Autologous Umbilical Cord Blood Transfusion in Very Young Children With Type 1 Diabetes

OBJECTIVE

Interest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord blood infusion to ameliorate type 1 diabetes.

RESEARCH DESIGN AND METHODS

Fifteen patients diagnosed with type 1 diabetes and for whom autologous umbilical cord blood was stored underwent a single intravenous infusion of autologous cells and completed 1 year of postinfusion follow-up. Intensive insulin regimens were used to optimize glycemic control. Metabolic and immunologic assessments were performed before infusion and at established time periods thereafter.

RESULTS

Median (interquartile range [IQR]) age at infusion was 5.25 (3.1–7.3) years, with a median postdiagnosis time to infusion of 17.7 (10.9–26.5) weeks. No infusion-related adverse events were observed. Metabolic indexes 1 year postinfusion were peak C-peptide median 0.50 ng/ml (IQR 0.26–1.30), P = 0.002; A1C 7.0% (IQR 6.5–7.7), P = 0.97; and insulin dose 0.67 units · kg⁻¹ · day⁻¹ (IQR 0.55–0.77), P = 0.009. One year postinfusion, no changes were observed in autoantibody titers, regulatory T-cell numbers, CD4-to-CD8 ratio, or other T-cell phenotypes.

CONCLUSIONS

Autologous umbilical cord blood transfusion in children with type 1 diabetes is safe but has yet to demonstrate efficacy in preserving C-peptide. Larger randomized studies as well as 2-year postinfusion follow-up of this cohort are needed to determine whether autologous cord blood–based approaches can be used to slow the decline of endogenous insulin production in children with type 1 diabetes.Type 1 diabetes is an autoimmune disorder characterized by T-cell–mediated destruction of insulin-producing β-cells and lifelong dependence on exogenous insulin administration. To date, the majority of efforts seeking to ameliorate the autoimmune process and reverse hyperglycemia have focused on the use of immunosuppressive or immunomodulatory drugs (1–4). Although several agents have shown and continue to show promise, no single agent has succeeded in demonstrating long-term success in preventing or reversing type 1 diabetes as a means of standard medical practice. More recently, efforts have focused on the use of either autologous or allogeneic hematopoietic stem/progenitor cells as potential immunoregulatory agents to reverse this disease. Whereas hematopoietic stem cells have successfully been directed in vitro to differentiate into insulin- and C-peptide–producing cells (5), and infusion of human hematopoietic stem cells into diabetic animals has demonstrated reversal of disease (6,7), the potential of such cells to provide a source of safe and effective immunomodulation may be of the greatest importance in treating type 1 diabetes, but this has yet to be realized (8–10).Among the broad array of potential cell-based therapies, the use of autologous umbilical cord blood as a source of immunomodulatory cells for the treatment of autoimmune diseases has become increasingly popular (11–14), this based on the potential for umbilical cord blood to restore proper immune regulation. Umbilical cord blood contains a robust population of immature unprimed highly functional regulatory T-cells (Tregs) (15). These highly functional Tregs could, in theory, limit inflammatory cytokine responses and anergize effector T-cells, which are thought to play a key role in cellular-mediated autoimmune processes (16,17). As such, umbilical cord blood Tregs have become a major focus of our work in designing cell-based therapies for children with type 1 diabetes (18).Practical matters provide an additional rationale for umbilical cord blood–based therapies. First, the lack of low-risk (i.e., safe) diabetes intervention trials seeking to reverse disease, especially for young children with type 1 diabetes, renders the potential use of umbilical cord blood particularly appealing. Second, as the rates of umbilical cord blood storage continue to increase exponentially, the number of potential subjects for autologous umbilical cord blood–based clinical trials continues to grow. Third, the fact that umbilical cord blood is stored at birth without need for additional intervention (i.e., bone marrow biopsy or stem cell mobilization and aphaeresis) is an additional practical advantage in considering a cell-based therapy for children. Finally, as umbilical cord blood storage facilities continue to reevaluate storage methods that would allow for multiple withdrawals, potential exists for protocols that involve cell expansion and/or multiple cell infusions.Although we focused our interest on the notion that umbilical cord blood Tregs might affect tolerance, we also considered that autologous umbilical cord blood transfusion in the setting of type 1 diabetes may help mitigate the autoimmune process by a variety of mechanisms beyond those of direct immune modulation (19). First, umbilical cord blood stem cells may migrate to the damaged pancreas, where they could differentiate into insulin-producing β-cells (2). In addition, umbilical cord blood stem cells might act as nurse cells to foster the proliferation or replication of new β-cells from remnant viable tissue (20). Finally, umbilical cord blood Tregs may facilitate bystander suppression of effector T-cells, allowing for the restoration of tolerance by their inhibitory effects on multiple cell types (21).Based on available preclinical data and the agreement that infusion of minimally manipulated autologous umbilical cord blood was likely to be extremely safe, we performed an unblinded observational pilot study to determine whether autologous umbilical cord blood infusion could impede the type 1 diabetes autoimmune process and preserve remaining endogenous insulin production. Peak C-peptide after a standard mixed-meal tolerance test (MMTT), A1C, and daily insulin requirement were set as the primary outcome variables, with a variety of immunologic markers assessed for their potential mechanistic insights.     

Promoting Normalization in Families With Preschool Children With Type 1 Diabetes

issues and purpose. The family environment is the most important influence on child adaptation to type 1 diabetes. A plan of care assists parental adaptation in families with a preschool child with type 1 diabetes.
conclusions. The family environment is affected by the family's progress toward normalcy. Normalization can be facilitated by nursing interventions that promote parental mutuality in management and the development of a parental support system.
practice implications. Nurses can provide education about Type 1 diabetes and its management in preschool children to fathers, other family members, and family friends to encourage their involvement in caregiving. Parental mutuality in management and an adequate parental instrumental support system facilitates normalization and affects the family environment, thus promoting child adaptation.     

Visuomotor Performance in KCNJ11-Related Neonatal Diabetes Is Impaired in Children With DEND-Associated Mutations and May Be Improved by Early Treatment With Sulfonylureas

OBJECTIVE To assess performance on an age-standardized neuromotor coordination task among sulfonylurea-treated KCNJ11-related neonatal diabetic patients. RESEARCH DESIGN AND METHODS Nineteen children carrying KCNJ11 mutations associated with isolated diabetes (R201H; n = 8), diabetes with neurodevelopmental impairment (V59M or V59A [V59M/A]; n = 8), or diabetes not consistently associated with neurodevelopmental disability (Y330C, E322K, or R201C; n = 3) were studied using the age-standardized Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI). RESULTS Although R201H subjects tested in the normal range (median standard score = 107), children with V59M/A mutations had significantly lower than expected VMI standard scores (median = 49). The scores for all three groups were significantly different from each other (P = 0.0017). The age of sulfonylurea initiation was inversely correlated with VMI scores in the V59M/A group (P < 0.05). CONCLUSIONS Neurodevelopmental disability in KCNJ11-related diabetes includes visuomotor problems that may be ameliorated by early sulfonylurea treatment. Comprehensive longitudinal assessment on larger samples will be imperative.     

Early Hyperglycemia Detected by Continuous Glucose Monitoring in Children at Risk for Type 1 Diabetes

OBJECTIVE

We explore continuous glucose monitoring (CGM) as a new approach to defining early hyperglycemia and diagnosing type 1 diabetes in children with positive islet autoantibodies (Ab+).

RESEARCH DESIGN AND METHODS

Fourteen Ab+ children, free of signs or symptoms of diabetes, and nine antibody-negative (Ab−) subjects, followed by the Diabetes Autoimmunity Study in the Young, were asked to wear a Dexcom SEVEN CGM.

RESULTS

The Ab+ subjects showed more hyperglycemia, with 18% time spent above 140 mg/dL, compared with 9% in Ab− subjects (P = 0.04). Their average maximum daytime glucose value was higher, and they had increased glycemic variability. The mean HbA_1c in the Ab+ subjects was 5.5% (37 mmol/mol). Among Ab+ subjects, ≥18–20% CGM time spent above 140 mg/dL seems to predict progression to diabetes.

CONCLUSIONS

CGM can detect early hyperglycemia in Ab+ children who are at high risk for progression to diabetes. Proposed CGM predictors of progression to diabetes require further validation.     

Blood Glucose Control in Type 1 Diabetes With a Bihormonal Bionic Endocrine Pancreas

OBJECTIVE

To test whether safe and effective glycemic control could be achieved in type 1 diabetes using a bihormonal bionic endocrine pancreas driven by a continuous glucose monitor in experiments lasting more than two days and including six high-carbohydrate meals and exercise as challenges to glycemic control.

RESEARCH DESIGN AND METHODS

Six subjects with type 1 diabetes and no endogenous insulin secretion participated in two 51-h experiments. Blood glucose was managed with a bionic endocrine pancreas controlling subcutaneous delivery of insulin and glucagon with insulin pumps. A partial meal-priming bolus of insulin (0.035 units/kg/meal, then 0.05 units/kg/meal in repeat experiments) was administered at the beginning of each meal (on average 78 ± 12 g of carbohydrates per meal were consumed). Plasma glucose (PG) control was evaluated with a reference quality measurement on venous blood every 15 min.

RESULTS

The overall mean PG was 158 mg/dL, with 68% of PG values in the range of 70–180 mg/dL. There were no significant differences in mean PG between larger and smaller meal-priming bolus experiments. Hypoglycemia (PG <70 mg/dL) was rare, with eight incidents during 576 h of closed-loop control (0.7% of total time). During 192 h of nighttime control, mean PG was 123 mg/dL, with 93% of PG values in the range of 70–180 mg/dL and only one episode of mild hypoglycemia (minimum PG 62 mg/dL).

CONCLUSIONS

A bihormonal bionic endocrine pancreas achieved excellent glycemic control with minimal hypoglycemia over the course of two days of continuous use despite high-carbohydrate meals and exercise. A trial testing a wearable version of the system under free-living conditions is justified.Development of a fully or semiautomated device that achieves glycemic levels demonstrated to reduce long-term complications (1–4) while lowering the risk for hypoglycemia (5) and reducing patient burden has long been a goal in the treatment of type 1 diabetes and would improve quality of life for people with type 1 diabetes. We previously demonstrated the feasibility of safe and effective bihormonal therapy with subcutaneous insulin and glucagon directed by a computer algorithm using frequently sampled venous plasma glucose (PG) in sedentary subjects over the course of 27 h (6). In the same study we also compared the accuracy and reliability of three commercially available continuous glucose monitors (CGMs) in each subject. Based on these results and preclinical studies in diabetic pigs, we hypothesized that glycemic control could be achieved in humans with type 1 diabetes using glucose values from one of these CGMs as the sole input to the controller. Here, we report the results of a study testing this hypothesis in experiments more than 2 days in length that included six high-carbohydrate meals and a period of exercise as challenges to glycemic control. Subcutaneous dosing of glucagon and insulin was controlled by an algorithm requiring only the subject weight for initialization.     

Safety and Glycemic Outcomes With a Tubeless Automated Insulin Delivery System in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Clinical Trial

OBJECTIVEVery young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population.RESEARCH DESIGN AND METHODSA total of 80 children aged 2.0–5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy.RESULTSThere were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA_1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70–180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204).CONCLUSIONSUse of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.     

A Randomized Clinical Trial Assessing Continuous Glucose Monitoring (CGM) Use With Standardized Education With or Without a Family Behavioral Intervention Compared With Fingerstick Blood Glucose Monitoring in Very Young Children With Type 1 Diabetes

OBJECTIVEThis study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to <8 years with type 1 diabetes.RESEARCH DESIGN AND METHODSThis was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to <8 years of age with type 1 diabetes. Primary analysis included treatment group comparisons of percent time in range (TIR) (70–180 mg/dL) across follow-up visits.RESULTSApproximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level <70 mg/dL was reduced from baseline to follow-up in the CGM+FBI (from 5.2% to 2.6%) and Standard-CGM (5.8% to 2.5%) groups, compared with 5.4% to 5.8% with BGM (CGM+FBI vs. BGM, P < 0.001, and Standard-CGM vs. BGM, P < 0.001). No severe hypoglycemic events occurred in the CGM+FBI group, one occurred in the Standard-CGM group, and five occurred in the BGM group. CGM+FBI parents reported greater reductions in diabetes burden and fear of hypoglycemia compared with Standard-CGM (P = 0.008 and 0.04) and BGM (P = 0.02 and 0.002).CONCLUSIONSCGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.     

Serum Monocyte Chemoattractant Protein-1 Concentrations Associate With Diabetes Status but Not Arterial Stiffness in Children With Type 1 Diabetes

OBJECTIVE

The relationship between circulating markers of inflammation and arterial stiffness in children with type 1 diabetes is not well studied. We tested whether inflammatory monocyte chemoattractant protein (MCP)-1 concentrations correlate with arterial stiffness or type 1 diabetes status.

RESEARCH DESIGN AND METHODS

MCP-1 concentrations and radial tonometry data were available for 98 children with type 1 diabetes and 55 healthy control subjects. Arterial stiffness was calculated as augmentation index corrected for a heart rate of 75 (AI75). Correlation between MCP-1 and AI75 and differences in MCP-1 concentrations between case and control subjects were tested.

RESULTS

MCP-1 was significantly higher in children with type 1 diabetes than in control subjects (P < 0.001). However, there were no correlations between MCP-1 and AI75 in the overall sample or upon stratification by type 1 diabetes status (range P = 0.28–0.66).

CONCLUSIONS

Circulating MCP-1 was not associated with arterial stiffness but was significantly elevated in children with type 1 diabetes, indicating a proinflammatory state in children as young as 10 years. The clinical significance of MCP-1 elevation in type 1 diabetes needs further investigation.Type 1 diabetes is associated with endothelial inflammation and arterial stiffness. We previously demonstrated that arterial stiffness is apparent in type 1 diabetic children as young as 10 years when compared with matched control subjects (1) but noted poor correlation with both traditional cardiovascular disease (CVD) risk factors (A1C, LDL cholesterol, and family history) and novel serum CVD risk factors (interleukin-6, tumor necrosis factor, C-reactive protein, superoxide dismutase, and nitric oxide) (1,2). Notably, a genetic association with arterial stiffness was seen (3). We postulated that the lack of correlation between arterial stiffness and previously studied risk factors was likely representative of the low short-term absolute risk for macrovascular events in our young type 1 diabetic cohort. Given that the majority of CVD events in type 1 diabetic patients are clustered among those with concurrent diabetic nephropathy, we sought to determine if monocyte chemoattractant protein (MCP)-1, a serum marker with known correlation to CVD events and diabetic nephropathy, would correlate with arterial stiffness in children with type 1 diabetes (4). As MCP-1 is stimulated by chronic hyperglycemia and is responsible for induction of superoxide anion, cytokine production, and adhesion molecule expression (5), exploration of potential correlation with global vascular dysfunction in children with type 1 diabetes was warranted. In this analysis, we sought to determine whether MCP-1 concentrations correlate with arterial stiffness as measured by radial artery tonometry and to validate previous associations between circulating MCP-1 concentrations and type 1 diabetes status in a case-control analysis.     

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.     

Extended Family History of Diabetes and Autoimmune Diseases in Children With and Without Type 1 Diabetes

OBJECTIVE

To determine the extended family history of diabetes or autoimmune diseases in families with and without children having type 1 diabetes.

RESEARCH DESIGN AND METHODS

Three hundred case families and 381 control families were interviewed using structured questionnaires.

RESULTS

The proportion of case children having at least one relative with type 1 diabetes outside the nuclear family was higher than that of control children (50.3 vs. 31.8%, P < 0.001). The proportions of case and control children having relatives with type 2 diabetes or gestational diabetes were similar. Other autoimmune diseases occurred more frequently among the case children (9.7 vs. 1.1%, P < 0.001), in the case nuclear families (22.0 vs. 12.9%, P = 0.002) and in relatives outside the case nuclear family (72.0 vs. 62.2%, P = 0.007).

CONCLUSIONS

Type 1 diabetes and autoimmune diseases not only cluster in the nuclear families of children with type 1 diabetes but are also overrepresented in their extended families.First degree relatives of patients with type 1 diabetes clearly have an increased disease risk (1–5), but little information is available about the occurrence of type 1 diabetes outside the nuclear family (6). It is also unclear whether type 2 diabetes and gestational diabetes are more frequently present in the families of children with type 1 diabetes (7–9). Type 1 diabetes is known to be associated with other autoimmune diseases, but there is a scarcity of data on the frequency of autoimmune diseases among other family members (10).     

Impact of Carbohydrate Counting on Glycemic Control in Children With Type 1 Diabetes

OBJECTIVE

To study the association between parent carbohydrate counting knowledge and glycemic control in youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

We assessed 67 youth ages 4–12 years with type 1 diabetes (duration ≥1 year). Parents estimated carbohydrate content of children''s meals in diet recalls. Ratios of parent estimates to computer analysis defined carbohydrate counting knowledge; the mean and SD of these ratios defined accuracy and precision, respectively. A1C defined glycemic control.

RESULTS

Greater accuracy and precision were associated with lower A1C in bivariate analyses (P < 0.05). In a multivariate analysis (R²= 0.25, P = 0.007) adjusting for child age, sex, and type 1 diabetes duration, precision (P = 0.02) and more frequent blood glucose monitoring (P = 0.04), but not accuracy (P = 0.9), were associated with lower A1C. A1C was 0.8% lower (95% CI −0.1 to −1.4) among youth whose parents demonstrated precision.

CONCLUSIONS

Precision with carbohydrate counting and increased blood glucose monitoring were associated with lower A1C in children with type 1 diabetes.Medical nutrition therapy in type 1 diabetes is associated with improved glycemic outcomes (1,2). Meal-planning strategies for type 1 diabetes emphasize the relationship between prandial insulin dose selection and the anticipated amount of carbohydrate to be consumed. Although no method for carbohydrate estimation has proven superior in the management of youth with type 1 diabetes, carbohydrate counting has become a principal strategy for children with type 1 diabetes (3,4). In this study, we investigated the association between parental carbohydrate counting knowledge and glycemic control in youth with type 1 diabetes.     

Mixing Insulin Aspart With Detemir Does Not Affect Glucose Excursion in Children With Type 1 Diabetes

OBJECTIVE

We hypothesized that insulin detemir mixed with aspart had equivalent effects on blood glucose as if being given as separate injections in pediatric type 1 diabetes patients.

RESEARCH DESIGN AND METHODS

Fourteen children with type 1 diabetes were randomly assigned to either Study A (mixed insulins) or Study B (separate insulins) for the first 10 days and crossed over for the last 10 days. Each subject underwent continuous glucose monitoring on the last 72 h of each study.

RESULTS

The 48-h area under the curve (mmol/hour/l), M-value, and mean amplitude of glucose excursion (mmol/l) for Study A versus Study B were 457 ± 70 versus 469 ± 112 (P = 0.58), 39.67 ± 15.37 versus 39.75 ± 9.69 (P = 0.98), and 6.35 ± 1.92 versus 5.98 ± 0.92 (P = 0.42), respectively.

CONCLUSIONS

Insulin detemir mixed with aspart had equivalent effects on blood glucose versus giving them as separate injections in children with type 1 diabetes.One of the barriers to good glycemic control in children with type 1 diabetes is multiple daily insulin injections (1,2). Mixing rapid-acting and slow-acting insulins in the same syringe would decrease the number of injections and may improve adherence (3,4). Although there are concerns that mixing the insulins would change the glucose excursion (5), mixing rapid-acting insulin (aspart or lispro) with slow-acting insulin glargine in the same syringe immediately before use did not change the glucose excursion and rates of hypoglycemia (3,4). We hypothesized that slow-acting insulin detemir mixed with aspart would have equivalent effects on blood glucose versus giving them as separate injections in children with type 1 diabetes.     

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.     

Labile A1C Is Inversely Correlated With the Hemoglobin Glycation Index in Children With Type 1 Diabetes

OBJECTIVE

We hypothesized that labile A1C (LA1C) is directly correlated with stable A1C (SA1C) and between-patient differences in SA1C, which are independent of mean blood glucose (MBG).

RESEARCH DESIGN AND METHODS

We measured SA1C, LA1C, MBG, and a single clinic capillary glucose (CCG) from 152 pediatric patients with type 1 diabetes. Patients were grouped as high, moderate, or low glycators by hemoglobin glycation index (HGI).

RESULTS

LA1C and SA1C were correlated with CCG and MBG. LA1C was not correlated with SA1C (r = 0.06, P = 0.453). LA1C level was significantly associated with glycator group status (P < 0.0019) and CCG (P < 0.0001). Adjusted LA1C levels were highest in the low-HGI patients and lowest in the high-HGI group.

CONCLUSIONS

A conventional model of SA1C being directly correlated with LA1C concentration was not confirmed. Between-patient differences in SA1C at the same MBG may be due to complex intracellular factors influencing formation of SA1C from LA1C.Our team and others have described groups of diabetic patients who consistently demonstrate markedly higher (high glycators) or lower (low glycators) A1C despite both groups having similar preceding mean blood glucose (MBG) (1,2). As A1C is formed by the stable Amadori rearrangement of a precursor known as labile A1C (LA1C) (3), we hypothesized that high glycators would also have higher levels of LA1C, compared with low glycators. We tested this hypothesis in a well-characterized group of children with type 1 diabetes.