for 3–6 years were included. RBF was assessed by testing meal-stimulated C-peptide concentrations. Information regarding severe hypoglycemia within the past year, current HbA_1c, and daily insulin requirements was retrieved from the medical records and through patient interviews.

RESULTS

Ninety-two children (27%) had RBF >0.04 nmol/L. Patients with RBF <0.04 nmol/L were significantly more likely to have severe hypoglycemia than patients with RBF >0.04 nmol/L (odds ratio, 2.59; 95% CI, 1.10–7.08; P < 0.03). HbA_1c was significantly higher in patients with RBF <0.04 nmol/L compared with patients with RBF >0.04 nmol/L (mean, 8.49 ± 0.08% [69.3 ± 0.9 mmol/mol] vs. 7.92 ± 0.13% [63.1 ± 1.4 mmol/mol]; P < 0.01), and insulin requirements were significantly lower in patients with RBF >0.2 nmol/L (mean ± SE: 1.07 ± 0.02 vs. 0.93 ± 0.07 units/kg/day; P < 0.04).

CONCLUSIONS

We demonstrated considerable phenotypic diversity in RBF among children after 3–6 years of type 1 diabetes. Children with RBF are at lower risk for severe hypoglycemia, have better diabetes regulation, and have lower insulin requirements compared with children without RBF. There appears to be a lower limit for stimulated RBF of ∼0.04 nmol/L that confers a beneficial effect on hypoglycemia and metabolic control.Type 1 diabetes is the result of a selective immune-mediated destruction of the insulin-producing β-cells in the islets of Langerhans in the pancreas (1). Partial remission of type 1 diabetes often is seen in children and adolescents soon after initiating insulin treatment, and it is characterized by continuous and effective endogenous insulin secretion. After this period of remission of variable duration, the autoimmune cellular-mediated destruction of the β-cells continues and the endogenous insulin production declines gradually (2–4).The Diabetes Control and Complication Trial (DCCT) showed that a significant proportion of adults had sustained β-cell function several years after the onset of type 1 diabetes (5), and some type 1 diabetic patients even have detectable C-peptide after 50 years of diabetes (6). In adults, residual β-cell function (RBF) may have positive effects on diabetes regulation and complications. RBF may reduce the risk of hypoglycemia, improve metabolic control estimated by HbA_1c, lower exogenous insulin requirements, and lower the risk of long-term complications (5,7–13). Based on data from the DCCT adult population, it was reported that the incidence of severe hypoglycemia varied with differences in RBF (7). In the group with the highest RBF, the lowest incidence of hypoglycemia occurred (7). Yet, even those with “minimal” RBF, defined as stimulated C-peptide level of 0.04–0.2 nmol/L, showed lower incidence of severe hypoglycemia compared with the group with undetectable RBF (7).In children, the majority of studies of RBF have focused on the first year after clinical diagnosis (14–18). Data for RBF in children during later stages of type 1 diabetes and its effect on metabolic control and complications are scarce. In a population of 151 children with type 1 diabetes for 3 years, 23% had a stimulated C-peptide level of >0.06 nmol/L (19). Furthermore, in a case-control study, it was demonstrated that RBF was significantly higher in children without severe hypoglycemia compared with children with severe hypoglycemia (20).The increasing incidence of diabetes in children with reduced contribution of high-risk HLA haplotypes (21,22) may have changed the type 1 diabetes phenotype toward an increased number of children with detectable C-peptide years after diagnosis, which may have favorable effects on the incidence of severe hypoglycemia and glycemic control. Therefore, the aims of this study were to investigate the phenotypical characteristics regarding RBF among Danish children with type 1 diabetes for a duration of 3–6 years; to examine possible benefits of RBF on the incidence of severe hypoglycemia, glycemic control, and insulin requirements; and, finally, to evaluate the data to determine whether there is a lower limit of RBF at which RBF exerts beneficial effect on the incidence of severe hypoglycemia and metabolic control.     

Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes

OBJECTIVE: To examine the extent to which type 2 diabetes is associated with poorer performance on measures of learning, memory, psychomotor speed, and problem-solving in middle-aged adults. RESEARCH DESIGN AND METHODS: This cross-sectional study evaluated 50 adults (age range 34-65 years, mean 50.8) with type 2 diabetes and 50 demographically similar community control subjects without diabetes. Each subject received a thorough physical examination and a detailed neuropsychological assessment. Factor analysis was used to assign specific tests to 1 of 4 cognitive domains (learning, memory for stories, problem-solving, and psychomotor speed). Hierarchical regression analysis was used to identify demographic and biomedical variables associated with cognitive dysfunction. RESULTS: Learning, memory, and problem-solving skills were unaffected by type 2 diabetes. In contrast, psychomotor slowing was predicted by a diagnosis of diabetes (r2 change = 0.075, P < 0.002) with additional variance in psychomotor efficiency explained independently by HbA1 (r2 = 0.064, P < 0.003) and vibratory threshold (r2 = 0.112, P < 0.0001). The magnitude of psychomotor slowing on specific tests ranged from 12% (Digit Vigilance) to 23% (Grooved Pegboard). CONCLUSIONS: Middle-aged adults with type 2 diabetes manifest psychomotor slowing that is associated with poorer metabolic control, whereas learning, memory, and problem-solving skills appear to be largely intact. The development of psychomotor slowing may be a manifestation of a "central neuropathy" induced by chronic hyperglycemia.     

Neurocognitive outcomes in young adults with early-onset type 1 diabetes: a prospective follow-up study

OBJECTIVE

The aim of this study was to reexamine the neurocognitive function of a cohort of young adults with early-onset type 1 diabetes and compare their cognitive function to a matched control group. We also examined whether cognitive function was related to prospectively obtained severe hypoglycemia history, long-term glycemic control, or severe diabetic ketoacidosis.

RESEARCH DESIGN AND METHODS

Testing included Wechsler Intelligence Scale for Children and Adults, Wechsler Memory Scale, Cattell Culture Fair Intelligence Test (CCFIT), Wisconsin Card Sorting Test (WCST), youth and adult self-report, and Beck Depression Inventory. We tested 34 control subjects (mean ± SE, age 19.5 ± 0.5 years) and 33 type 1 diabetic subjects (age 19.3 ± 0.5 years, age at type 1 diabetes onset 3.3 ± 0.3 years, A1C from diagnosis 8.7 ± 0.1%, and diabetes duration 16.0 ± 0.5 years).

RESULTS

There was no difference in full-scale IQ scores in type 1 diabetic and control subjects (100.7 ± 2.0 vs. 102.5 ± 1.4). There was no difference between groups in memory subtests or in reporting of emotional and behavioral difficulties. The type 1 diabetes group scored lower on the CCFIT for fluid intelligence compared with control subjects (P = 0.028) and also scored lower on WCST with more perseverative errors (P = 0.002) and fewer categories completed (P = 0.022).

CONCLUSIONS

These data suggest no difference in general intellectual ability, memory, and emotional difficulties in our cohort of young adults with early-onset type 1 diabetes compared with control subjects and no deterioration over time. There were, however, findings to suggest subtle changes leading to poorer performance on complex tasks of executive function.The impact of type 1 diabetes on the developing brain remains controversial. Earlier age of diabetes onset has long been identified as one of the strongest risk factors associated with cognitive dysfunction, ranging from poorer performance on general intellectual testing (1,2) to specific deficits with visuospatial tasks, attention, and psychomotor efficiency. The effect of early-onset diabetes, however, is confounded by the impact of recurrent severe hypoglycemia. Repeated severe hypoglycemia has been reported to adversely affect various cognitive domains, in particular long-term memory, attention, and verbal IQ, although this has not been consistent across studies (3,4). Moreover, many of these studies are limited by their retrospective collection of hypoglycemia history.We previously reported neurocognitive outcomes in 84 children with early-onset diagnosis of type 1 diabetes defined as type 1 diabetes onset before 6 years of age (4). In that initial study, we compared those subjects who had a history of early severe hypoglycemia with those who had a history of late severe hypoglycemia and also compared those who had experienced severe hypoglycemia with peers who had no history of seizures. Surprisingly, there were no group differences revealed on intellectual, memory, or behavioral measures. Furthermore, there was no evidence that episodes of seizure or coma, even those occurring in early childhood, resulted in broad cognitive dysfunction, nor was there evidence of specific memory difficulties at the time of testing.In this study, we reevaluate the neurocognitive function of the cohort—with onset of type 1 diabetes before age 6 years—now that they are young adults. This early-onset type 1 diabetes cohort is unique in that all subjects were initially recruited from a population-based cohort and have been prospectively followed from diagnosis with documentation of hypoglycemia rates and other key clinical data, including A1C, at regular 3-month clinic visits.Our aims were, first, to determine whether there had been any deterioration in neurocognitive function in this population-based cohort of young adults with early-onset type 1 diabetes over the 10 years since they were previously tested. Second, we sought for the first time to compare the neurocognitive outcomes of this cohort to a group of age- and sex-matched healthy young adults. Finally, we aimed to determine whether cognitive function in this cohort of patients with early-onset type 1 diabetes was related to their severe hypoglycemia history, long-term glycemic control, or history of severe diabetic ketoacidosis.     

Continuous glucose monitoring and the reality of metabolic control in preschool children with type 1 diabetes

OBJECTIVE: To determine using the MiniMed continuous glucose monitoring system (CGMS) 1) whether twice-daily insulin injection therapy achieves adequate control in preschool children with type 1 diabetes and 2) whether the CGMS is more informative than self-monitoring of blood glucose (SMBG) regarding glucose control and well tolerated by preschool children and their families. RESEARCH DESIGN AND METHODS: Ten children <6 years of age with type 1 diabetes were monitored twice using the CGMS. The distribution of glucose values was analyzed, particularly the frequency, duration, and distribution of hypoglycemia. We analyzed the accuracy of the CGMS in detecting hypoglycemia as well as the clinical relevance of the difference between CGMS and SMBG values. RESULTS: Although hypoglycemia was more frequent during the night (0.8 nighttime episodes . subject(-1) . 24 h(-1) vs. 0.3 daytime episodes . subject(-1) . 24 h(-1)), the difference did not reach statistical significance (P=0.07). However, nighttime episodes lasted longer than daytime episodes (1.2 vs. 0.2 h . subject(-1) . 24 h(-1), P=0.006). Hypoglycemia accounted for 7% and normoglycemia for 24%, while hyperglycemia occurred 64% of the time, with postprandial hyperglycemia being an almost universal feature (94 +/- 7% of all postmeal values). The CGMS correlated well with SMBG without significant clinical discrepancy. The CGMS sensitivity to detect hypoglycemia was 70% with a specificity of 99%; however, the CGMS detected twice as many total episodes as SMBG (82 vs. 40). CONCLUSIONS: Twice-daily insulin injection rarely achieves control in preschool children with type 1 diabetes. The CGMS is well tolerated by patients and has the advantage of revealing daily glucose trends missed by SMBG.     

The Neurocognitive Effects of Type 1 Diabetes Mellitus in Children and Young Adults With and Without Hypoglycemia

Type 1 Diabetes Mellitus is one of the most common illnesses found in children under the age of 18 as well as in young adults. Symptoms of this disease, including those with and without severe hypoglycemia, create abnormal blood glucose levels along with abnormal insulin levels. These abnormal chemical levels have been associated with neurocognitive deficits in memory, attention, motor skills, visuospatial abilities and executive functioning. In this paper, available literature on the central nervous system changes associated with the effects of insulin-dependent diabetes on school-aged children and young adults is reviewed. Implications for learning as well as a neurobiological cause of executive function deficits are discussed.     

Absence of adverse effects of severe hypoglycemia on cognitive function in school-aged children with diabetes over 18 months

OBJECTIVE: Some children with type 1 diabetes may be at risk of cognitive impairments, but mechanisms of this effect have not been confirmed. The objective of this study was to determine whether severe hypoglycemia (SH) in children with type 1 diabetes is associated with cognitive decline over 18 months. RESEARCH DESIGN AND METHODS: A sample of 142 6- to 15-year-old children with type 1 diabetes (mean age 11.6 +/- 2.7 years) enrolled in a trial of intensive therapy (IT) or usual care (UC) were tested with the Das-Naglieri Cognitive Assessment System at baseline and after 9 and 18 months. Episodes of SH were recorded by parents and reported promptly for verification by study nurses. HbA(1c) was measured quarterly. RESULTS: Over 18 months, 58 of 142 patients (41%) experienced 111 SH episodes, with a RR of SH of 1.12 for IT over UC. Neither occurrence nor frequency of SH was associated with decline in full-scale intelligence quotient (IQ), standard scores for planning, attention, simultaneous processing, or successive processing, or scaled scores on any of eight subtests. The same findings emerged when only patients who had experienced hypoglycemic seizures or coma were included in the SH group for analyses. These effects persisted when the child's age, sex, type 1 diabetes duration, and age at diagnosis were controlled statistically. HbA(1c) during the trial was not associated with cognitive changes. CONCLUSIONS: SH did not induce adverse changes in the measures of cognitive function administered to 6- to 15-year-old children with type 1 diabetes in this study. Although SH should be avoided in all children with diabetes, these episodes did not have adverse effects on cognition in this age-group over 18 months.     

Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function

OBJECTIVE: Children who develop type 1 diabetes before age 7 years (early-onset diabetes; EOD) have comparatively poorer cognitive abilities. Whether this relates to psychosocial consequences of chronic illness or organic factors related to diabetes and its complications remains unresolved. We hypothesized that if differences in neuroradiological structure and cognitive ability coexisted in those who had EOD, then an organic component to their etiology was likely. RESEARCH DESIGN AND METHODS: A cohort of 71 young adults with long-duration type 1 diabetes diagnosed during childhood or adolescence participated in a cross-sectional evaluation of cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging). Diabetes onset age, preceding severe hypoglycemia exposure, retinopathy status, and diabetes duration were examined as potential correlates of cognitive and neuroradiological differences. No participants had previous neuropsychological pathology. RESULTS: In EOD participants (n = 26), current intellectual ability (Wechsler Adult Intelligence Scale-Revised performance IQ; P = 0.03) and information processing ability (Choice Reaction Time; P = 0.006) were comparatively poorer than was observed in those with later- onset diabetes (n = 45). Furthermore, lateral ventricular volumes were 37% greater (P = 0.002) and ventricular atrophy was more prevalent (61 vs. 20%; P = 0.01) in the EOD group than in those who had later-onset type 1 diabetes. CONCLUSIONS: An early childhood onset of type 1 diabetes was associated with mild central brain atrophy and significant differences in intellectual performance in adulthood, implying that neurodevelopment may be adversely affected by EOD. The differences observed in brain structure support an organic contribution to their etiology but do not exclude a coexistent contribution of psychosocial factors.     

Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: an Italian multicenter study

OBJECTIVE: To estimate the prevalence of biopsy-confirmed celiac disease in Italian children and adolescents with type 1 diabetes and to assess whether age at onset of type 1 diabetes is independently associated with diagnosis of celiac disease. RESEARCH DESIGN AND METHODS: The study group was a clinic-based cohort of children and adolescents with type 1 diabetes cared for in 25 Italian centers for childhood diabetes. Yearly screening for celiac disease was performed using IgA/IgG anti-gliadin and IgA anti-endomysium antibodies. RESULTS: Of the 4,322 children and adolescents (age 11.8 +/- 4.2 years) identified with type 1 diabetes, biopsy-confirmed celiac disease was diagnosed in 292 (prevalence 6.8%, 95% confidence interval [CI] 6.0-7.6), with a higher risk seen in girls than in boys (odds ratio [OR] 1.93, 1.51-2.47). In 89% of these, diabetes was diagnosed before celiac disease. In logistic regression analyses, being younger at onset of diabetes, being female, and having a diagnosis of a thyroid disorder were independently associated with the risk of having diabetes and celiac disease. In comparison with subjects who were older than 9 years at onset of diabetes, subjects who were younger than 4 years at onset had an OR of 3.27 (2.20-4.85). CONCLUSIONS: We have provided evidence that 1) the prevalence of biopsy-confirmed celiac disease in children and adolescents with type 1 diabetes is high (6.8%); 2) the risk of having both diseases is threefold higher in children diagnosed with type 1 diabetes at age <4 years than in those age >9 years; and 3) girls have a higher risk of having both diseases than boys.     

Clinical, autoimmune, and genetic characteristics of very young children with type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group

OBJECTIVE: To study the characteristics of type 1 diabetes in very young children. RESEARCH DESIGN AND METHODS: Clinical outcome, islet cell antibodies (ICA), insulin autoantibodies (IAA), antibodies against GAD (GADA), IA-2 antibodies (IA-2A), and HLA-DQB1-defined genetic risk were analyzed in 35 children diagnosed with type 1 diabetes before 2 years of age and compared with those in 146 children who were diagnosed between 2.0 and 4.9 years of age and with those in 620 children diagnosed between 5.0 and 14.9 years of age. RESULTS: The youngest age-group had severer metabolic decompensation at clinical onset, and their serum C-peptide levels, compared with those of older children, were lower at the time of diagnosis and during the first 2 years after the diagnosis. The levels of ICA and IAA were highest in children < 2 years of age, but there were no differences in GADA levels among the three age-groups. The youngest age-group had the lowest IA-2A levels. The HLA DQB1*02/*0302 genotype associated with strong genetic susceptibility was more frequent in children diagnosed < 5 years of age, whereas the proportion of children carrying a genotype, which includes protective alleles, was higher among those diagnosed at > or = 5 years of age. CONCLUSIONS: The clinical presentation of type 1 diabetes at a very young age is associated with severe metabolic decompensation, poorly preserved residual beta-cell function, strong humoral autoimmunity against islet cells and insulin, and strong HLA-defined disease susceptibility.     

Counterregulation during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes.

OBJECTIVE: To examine counterregulatory responses during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 29 prepubertal patients with type 1 diabetes underwent two overnight profiles. Data were analyzed from 16 children (median [range] 8.7 [5.9-12.9] years of age) with a night of hypoglycemia and a nonhypoglycemic night. Children hypoglycemic (< 3.5 mmol/l) on night 1 were given 25% extra carbohydrate as uncooked cornstarch with their usual evening snack on night 2 to avoid hypoglycemia. Glucose, growth hormone, and cortisol were measured every 15 min, catecholamines every 30 min, and glucagon, pancreatic polypeptide, insulin, and ketones every 60 min. A group of 15 healthy control subjects, aged 9.5 (5.6-12.1) years, underwent one overnight profile. RESULTS: Median duration of hypoglycemia was 225 (30-630) min, and glucose nadir was 2.0 (1.2-3.3) mmol/l. Insulin levels were not different on the two nights (P = 0.9, analysis of variance), but children with diabetes had higher insulin levels than normal control subjects between 2300 and 0300, maximal at 0200 (mean +/- SEM 57.4 +/- 5.7 vs. 31.6 +/- 5.0 pmol/l, P = 0.002). Peak epinephrine was higher on the night of hypoglycemia (0.98 [0.52-2.09] nmol/l) versus nonhypoglycemia (0.32 [0.21-0.62] nmol/l), P = 0.001, but norepinephrine (1.29 [1.07-2.64] vs. 1.26 [1.04-1.88] nmol/l, P = 0.5), glucagon (93 [64.2-125.6] vs. 100.5 [54.6-158] ng/l, P = 0.6), pancreatic polypeptide (410.2 [191-643.2] vs. 270.8 [158.2-777.8] ng/l, P = 0.5), and cortisol (513 [300-679] vs. 475 [235-739] nmol/l, P = 0.6) were not different. Glucose threshold for epinephrine release was very low, 1.9 +/- 0.2 mmol/l. There was a short-lived rise in growth hormone from 75-105 min after onset of hypoglycemia, maximal at 90 min (7.8 +/- 1.2 vs. 3.5 +/- 0.9 ng/ml, P = 0.02). CONCLUSIONS: The prolonged nature of nocturnal hypoglycemic episodes may be explained in part by defective counterregulation. The risk of nocturnal hypoglycemia needs to be reduced before intensification of insulin therapy can be contemplated in this age-group.