CGM Metrics Identify Dysglycemic States in Participants From the TrialNet Pathway to Prevention Study.

OBJECTIVE: Continuous glucose monitoring (CGM) parameters may identify individuals at risk for progression to overt type 1 diabetes. We aimed to determine whether CGM metrics provide additional insights into progression to clinical stage 3 type 1 diabetes. RESEARCH DESIGN AND METHODS: One hundred five relatives of individuals in type 1 diabetes probands (median age 16.8 years; 89% non-Hispanic White; 43.8% female) from the TrialNet Pathway to Prevention study underwent 7-day CGM assessments and oral glucose tolerance tests (OGTTs) at 6-month intervals. The baseline data are reported here. Three groups were evaluated: individuals with 1) stage 2 type 1 diabetes (n = 42) with two or more diabetes-related autoantibodies and abnormal OGTT; 2) stage 1 type 1 diabetes (n = 53) with two or more diabetes-related autoantibodies and normal OGTT; and 3) negative test for all diabetes-related autoantibodies and normal OGTT (n = 10). RESULTS: Multiple CGM metrics were associated with progression to stage 3 type 1 diabetes. Specifically, spending ≥5% time with glucose levels ≥140 mg/dL (P = 0.01), ≥8% time with glucose levels ≥140 mg/dL (P = 0.02), ≥5% time with glucose levels ≥160 mg/dL (P = 0.0001), and ≥8% time with glucose levels ≥160 mg/dL (P = 0.02) were all associated with progression to stage 3 disease. Stage 2 participants and those who progressed to stage 3 also exhibited higher mean daytime glucose values; spent more time with glucose values over 120, 140, and 160 mg/dL; and had greater variability. CONCLUSIONS: CGM could aid in the identification of individuals, including those with a normal OGTT, who are likely to rapidly progress to stage 3 type 1 diabetes.

Adherence to multiple medications in the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) cohort: effect of additional medications on adherence to primary diabetes medication.

Background Non-adherence to diabetes medication leads to poor outcomes and increased healthcare costs. Multiple factors affecting adherence in adults with type 2 diabetes (T2D) have been identified, but pediatric data is sparse. We aimed to determine whether initiation of additional oral medications or insulin affects adherence to primary study medication (PSM) in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods Six hundred and ninety-nine youth (aged 10-17 years) with recent-onset T2D were randomized in the TODAY study. Participants were categorized as adherent (≥80% taken by pill count) or non-adherent (<80%), and adherence was compared between those on additional medications or not. Subgroup analyses to assess influence of race/ethnicity, gender, medication type, or depression were performed. Results At 36 months, 46.3% of participants were taking additional oral medications and 31.9% were on insulin. There was no difference in study medication adherence with additional oral medications (55.1%, 67.1%, and 56.7% at month 36 in those prescribed 0, 1, or 2+ additional medications; p = 0.16). Girls on oral contraceptives (OC) had higher adherence (65.2% vs. 55.8% at month 36; p = 0.0054). Participants on insulin had lower adherence (39.7% vs. 59.3% at 36 months; p < 0.0001). There was decreased adherence in participants with baseline depression (p = 0.008). Conclusions Additional oral medications did not influence adherence to diabetes medications in TODAY. Addition of insulin led to reduced adherence. In subgroup analyses, OC use was associated with higher adherence in girls, while baseline depression was associated with lower adherence overall. Further studies examining potentially modifiable risk factors of adherence in pediatric T2D are needed.

Menstrual Dysfunction in Girls From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study.

Context: Little is known about reproductive function in girls with youth-onset type 2 diabetes. Objectives: To characterize girls with irregular menses and effects of glycemic treatments on menses and sex steroids in the Treatment Options for Type 2 Diabetes in Youth (TODAY) study. Design: Differences in demographic, metabolic, and hormonal characteristics between regular- vs irregular-menses groups were tested; treatment group (metformin with or without rosiglitazone, metformin plus lifestyle) effect on menses and sex steroids over time in the study was assessed. This is a secondary analysis of TODAY data. Setting: Multicenter study in an academic setting. Patients: TODAY girls not receiving hormonal contraception and those at least 1-year postmenarche were included. Irregular menses was defined as three or fewer periods in the prior 6 months. Results: Of eligible participants with serum measurement of sex steroids (n = 190; mean age, 14 years), 21% had irregular menses. Those with irregular vs regular menses had higher body mass index (BMI) (P = 0.001), aspartate aminotransferase (AST) (P = 0.001), free androgen index (P = 0.0003), and total testosterone (P = 0.01) and lower sex hormone-binding globulin (SHBG) (P = 0.004) and estradiol (P = 0.01). Differences remained after adjustment for BMI. There was no treatment group effect on menses or sex steroids at 12 or 24 months, and no association of sex steroids was seen with measures of insulin sensitivity or secretion. Conclusions: Menstrual dysfunction is common in girls with recently diagnosed type 2 diabetes and associated with alterations in sex steroids, SHBG, and AST but not with alteration in insulin sensitivity or ß-cell function and did not improve with 2 years of antihyperglycemic treatment.

Correlates of Medication Adherence in the TODAY Cohort of Youth With Type 2 Diabetes.

OBJECTIVE: To identify factors that predict medication adherence and to examine relationships among adherence, glycemic control, and indices of insulin action in TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth). RESEARCH DESIGN AND METHODS: A total of 699 youth 10-17 years old with recent-onset type 2 diabetes and ≥80% adherence to metformin therapy for ≥8 weeks during a run-in period were randomized to receive one of three treatments. Participants took two study pills twice daily. Adherence was calculated by pill count from blister packs returned at visits. High adherence was defined as taking ≥80% of medication; low adherence was defined as taking <80% of medication. Depressive symptoms, insulin sensitivity (1/fasting insulin), insulinogenic index, and oral disposition index (oDI) were measured. Survival analysis examined the relationship between medication adherence and loss of glycemic control. Generalized linear mixed models analyzed trends in adherence over time. RESULTS: In this low socioeconomic cohort, high and low adherence did not differ by sex, age, family income, parental education, or treatment group. Adherence declined over time (72% high adherence at 2 months, 56% adherence at 48 months, P < 0.0001). A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%, P = 0.0415). No adherence threshold predicted the loss of glycemic control. Longitudinally, participants with high adherence had significantly greater insulin sensitivity and oDI than those with low adherence. CONCLUSIONS: In the cohort, the presence of baseline clinically significant depressive symptoms was associated with subsequent lower adherence. Medication adherence was positively associated with insulin sensitivity and oDI, but, because of disease progression, adherence did not predict long-term treatment success.

The Relationship between Self-Management and Glycemic Control in a Cohort of Children with Type 1 and Type 2 Diabetes.

AIM: Self-management of diabetes improves glycemic control. The development of a quick, objective questionnaire in the clinic setting may provide data to the clinician caring for the patient in overall evaluation. OBJECTIVE: We developed a 23 question tool (clinic preparedness score) and administered it to type 1 and 2 (T1DM & T2DM) diabetes patients. Clinicians of patients were surveyed to determine their perception of adherence by patients. A total of 350 T1DM patients and families and 137 T2DM families were administered the questionnaire. Additionally, HbA1C was correlated to the various parameters that are related to improved glycemic control such as having a meter, carrying glucose tablets for hypoglycemia, and downloading/ writing blood sugars in log book in T1DM and T2DM. RESULTS: T1DM subjects had a lower HbA1C with better clinic preparedness (8.2 ± 1.3 vs. 9.4 ± 1.9%) However, this did not hold true for T2DM (p NS). If T1DM subjects adjusted their insulin dose and reported that their parent was involved they had better HbA1C than those that did not change insulin dose and if parent was uninvolved in the care. Clinicians of patients were able to accurately predict that appropriate dose adjustments resulted in good glycemic control. CONCLUSIONS: Pediatric T2DM adherence measures do not mirror similar characteristics of T1DM in childhood. The variability in glucose monitoring, medication and insulin administration may affect T2DM differently than T1DM.

Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine.

OBJECTIVE: Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on GSH synthesis rate and oxidative stress. RESEARCH DESIGN AND METHODS: We infused 12 diabetic patients and 12 nondiabetic control subjects with [²H2]-glycine to measure GSH synthesis. We also measured intracellular GSH concentrations, reactive oxygen metabolites, and lipid peroxides. Diabetic patients were restudied after 2 weeks of dietary supplementation with the GSH precursors cysteine and glycine. RESULTS: Compared with control subjects, diabetic subjects had significantly higher fasting glucose (5.0 ± 0.1 vs. 10.7 ± 0.5 mmol/l; P < 0.001), lower erythrocyte concentrations of glycine (514.7 ± 33.1 vs. 403.2 ± 18.2 µmol/l; P < 0.01), and cysteine (25.2 ± 1.5 vs. 17.8 ± 1.5 µmol/l; P < 0.01); lower concentrations of GSH (6.75 ± 0.47 vs. 1.65 ± 0.16 µmol/g Hb; P < 0.001); diminished fractional (79.21 ± 5.75 vs. 44.86 ± 2.87%/day; P < 0.001) and absolute (5.26 ± 0.61 vs. 0.74 ± 0.10 µmol/g Hb/day; P < 0.001) GSH synthesis rates; and higher reactive oxygen metabolites (286 ± 10 vs. 403 ± 11 Carratelli units [UCarr]; P < 0.001) and lipid peroxides (2.6 ± 0.4 vs. 10.8 ± 1.2 pg/ml; P < 0.001). Following dietary supplementation in diabetic subjects, GSH synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly. CONCLUSIONS: Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia.

Morbid obesity in pediatric diabetes mellitus: surgical options and outcomes.

The current obesity epidemic has led to a dramatic increase in insulin resistance and type 2 diabetes mellitus among adolescents, along with other obesity-related comorbidities, such as hypertension, hyperlipidemia, obstructive sleep apnea, psychosocial impairment and nonalcoholic fatty liver disease. Medical treatment of severe obesity is effective in only a small percentage of adolescent patients. In light of the potentially life-threatening complications of obesity, bariatric surgery can be considered a treatment option for adolescent patients with morbid obesity. Indications for surgery rely on both BMI and comorbidity criteria, as well as the ability of the adolescents and their family to understand and comply with perioperative protocols. The long-term effects of bariatric surgery in adolescents are not known; therefore, participation in prospective outcome studies is important. The risk associated with bariatric surgery in adolescents seems to be similar to that observed in adult patients in the short term. Data suggest that bypass procedures successfully reverse or improve abnormal glucose metabolism in the majority of patients and may be more effective in adolescents than adults. This improvement in glucose metabolism occurs before marked weight loss in patients undergoing bypass procedures, suggesting a direct effect on the hormonal control of glucose metabolism.

Effects of 1,25-dihydroxycholecalciferol on recovery and resolution of late transient neonatal hypocalcemia.

Background. Late transient neonatal hypocalcemia with hyperphosphatemia is potentially life-threatening. The use of 1.25 dihydroxycholecalciferol in the management of neonatal hypocalcemia is unexplored. Objective. We hypothesized adding 1.25 dihydroxycholecalciferol to intravenous continuous calcium infusion (CaI) will achieve accelerated correction of hypocalcemia. Design/Methods. A controlled double-blind randomized placebo group was organized to compare the addition of 1.25 dihydroxycholecalciferol to CaI in 3-14 day old neonates presenting with hypocalcemia, hyperphosphatemia and seizures. Ionized calcium and phosphorus were measured to adjust CaI and maintain eucalcemia. Time to resolution of hypocalcemia was defined as time from starting CaI to the first ionized calcium of >/=1.1 mmol/L. CaI was discontinued when ionized calcium levels were >/=1.1 mmol/L on two measurements and the infant tolerated feeds. Results. Fourteen neonates were studied without statistical difference between groups. Time to correction of hypocalcemia for 1,25 dihydroxycholecalciferol versus placebo was 7.2 +/- 1.9 versus 11.5 +/- 3.4 hours respectively (p = .26). The duration of CaI was 15.0 +/- 1.5 versus 24.8 +/- 4.4 hours respectively (p = .012). Conclusions. The addition of 1.25 dihydroxycholecalciferol to standard CaI therapy reduced the duration of CaI, but did not reduce the time to correct hypocalcemia in neonates with late transient hypocalcemia.

Dyadic measures of the parent-child relationship during the transition to adolescence and glycemic control in children with type 1 diabetes.

To identify aspects of family behavior associated with glycemic control in youth with type 1 diabetes mellitus during the transition to adolescence, the authors studied 121 9- to 14-year-olds (M = 12.1 yrs) and their parents, who completed the Diabetes Family Conflict Scale (DFCS) and the Diabetes Family Responsibility Questionnaire (DFRQ). From the DFRQ, the authors derived 2 dyadic variables, frequency of agreement (exact parent and child concurrence about who was responsible for a task) and frequency of discordance (opposite parent and child reports about responsibility). The authors divided the cohort into Younger (n = 57, M = 10.6 yrs) and Older (n = 64, M = 13.5 yrs) groups. Family conflict was significantly related to glycemic control in the entire cohort and in both the Younger and Older groups. However, only in the Younger group was Agreement related to glycemic control, with higher Agreement associated with better glycemic control. Findings suggest that Agreement about sharing of diabetes responsibilities may be an important target for family-based interventions aiming to optimize glycemic control in preteen youth.

Hyperglycemia during induction therapy is associated with poorer survival in children with acute lymphocytic leukemia.

OBJECTIVES: To investigate whether children with acute lymphocytic leukemia (ALL) who have development of hyperglycemia during induction may have worse relapse-free (RFS) and overall survival (OS) rates. STUDY DESIGN: A review of 167 children diagnosed with ALL between 1999 to 2002 at Texas Children's Hospital was performed. Blood glucose concentrations during induction therapy were reviewed; patients were assigned to 3 groups: euglycemia (blood glucose < 140 mg/dL), mild hyperglycemia (blood glucose between 140-200 mg/dL), and overt hyperglycemia (blood glucose > 200 mg/dL). RFS and OS among groups were compared by use of Kaplan-Meier and Cox-proportional hazard analyses, adjusting for potential confounding variables. RESULTS: The median follow-up in survivors was 6 years; there were 18 deaths and 36 relapses. Overt hyperglycemia was seen in 56 (34%) patients. Patients with overt hyperglycemia had poorer RFS (68% +/- [SE] 6.7 vs 85% +/- 3.6, P = .025) and OS (74% +/- 6.1 vs 96% +/- 1.9, P < .0001) at 5 years than their counterparts. Patients with overt hyperglycemia had 6.2 times (95% CI 1.6-24.7, P = .01) greater risk for death, independent of risk group and type of steroid. CONCLUSIONS: Overt hyperglycemia may be an independent predictor of survival in children with ALL.

Psychosocial issues in youth with type 2 diabetes mellitus.

Little published research exists on psychosocial issues in adolescents with type 2 diabetes mellitus (T2DM), because until two decades ago, diabetes diagnosed in children and adolescents was almost exclusively type 1 diabetes mellitus or insulin-dependent diabetes. In the past two decades, rates of T2DM have increased, especially in adolescents from families of minority racial and ethnic groups. Youth with T2DM are most often obese, have a parent or other first-degree relative with T2DM, and are of low socioeconomic status. To understand the complex set of interrelated psychological and social influences that affect the well-being of youth with T2DM, levels of influence from determinants of genetics, family, and community/societal and minority ethnic groups must be included.

Hyperglycemia during induction therapy is associated with increased infectious complications in childhood acute lymphocytic leukemia.

BACKGROUND: Children with acute lymphocytic leukemia (ALL) are at high risk for developing hyperglycemia. Hyperglycemic adult ALL patients have shorter remissions, more infections, and increased mortality. No corresponding data are available in children. We hypothesized that children with ALL who become hyperglycemic during induction chemotherapy have an increased risk for infection during their first year of treatment. PROCEDURE: We conducted a retrospective chart review of 135 patients diagnosed with ALL during 1999-2001 at Texas Children's Hospital. Infectious outcomes during the first year of therapy were compared in three groups patients based on blood glucose concentrations during induction therapy: euglycemic (<140 mg/dl), mild hyperglycemic (MH) (140-199 mg/dl) and overt hyperglycemic (OH) (blood glucose >200 mg/dl). RESULTS: Seventy-five (56%) patients met criteria for either MH (21%) or OH (35%). Hyperglycemia was more prevalent in older children (P < 0.001) and those at risk for being overweight (BMI% >85%) at diagnosis (P < 0.01). Patients with MH and OH were 2.5 times (95% CI 1.0-6.2) and 2.1 times (95% CI 1.0-4.6) more likely to have documented infections, respectively. Patients with OH were 4.2 times (95% CI 1.5-12) more likely to have bacteremia/fungemia, 3.8 times (95% CI 1.2-11.6) more likely to have cellulitis, and 4.0 times (95% CI 1.7-9.3) more likely to be admitted for fever and neutropenia than the euglycemia group. CONCLUSION: Hyperglycemia, especially when overt, may be a previously unrecognized risk factor of infectious complications in children with ALL during the first year of treatment.