Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience

OBJECTIVE

We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

RESEARCH DESIGN AND METHODS

The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother’s prenatal care and delivery and the infant’s health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed.

RESULTS

Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly.

CONCLUSIONS

Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity.     

Impact of Obesity on Measures of Cardiovascular and Kidney Health in Youth With Type 1 Diabetes as Compared With Youth With Type 2 Diabetes

OBJECTIVEInsulin resistance and obesity are independently associated with type 1 diabetes (T1D) and are known risk factors for cardiovascular and kidney diseases, the leading causes of death in T1D. We evaluated the effect of BMI on cardiovascular and kidney outcomes in youth with T1D versus control youth with normal weight or obesity and youth with type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSPubertal youth (n = 284) aged 12–21 years underwent assessments of resting heart rate (RHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), leptin, hs-CRP, adiponectin, ratio of urine albumin to creatinine, and estimated glomerular filtration rate. Participants with T1D underwent bicycle ergometry for VO₂peak, monitoring for peripheral brachial artery distensibility (BAD), endothelial function testing for reactive hyperemic index, and aortic MRI for central arterial stiffness or shear.RESULTSIn adolescents with T1D, RHR, SBP, DBP, mean arterial pressure, leptin, hs-CRP, and hypertension prevalence were significantly higher, and BAD, descending aorta pulse wave velocity, and VO₂peak lower with an obese versus normal BMI. Although hypertension prevalence and RHR were highest in obese adolescents with T1D and adiponectin lowest in youth with T2D, other measures were similar between obese adolescents with T1D and those with T2D.CONCLUSIONSObesity, now increasingly prevalent in people with T1D, correlates with a less favorable cardiovascular and kidney risk profile, nearly approximating the phenotype of youth with T2D. Focused lifestyle management in youth-onset T1D is critically needed to reduce cardiovascular risk.     

Missed Insulin Boluses for Snacks in Youth With Type 1 Diabetes

OBJECTIVE

To evaluate the effects of missed insulin boluses for snacks in youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Three months of simultaneous continuous subcutaneous insulin infusion and continuous glucose monitoring data from nine subjects were retrospectively evaluated. Glucose excursions between 1330 and 1700 h were defined as relating to snacks with insulin or snacks with no insulin administered. Area under the curve >180 mg/dl (AUC >180), average Δ glucose, and rate of change were analyzed and compared within and between groups.

RESULTS

A total of 94 snacks without insulin and 101 snacks with insulin were analyzed. Snacks without insulin had significantly higher log (AUC >180 + 1) (1.26 vs. 0.44 mg/dl per event; P < 0.001), Δ glucose (114 vs. 52 mg/dl; P < 0.001), and average rate of change (1.3 vs. 1.1 mg/dl per minute; P < 0.001).

CONCLUSIONS

This study shows that afternoon snacks without insulin boluses are common and result in significantly higher glucose excursions than snacks with insulin administration.Previous studies have demonstrated the deleterious effect of missed insulin doses for meals (1–4). None, however, have examined the effect of missed insulin boluses for snacks. Because youth frequently snack when unsupervised, it is likely that missed insulin boluses are even more common for snacks than for meals. The purpose of this investigation was to use data from continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) together to evaluate the glycemic profiles of missed insulin boluses for afternoon snacks.     

Measures of Arterial Stiffness in Youth With Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth study

OBJECTIVE

Arterial stiffness occurs early in the atherosclerotic process; however, few data are available concerning risk factors for arterial stiffness in youth with diabetes. We identified factors associated with arterial stiffness in youth with diabetes and assessed the effects of these factors on the relationship between arterial stiffness and diabetes type (type 1 vs. type 2).

RESEARCH DESIGN AND METHODS

A subset of patients from the SEARCH for Diabetes in Youth study with type 1 (n = 535) and type 2 diabetes (n = 60), aged 10–23 years (52% male; 82% non-Hispanic white; diabetes duration 65 ± 49 months) had arterial stiffness, anthropometrics, blood pressure, fasting lipids, and A1C measured. Arterial stiffness was measured by brachial distensibility (brachD), pulse wave velocity (PWV), and augmentation index adjusted to heart rate of 75 beats/min (AI75).

RESULTS

Youth with type 2 diabetes had worse brachD (5.2 ± 0.9 vs. 6.1 ± 1.2%/mmHg), PWV (6.4 ± 1.3 vs. 5.3 ± 0.8 m/s), and AI75 (6.4 ± 9.9 vs. 2.2 ± 10.2%) than those with type 1 diabetes (P < 0.01 for each). These differences were largely mediated through increased central adiposity and higher blood pressure in youth with type 2 diabetes. We also found a pattern of association of arterial stiffness measures with waist circumference and blood pressure, independent of diabetes type.

CONCLUSIONS

Youth with type 2 diabetes have worse arterial stiffness than similar youth with type 1 diabetes. Increased central adiposity and blood pressure are associated with measures of arterial stiffness, independent of diabetes type. Whether these findings indicate that youth with type 2 diabetes will be at higher risk for future complications requires longitudinal studies.Adults with type 1 or type 2 diabetes are at greater risk for developing cardiovascular disease (CVD) than the general population (1). Nevertheless, the process of atherosclerosis is known to begin in childhood (1,2). Whereas most pediatric diabetes studies have focused on youth with type 1 diabetes, data are now emerging to show that the burden of diabetes-related complications among adolescents with type 2 diabetes is at least as high as that for those with type 1 diabetes (3).Vascular dysfunction occurs early in the atherosclerotic process and is associated with obesity and insulin resistance (4). Multiple methods have been developed to evaluate vascular function noninvasively, including several measures of arterial stiffness, such as brachial distensibility, pulse wave velocity (PWV), and augmentation index (5). Because atherosclerosis develops in a nonuniform fashion (6), multiple measures are needed in any noninvasive study of early CVD in youth.The aim of this report was to identify factors associated with measures of arterial stiffness in youth with diabetes participating in the SEARCH for Diabetes in Youth (SEARCH) study and to assess the effect of these factors on the relationship between arterial stiffness and diabetes type (type 1 vs. type 2).     

Once-Weekly Exenatide in Youth With Type 2 Diabetes

OBJECTIVEApproved treatments for type 2 diabetes in pediatric patients include metformin, liraglutide, and insulin. However, approximately one-half of the youth fail metformin monotherapy within 1 year, insulin therapy is associated with challenges, and liraglutide requires daily injections. Consequently, the efficacy and safety of once-weekly injections of exenatide for the treatment of youth with type 2 diabetes was evaluated.RESEARCH DESIGN AND METHODSParticipants (aged 10 to <18 years) were randomized (5:2) to once-weekly exenatide 2 mg or placebo, respectively. The primary efficacy end point was change in glycated hemoglobin from baseline to week 24. Secondary efficacy end points were also evaluated, and the frequency of adverse events (AEs) was assessed.RESULTSA total of 83 participants were randomized (exenatide, 59; placebo, 24) and 72 completed 24-week treatment (exenatide, 49; placebo, 23). At 24 weeks, the least squares mean change in glycated hemoglobin was −0.36% for the exenatide and +0.49% for the placebo groups (between-group difference, −0.85%; 95% CI −1.51, −0.19; P = 0.012). Nonsignificant least squares mean differences from baseline to 24 weeks favoring exenatide were observed: fasting glucose −21.6 mg/dL (−49.0, 5.7; P = 0.119), systolic blood pressure −2.8 mmHg (−8.0, 2.4; P = 0.284), and body weight −1.22 kg (−3.59, 1.15; P = 0.307). AEs occurred in 36 (61.0%) and 17 (73.9%) participants in the exenatide and placebo groups, respectively.CONCLUSIONSIn youth with type 2 diabetes suboptimally controlled with current treatments, once-weekly exenatide reduced glycated hemoglobin at 24 weeks and was well tolerated.     

Parental Characteristics Associated With Outcomes in Youth With Type 2 Diabetes: Results From the TODAY Clinical Trial

OBJECTIVEThis study examined parental factors associated with outcomes of youth in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial.RESULTSParental diabetes (43.6% of parents) was associated with higher baseline HbA_1c (P < 0.0001) and failure of youths to maintain glycemic control on study treatment (53.6% vs. 38.2% failure rate among those without a diabetic parent, P = 0.0002). Parental hypertension (40.6% of parents) was associated with hypertension in youth during TODAY (40.4% vs. 27.4% of youth with and without parental hypertension had hypertension, P = 0.0008) and with higher youth baseline BMI z scores (P = 0.0038). Parents had a mean baseline BMI of 33.6 kg/m². Parental obesity (BMI >30 kg/m²) was associated with higher baseline BMI z scores in the youth (P < 0.0001). Depressive symptoms in parents (20.6% of parents) were related to youth depressive symptoms at baseline only (P = 0.0430); subclinical BE in parents was related to the presence of subclinical BE (P = 0.0354) and depressive symptoms (P = 0.0326) in youth throughout the study period.CONCLUSIONSParental diabetes and hypertension were associated with lack of glycemic control, hypertension, and higher BMI z scores in youth. Further research is needed to better understand and address parental biological and behavioral factors to improve youth health outcomes.     

Bone Age Corresponds With Chronological Age at Type 1 Diabetes Onset in Youth

OBJECTIVE

To our knowledge, only two controversial articles have reported the study of bone age at diagnosis in diabetic children. The aim of this study was to compare chronological age with bone age and to evaluate the impact of A1C on bone age in children at diagnosis of type 1 diabetes.

RESEARCH DESIGN AND METHODS

In 496 diabetic children, height was measured at diagnosis and height SD score was calculated using the British 1990 growth reference. Bone age was determined according to the Greulich and Pyle method, and A1C levels were measured.

RESULTS

Participants'' height was normal for age and sex. No significant differences were found between chronological age and bone age, and there was no correlation between Δ (bone age − chronological age) and A1C.

CONCLUSIONS

This study showed that height and bone maturation among diabetic children are normal for age and sex and independent of A1C at diagnosis of type 1 diabetes.Adequate insulin secretion is needed to promote growth (1). Many controversies remain about height and bone maturation in diabetic children. Since 1959, the Greulich and Pyle atlas (2) has been used to assess bone age (3). There are only few data on skeletal maturation in diabetic children at diagnosis, and these are controversial (4,5). The aim of this study was to compare chronological age with bone age and to evaluate the impact of A1C on bone age at diagnosis of type 1 diabetes.     

Lipid and Lipoprotein Profiles in Youth With and Without Type 1 Diabetes: The SEARCH for Diabetes in Youth Case-Control Study

OBJECTIVE—The purpose of this study was to compare the lipid profile and the prevalence of lipid abnormalities in youth with and without type 1 diabetes and explore the role of glycemic control on the hypothesized altered lipid profile in youth with type 1 diabetes.RESEARCH DESIGN AND METHODS—We conducted a cross-sectional analysis of 512 youth with type 1 diabetes (mean duration 4.22 years) and 188 healthy control subjects aged 10–22 years in Colorado and South Carolina. SEARCH for Diabetes in Youth (SEARCH) participants with type 1 diabetes and healthy control subjects recruited from primary care offices in the same geographic regions were invited to attend a research visit. Fasting lipid profiles were compared between youth with type 1 diabetes (stratified according to categories of optimal [A1C <7.5%] and suboptimal [A1C ≥7.5%] glycemic control) and healthy nondiabetic youth, using multiple linear and logistic regression.RESULTS—Youth with type 1 diabetes and optimal A1C had lipid concentrations that were similar (total cholesterol, LDL cholesterol, and LDL particle size) or even less atherogenic (HDL cholesterol, non-HDL cholesterol, triglyceride, and triglyceride–to–HDL cholesterol ratio) than those observed in nondiabetic youth, whereas youth with suboptimal glycemic control had elevated standard lipid levels (total cholesterol, LDL cholesterol, and non-HDL cholesterol). Youth with type 1 diabetes also had significantly elevated apolipoprotein B levels and more small, dense LDL particles than nondiabetic youth, regardless of glycemic control.CONCLUSIONS—Youth with type 1 diabetes have abnormal lipid levels and atherogenic changes in lipoprotein composition, even after a relatively short disease duration. As in adults, glycemic control is an important mediator of these abnormalities.Diabetes is a major risk factor for cardiovascular disease (CVD) (1). In patients with type 1 diabetes, atherosclerosis occurs earlier in life, leading to increased morbidity and mortality compared with those in the general population (2). Moreover, studies of the natural history of atherosclerosis development point to an origin of the lesions in childhood and adolescence (3).Lipid concentrations are strongly related to the risk of CVD in adults with diabetes (4), Although lipid levels in adults with type 1 diabetes have been described as comparable to those in nondiabetic individuals (5), adults with type 1 diabetes are known to have a higher risk for atherosclerotic disease compared with that of the general population (2). The SEARCH for Diabetes in Youth (SEARCH) study recently showed that a substantial proportion of youth aged 10–22 years with type 1 diabetes had lipid levels outside the recommended targets (6). However, it is not known whether the lipid profile (lipid concentrations and lipoprotein composition) in youth with type 1 diabetes is proatherogenic compared with that in healthy nondiabetic youth. Some data suggest that, in adults with diabetes, lipoprotein composition is more atherogenic (7) and is substantially influenced by glycemic control (8). The goals of this study were to compare the lipid and lipoprotein profile, as measured by total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, non-HDL cholesterol, the triglyceride–to–HDL cholesterol ratio, apolipoprotein B (apoB), and LDL particle size and density in youth with and without type 1 diabetes, and to explore the role of glycemic control, as measured by A1C, on the hypothesized altered lipid profile in type 1 diabetic youth.     

Insulin Regimens and Clinical Outcomes in a Type 1 Diabetes Cohort: The SEARCH for Diabetes in Youth study

OBJECTIVE

To examine the patterns and associations of insulin regimens and change in regimens with clinical outcomes in a diverse population of children with recently diagnosed type 1 diabetes.

RESEARCH DESIGN AND METHODS

The study sample consisted of youth with type 1 diabetes who completed a baseline SEARCH for Diabetes in Youth study visit after being newly diagnosed and at least one follow-up visit. Demographic, diabetes self-management, physical, and laboratory measures were collected at study visits. Insulin regimens and change in regimen compared with the initial visit were categorized as more intensive (MI), no change (NC), or less intensive (LI). We examined relationships between insulin regimens, change in regimen, and outcomes including A1C and fasting C-peptide.

RESULTS

Of the 1,606 participants with a mean follow-up of 36 months, 51.7% changed to an MI regimen, 44.7% had NC, and 3.6% changed to an LI regimen. Participants who were younger, non-Hispanic white, and from families of higher income and parental education and who had private health insurance were more likely to be in MI or NC groups. Those in MI and NC groups had lower baseline A1C (P = 0.028) and smaller increase in A1C over time than LI (P < 0.01). Younger age, continuous subcutaneous insulin pump therapy, and change to MI were associated with higher probability of achieving target A1C levels.

CONCLUSIONS

Insulin regimens were intensified over time in over half of participants but varied by sociodemographic domains. As more intensive regimens were associated with better outcomes, early intensification of management may improve outcomes in all children with diabetes. Although intensification of insulin regimen is preferred, choice of insulin regimen must be individualized based on the child and family’s ability to comply with the prescribed plan.The Diabetes Control and Complication Trial (DCCT) clearly established the benefits of intensive versus conventional insulin therapy in adolescents and adults with type 1 diabetes (1). Improved glycemic control, measured by lower A1C levels, reduced the risk for onset and progression of long-term diabetes microvascular and macrovascular complications (2).Since the DCCT was conducted, significant advances in diabetes management have occurred, including newer and more physiologic insulin analogs, sophisticated blood glucose monitoring, and insulin delivery technologies such as continuous subcutaneous insulin pump therapy (CSII) and continuous glucose monitoring (CGM). Current recommendations from the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes endorse the use of intensive insulin regimens in most pediatric patients. Additionally, the ADA recommends the following age-specific A1C goals for children: <6 years of age, 7.5–8.5%; 6–12 years, ≤8.0%; 13–18 years, ≤7.5%; and >19 years, ≤7.0% (3). However, it is unclear whether intensive insulin regimens used in clinical pediatric diabetes care result in different A1C outcomes (4,5).The SEARCH for Diabetes in Youth study has reported that insulin treatment regimens were cross-sectionally associated with sociodemographic, clinical, and metabolic characteristics among youth with type 1 diabetes (6). Sociodemographic factors were strongly associated with insulin regimen used, with participants more likely to be using intensive regimens, such as CSII, if they were of non-Hispanic white race/ethnicity and from families with higher income and higher parental education, and had private health insurance. CSII therapy was associated with lowest A1C levels in all age-groups. Higher frequency of blood glucose monitoring was also associated with a lower A1C within each treatment group. No significant differences were observed in the frequency of hypoglycemia or emergency department visits between insulin regimen groups; however, frequency of hospitalizations was lower in participants who were on CSII therapy than other insulin regimens. Overall, adolescents had unacceptably high A1C levels, with 70% having levels >7.5% regardless of insulin regimen. While these observations yield valuable information about insulin regimens and A1C outcomes, gaps in our existing knowledge result in limited evidence-based guidelines to indicate how such regimens can be applied most optimally over time to individuals with varied resources.There is a paucity of information about changes in insulin regimens and outcomes over time, particularly early in the clinical course of type 1 diabetes. In the DCCT, intensive therapy was associated with preserved β-cell function, which in turn was associated with improved glycemic control and decreased risk of severe hypoglycemia. In fact, current immuno-intervention trials are designed to preserve β-cell function and attempt to account for the effect of intensive therapy by ensuring that the control group as well as treatment group(s) are closely followed and managed with intensive regimens (7,8). However, there is little information regarding the role of insulin treatment regimens in preservation of β-cell function and short-term outcomes.This report describes a cohort of participants from the SEARCH study who have been followed over time with an initial visit in the first year after diagnosis, providing an opportunity to examine whether insulin regimen intensification over time significantly impacts metabolic outcomes in youth with type 1 diabetes.     

Increase in Prevalence of Diabetic Ketoacidosis at Diagnosis Among Youth With Type 1 Diabetes: The SEARCH for Diabetes in Youth Study

OBJECTIVEWe previously reported a high (˜30%) but stable prevalence of diabetic ketoacidosis (DKA) at youth-onset diagnosis of type 1 diabetes (2002 and 2010). Given the changing demographics of youth-onset type 1 diabetes, we sought to evaluate temporal trends in the prevalence of DKA at diagnosis of type 1 diabetes from 2010 to 2016 among youth <20 years of age and evaluate whether any change observed was associated with changes in sociodemographic distribution of those recently diagnosed.RESEARCH DESIGN AND METHODSWe calculated prevalence of DKA within 1 month of type 1 diabetes diagnosis by year and evaluated trends over time (2010–2016) (n = 7,612 incident diabetes cases; mean [SD] age 10.1 [4.5] at diagnosis). To assess whether trends observed were attributable to the changing distribution of sociodemographic factors among youth with incident type 1 diabetes, we estimated an adjusted relative risk (RR) of DKA in relation to calendar year, adjusting for age, sex, race/ethnicity, income, education, health insurance status, language, season of diagnosis, and SEARCH for Diabetes in Youth Study site.RESULTSDKA prevalence increased from 35.3% (95% CI 32.2, 38.4) in 2010 to 40.6% (95% CI 37.8, 43.4) in 2016 (P_trend = 0.01). Adjustment for sociodemographic factors did not substantively change the observed trends. We observed a 2% annual increase in prevalence of DKA at or near diagnosis of type 1 diabetes (crude RR 1.02 [95% CI 1.01, 1.04] and adjusted RR 1.02 [95% CI 1.01, 1.04]; P = 0.01 for both).CONCLUSIONSPrevalence of DKA at or near type 1 diabetes diagnosis has increased from 2010 to 2016, following the high but stable prevalence observed from 2002 to 2010. This increase does not seem to be attributable to the changes in distribution of sociodemographic factors over time.     

Emphasis on Carbohydrates May Negatively Influence Dietary Patterns in Youth With Type 1 Diabetes

OBJECTIVE

To assess perceptions of healthful eating and the influence of diabetes management on dietary behaviors among youth with type 1 diabetes and parents.

RESEARCH DESIGN AND METHODS

Youth with type 1 diabetes (n = 35), ages 8–21 years, and parents participated in focus groups. Focus group recordings were transcribed and coded into themes. Clinical data were abstracted from the electronic medical record.

RESULTS

Central topics were perceptions of healthful eating and the impact of diabetes management on diet. An emphasis on limiting postprandial glycemic excursions occasionally contradicted the traditional perception of healthful eating, which emphasized consumption of nutrient-dense whole foods in favor of prepackaged choices. Whereas fixed regimens required more rigid diets, basal-bolus regimens provided more opportunities for unhealthful eating. Most youth perceived “refined” grains as more healthful grains.

CONCLUSIONS

For youth with type 1 diabetes and parents, an emphasis on carbohydrate quantity over quality may distort beliefs and behaviors regarding healthful eating.Medical nutrition therapy for youth with type 1 diabetes is designed to maintain normal growth and development while optimizing glycemic outcomes (1,2). Even the most intensive insulin regimens cannot be successful without careful attention to meal planning (3–5). Nutrition education for youth with type 1 diabetes focuses on carbohydrate counting and overall healthful eating. However, recent data demonstrate that youth with diabetes are not meeting established nutrition guidelines (6–9).There remains a need to understand why youth with type 1 diabetes fail to achieve nutrition guidelines. In this study, we explored perceptions of healthful eating provided by youth with type 1 diabetes and their parents and assessed the influence of diabetes management on food choices. Findings could inform future interventions aimed at improving the nutrition of youth with type 1 diabetes.     

Central Nervous System Function in Youth With Type 1 Diabetes 12 Years After Disease Onset

OBJECTIVE—In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis.RESEARCH DESIGN AND METHODS—We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis.RESULTS—Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P < 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P < 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P < 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P < 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia.CONCLUSIONS—This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.The central nervous system (CNS) is a major organ system affected in type 1 diabetes, as both cerebral glucose and insulin levels are frequently abnormal even when diabetes is well controlled (1). Intracellular calcium toxicity and excitotoxic cellular damage, triggered by the synaptic release of excessive glutamate, have been identified as two potentially important mechanisms that produce selective neuronal necrosis during severe hypoglycemia (1), but other metabolite changes may also be important. Hyperglycemia disrupts blood-brain barrier function and depresses cerebral blood flow acutely, whereas chronic hyperglycemia is associated with cerebrovascular disease and neuropathy (1). The impact on the CNS of osmotic changes associated with constantly fluctuating glucose levels is unclear. Neurotransmitter pathways may also be affected in diabetes, as insulin is involved in regulation of the amine neurotransmitters (1).There is a growing body of literature documenting pathophysiological CNS changes and neurocognitive deficits in adults with type 1 diabetes (2–6) as sometimes, but not universally, linked to specific illness variables such as disease duration or history of severe hypoglycemia or chronic hyperglycemia. Cognitive difficulties have also been reported in children, with deficits most evident in those with early-onset (≤5 years old) disease (7,8). Neuroimaging studies of youth have been limited to date (9,10) and understanding of the impact of type 1 diabetes on neurodevelopment is still based largely on inferences drawn from neurocognitive studies and from adult neuroimaging reports. Controlled, longitudinal studies are particularly informative in documenting illness-related changes in the CNS. The Diabetes Control and Complications Trial (DCCT) (11) showed no deterioration in cognitive function in either conventionally or intensively treated patients over an 18-year period. However, this study did not enroll participants at diagnosis and recruitment was limited to those >13 years of age. Thus, the DCCT was unable to document any illness-related effects that may have occurred before recruitment—in particular, the impact of diabetes on a developing CNS. Children have high cerebral energy needs associated with brain growth and “neural pruning” and may be more sensitive than adults to glucose fluctuations (1,7). It is important to document the specific neuropathological correlates of type 1 diabetes in younger populations, as better understanding of the impact of childhood-onset disease on CNS development will facilitate evidence-based pediatric management regimens.Previously, we identified neurocognitive deficits 6 years after disease onset in youth studied prospectively from diagnosis (12). The current study reevaluated this cohort 12 years after study inception.     

Correlates of Treatment Patterns Among Youth With Type 2 Diabetes

OBJECTIVE

To describe treatment regimens in youth with type 2 diabetes and examine associations between regimens, demographic and clinical characteristics, and glycemic control.

RESEARCH DESIGN AND METHODS

This report includes 474 youth with a clinical diagnosis of type 2 diabetes who completed a SEARCH for Diabetes in Youth study visit. Diabetes treatment regimen was categorized as lifestyle alone, metformin monotherapy, any oral hypoglycemic agent (OHA) other than metformin or two or more OHAs, insulin monotherapy, and insulin plus any OHA(s). Association of treatment with demographic and clinical characteristics (fasting C-peptide [FCP], diabetes duration, and self-monitoring of blood glucose [SMBG]), and A1C was assessed by χ² and ANOVA. Multiple linear regression models were used to evaluate independent associations of treatment regimens and A1C, adjusting for demographics, diabetes duration, FCP, and SMBG.

RESULTS

Over 50% of participants reported treatment with metformin alone or lifestyle. Of the autoantibody-negative youth, 40% were on metformin alone, while 33% were on insulin-containing regimens. Participants on metformin alone had a lower A1C (7.0 ± 2.0%, 53 ± 22 mmol/mol) than those on insulin alone (9.2 ± 2.7%, 77 ± 30 mmol/mol) or insulin plus OHA (8.6 ± 2.6%, 70 ± 28 mmol/mol) (P < 0.001). These differences remained significant after adjustment (7.5 ± 0.3%, 58 ± 3 mmol/mol; 9.1 ± 0.4%, 76 ± 4 mmol/mol; and 8.6 ± 0.4%, 70 ± 4 mmol/mol) (P < 0.001) and were more striking in those with diabetes for ≥2 years (7.9 ± 2.8, 9.9 ± 2.8, and 9.8 ± 2.6%). Over one-half of those on insulin-containing therapies still experience treatment failure (A1C ≥8%, 64 mmol/mol).

CONCLUSIONS

Approximately half of youth with type 2 diabetes were managed with lifestyle or metformin alone and had better glycemic control than individuals using other therapies. Those with longer diabetes duration in particular commonly experienced treatment failures, and more effective management strategies are needed.     

Association of Type 1 Diabetes With Month of Birth Among U.S. Youth: The SEARCH for Diabetes in Youth Study

OBJECTIVE

Seasonal environment at birth may influence diabetes incidence in later life. We sought evidence for this effect in a large sample of diabetic youth residing in the U.S.

RESEARCH DESIGN AND METHODS

We compared the distribution of birth months within the SEARCH for Diabetes in Youth Study (SEARCH study) with the monthly distributions in U.S. births tabulated by race for years 1982–2005. SEARCH study participants (9,737 youth with type 1 diabetes and 1,749 with type 2 diabetes) were identified by six collaborating U.S. centers.

RESULTS

Among type 1 diabetic youth, the percentage of observed to expected births differed across the months (P = 0.0092; decreased in October–February and increased in March–July). Their smoothed birth-month estimates demonstrated a deficit in November–February births and an excess in April–July births (smoothed May versus January relative risk [RR] = 1.06 [95% CI 1.02–1.11]). Stratifications by sex or by three racial groups showed similar patterns relating type 1 diabetes to month of birth. Stratification by geographic regions showed a peak-to-nadir RR of 1.10 [1.04–1.16] in study regions from the northern latitudes (Colorado, western Washington State, and southern Ohio) but no birth-month effect (P > 0.9) in study regions from more southern locations. Among type 2 diabetic youth, associations with birth month were inconclusive.

CONCLUSIONS

Spring births were associated with increased likelihood of type 1 diabetes but possibly not in all U.S. regions. Causal mechanisms may involve factors dependent on geographic latitude such as solar irradiance, but it is unknown whether they influence prenatal or early postnatal development.Diabetes has been found by some investigators to be least common among youth who were born in the fall and/or most common among youth born in the spring. Similar reports have come from several regions of Europe (1–4), from New Zealand (where spring occurs in September–November) (5), and from Israeli Jews (6). This pattern was not demonstrated, however, by some studies elsewhere in Europe (3), in East Asia (7,8), or in Cuba (9). The sole previous publication from the U.S. that tested the birth month and diabetes relationship was restricted to 604 African American diabetic youth who lived in Chicago (10). This report showed that the standardized birth ratio for all participants was reduced for births in October but that this finding was statistically significant only for youth diagnosed with diabetes at 15–17 years of age (versus younger ages) or for youth classified as probably having type 2 diabetes.Motivated by our interest in the developmental origins of diabetes, we have examined the distribution of birth months in a population-based U.S. sample of youth with diabetes. The calendar date of birth may serve as a useful marker for environmental exposures during the prenatal and early postnatal periods. The date of birth is known precisely for nearly every individual in modern societies, its normative distributions are empirically available wherever births have been widely registered, and it can be categorized in conventional calendar units such as season, month, or week. Knowing the date of birth can also provide a reasonable estimate of the date of conception or of any other developmental “time window.” Thus, critical developmental periods can be associated ecologically with variations in environmental phenomena such as solar exposure, climate, microbial burden, culture, or maternal nutrition. These associations, however, may not be the same in all geographic regions.     

Cognitive Function in Adolescents and Young Adults With Youth-Onset Type 1 Versus Type 2 Diabetes: The SEARCH for Diabetes in Youth Study

OBJECTIVEPoor cognition has been observed in children and adolescents with youth-onset type 1 (T1D) and type 2 diabetes (T2D) compared with control subjects without diabetes. Differences in cognition between youth-onset T1D and T2D, however, are not known. Thus, using data from SEARCH for Diabetes in Youth, a multicenter, observational cohort study, we tested the association between diabetes type and cognitive function in adolescents and young adults with T1D (n = 1,095) or T2D (n = 285).RESEARCH DESIGN AND METHODSCognition was assessed via the National Institutes of Health Toolbox Cognition Battery, and age-corrected composite Fluid Cognition scores were used as the primary outcome. Confounder-adjusted linear regression models were run. Model 1 included diabetes type and clinical site. Model 2 additionally included sex, race/ethnicity, waist-to-height ratio, diabetes duration, depressive symptoms, glycemic control, any hypoglycemic episode in the past year, parental education, and household income. Model 3 additionally included the Picture Vocabulary score, a measure of receptive language and crystallized cognition.RESULTSHaving T2D was significantly associated with lower fluid cognitive scores before adjustment for confounders (model 1; P < 0.001). This association was attenuated to nonsignificance with the addition of a priori confounders (model 2; P = 0.06) and Picture Vocabulary scores (model 3; P = 0.49). Receptive language, waist-to-height ratio, and depressive symptoms remained significant in the final model (P < 0.01 for all, respectively).CONCLUSIONSThese data suggest that while youth with T2D have worse fluid cognition than youth with T1D, these differences are accounted for by differences in crystallized cognition (receptive language), central adiposity, and mental health. These potentially modifiable factors are also independently associated with fluid cognitive health, regardless of diabetes type. Future studies of cognitive health in people with youth-onset diabetes should focus on investigating these significant factors.     

Novel Biochemical Markers of Glycemia to Predict Pregnancy Outcomes in Women With Type 1 Diabetes

OBJECTIVEThe optimal method of monitoring glycemia in pregnant women with type 1 diabetes remains controversial. This study aimed to assess the predictive performance of HbA_1c, continuous glucose monitoring (CGM) metrics, and alternative biochemical markers of glycemia to predict obstetric and neonatal outcomes.RESEARCH DESIGN AND METHODSOne hundred fifty-seven women from the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) were included in this prespecified secondary analysis. HbA_1c, CGM data, and alternative biochemical markers (glycated CD59, 1,5-anhydroglucitol, fructosamine, glycated albumin) were compared at ∼12, 24, and 34 weeks’ gestation using logistic regression and receiver operating characteristic (ROC) curves to predict pregnancy complications (preeclampsia, preterm delivery, large for gestational age, neonatal hypoglycemia, admission to neonatal intensive care unit).RESULTSHbA_1c, CGM metrics, and alternative laboratory markers were all significantly associated with obstetric and neonatal outcomes at 24 weeks’ gestation. More outcomes were associated with CGM metrics during the first trimester and with laboratory markers (area under the ROC curve generally <0.7) during the third trimester. Time in range (TIR) (63–140 mg/dL [3.5–7.8 mmol/L]) and time above range (TAR) (>140 mg/dL [>7.8 mmol/L]) were the most consistently predictive CGM metrics. HbA_1c was also a consistent predictor of suboptimal pregnancy outcomes. Some alternative laboratory markers showed promise, but overall, they had lower predictive ability than HbA_1c.CONCLUSIONSHbA_1c is still an important biomarker for obstetric and neonatal outcomes in type 1 diabetes pregnancy. Alternative biochemical markers of glycemia and other CGM metrics did not substantially increase the prediction of pregnancy outcomes compared with widely available HbA_1c and increasingly available CGM metrics (TIR and TAR).