Siripoom V. McKay

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.

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.

Depressive Symptoms and Quality of Life in Adolescents With Type 2 Diabetes Baseline data from the TODAY study

OBJECTIVE The study objective was to examine the prevalence of depressive symptoms and relationships to quality of life and demographics in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study’s large, ethnically diverse youth with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 704 youth with type 2 diabetes <2 years’ duration, aged 10–17 years, and BMI ≥85th percentile completed depressive symptoms and quality of life measures. RESULTS Some 14.8% reported clinically significant depressive symptoms, and older girls had significantly higher rates than older boys. CONCLUSIONS Rates of significant depressive symptoms were similar to those of healthy adolescents and lower than those of teens with type 1 diabetes. Elevated depressive symptoms, particularly in older girls, suggest clinicians assess vulnerability.

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.

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 Childrens 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.

Barriers to glycemic control in youth with type 1 diabetes and type 2 diabetes.

Anderson BJ, McKay SV. Barriers to glycemic control in youth with type 1 diabetes and type 2 diabetes.

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

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.

Alterations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabetes participating in the TODAY clinical trial.

Data on cardiovascular disease (CVD) risk in adolescents with type 2 diabetes (T2D) are limited. Echocardiography was performed in the last year of the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial (median 4½ yr from diagnosis of T2D, average age 18 yr), including MMode and 2D measurements of left ventricular (LV) and left atrial (LA) dimensions, LV tissue Doppler imaging (TDI), and tricuspid annular plane systolic excursion (TAPSE). Relationships between cardiac structure and function with demographic characteristics and baseline and change‐from‐baseline in CVD risk factors were examined in 455 participants. Mean LV mass (LVM) was high/normal and 16.2% had adverse LV geometry (8.1% concentric geometry, 4.5% LV hypertrophy, and 3.6% both). Determinants of higher LVM were male gender, black race, baseline and increasing body mass index (BMI), baseline and increasing systolic blood pressure (SBP), use of blood pressure (BP) medications, maintenance of glycemic control, and smoking; heart rate (HR) was inversely related. LV shortening fraction was high/normal and related to increasing BMI and higher baseline SBP. LV relative wall thickness was related to race–ethnicity, change in BMI, baseline glycated hemoglobin (HbA1c), and baseline and change in SBP. Mean LA internal dimension was high/normal and gender, baseline and increasing BMI, increasing SBP, and HR (inverse) were related. LV TDI was positively related to obesity (higher with adverse geometry). TAPSE was normal and related to higher baseline BMI and lower HR. There was no effect of T2D treatment on cardiac target organ injury. Adolescents with T2D have adverse measures of cardiac structure and function positively related to BMI and BP.

Ethnicity affects the postprandial regulation of glycogenolysis

We investigated the effect of nutrient intake on glucose metabolism in normal Mexican-Americans (n = 6) and European-Americans (n = 6). Subjects were studied after an 18-h fast and after 5-6 h of ingestion of hourly meals that supplied 6.35 or 12.75 micromol glucose. kg(-1). min(-1). Endogenous glucose production (EGP), gluconeogenesis (GNG), and glycogenolysis (GLY) were estimated by mass isotopomer analysis with [U-(13)C]glucose infusions. Fasting EGP, GNG, and GLY did not differ between the groups. Food ingestion lowered the molar rate of GNG by only 31%. However, while consuming the lower quantity of nutrients, Mexican-Americans had higher plasma glucose (P < 0.05), a 39% higher rate of EGP (P < 0.05), and a 68% (P < 0.025) higher rate of GLY than the European-Americans. At the higher intake, EGP and GLY were suppressed completely in both groups. There was a linear relationship between insulin concentrations, EGP, and GLY in both groups, but the slope of the line was significantly (P < 0.05) greater in the European-Americans. We conclude that the sensitivity of GLY to nutrient intake differs between ethnic groups and that this may play a role in the increased predisposition of Mexican-Americans to type II diabetes.

Nonaqueous, Mini-Dose Glucagon for Treatment of Mild Hypoglycemia in Adults With Type 1 Diabetes: A Dose-Seeking Study

OBJECTIVE To evaluate mini-dose glucagon in adults with type 1 diabetes using a stable, liquid, ready-to-use preparation. RESEARCH DESIGN AND METHODS Twelve adults with type 1 diabetes receiving treatment with insulin pumps received subcutaneous doses of 75, 150, and 300 μg of nonaqueous glucagon. Plasma glucose, glucagon, and insulin concentrations were measured. At 180 min, subjects received insulin followed in ˜60 min by a second identical dose of glucagon. RESULTS Mean (±SE) fasting glucose concentrations (mg/dL) were 110 ± 7, 110 ± 10, and 109 ± 9 for the 75-, 150-, and 300-μg doses, respectively, increasing maximally at 60 min by 33, 64, and 95 mg/dL (all P < 0.001). The post–insulin administration glucose concentrations were 70 ± 2, 74 ± 5, and 70 ± 2 mg/dL, respectively, with maximal increases of 19, 24, and 43 mg/dL post–glucagon administration (P < 0.02) at 45–60 min. CONCLUSIONS Subcutaneous, nonaqueous, ready-to-use G-Pen Mini glucagon may provide an alternative to oral carbohydrates for the management of anticipated, impending, or mild hypoglycemia in adults with type 1 diabetes.