Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT).

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy of type 1 diabetes mellitus reduces the risk of development and progression of microvascular complications. The Epidemiology of Diabetes Interventions and Complications (EDIC) study assessed whether these benefits persisted after the end of DCCT. Results for the adolescent DCCT cohort are reported here. STUDY DESIGN: Of the DCCT adolescent cohort (n = 195), 175 participated in EDIC, 151 had fundus photography, and 156 had albumin excretion rate measured at year 3 or 4. The odds of progression of retinopathy and albuminuria from closeout of the DCCT until EDIC year 4 were assessed. RESULTS: In contrast to the 7.4 years of the DCCT, during which mean hemoglobin A(1c) levels were significantly lower with intensive therapy than conventional therapy (8.06% vs 9.76%; P <.0001), the subsequent first 4 years of EDIC had mean hemoglobin A(1c) levels that were similar between the former intensive and the former conventional groups (8.38% vs 8.45%). However, the prevalence of worsening of 3 steps or more in retinopathy and of progression to proliferative or severe nonproliferative retinopathy were reduced by 74% (P <.001) and 78% (P <.007), respectively, in the former intensive therapy group compared with the former conventional group. CONCLUSIONS: These findings provide further support for the DCCT recommendation that most adolescents with type 1 diabetes receive intensive therapy aimed at achieving glycemic control as close to normal as possible to reduce the risk of microvascular complications.

Coping skills training for youth with diabetes mellitus has long-lasting effects on metabolic control and quality of life.

OBJECTIVE: To determine whether initial effects on metabolic control and quality of life associated with a behavioral intervention combined with intensive diabetes management (IDM) can be sustained over 1 year in youth implementing intensive therapy regimens. STUDY DESIGN: Seventy-seven patients (43 females, 95% white) 12 to 20 years (mean = 14.2 +/- 1.9; duration, 8.7 +/- 3.9) electing to initiate IDM were randomly assigned to one of two groups: with or without coping skills training (CST), which consists of 6 small group sessions and monthly follow-up to help youth cope with their lives in the context of diabetes management; skills included social problem solving, cognitive behavior modification, and conflict resolution. Data were collected before the intervention and at 3, 6, and 12 months after the intervention by using the Self-Efficacy for Diabetes Scale, Children's Depression Inventory, Issues in Coping with IDDM, and the Diabetes Quality of Life: Youth scales. Clinical data (glycosylated hemoglobin level, height, weight, adverse effects) were collected monthly. RESULTS: The CST and IDM groups were comparable at baseline. CST subjects had lower glycosylated hemoglobin (P =.001) and better diabetes (P =.002) and medical (P =. 04) self-efficacy, and less impact of diabetes on their quality of life (P =.005) than youth receiving IDM alone after 1 year. In males, CST did not affect adverse outcomes of IDM hypoglycemia, diabetic ketoacidosis, and weight gain, but CST decreased the incidence of weight gain (P =.05) and hypoglycemia in females (P =.03). CONCLUSIONS: The addition of behavioral intervention to IDM in adolescence results in improved metabolic control and quality of life over 1 year.

Enhanced adrenomedullary response and increased susceptibility to neuroglycopenia: mechanisms underlying the adverse effects of sugar ingestion in healthy children.

OBJECTIVE: Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children, but a physiologic mechanism has not been established. This study was performed to address this issue. DESIGN: Metabolic, hormonal, and symptomatic responses to a standard oral glucose load (1.75 gm/kg; maximum, 120 gm) were compared in 25 healthy children and 23 young adults, and the hypoglycemic clamp, together with measurements of P300 auditory evoked potentials, was used to assess whether children are more vulnerable than adults to neuroglycopenia. SETTING: Children's Clinical Research Center, Yale University School of Medicine. RESULTS: Baseline and oral glucose-stimulated plasma glucose and insulin levels were similar in both groups, including the nadir glucose level 3 to 5 hours after oral administration of glucose (3.4 +/- 0.1 mmol/L (61 +/- 1.8 mg/dl) in children and 3.5 +/- 0.1 mmol/L (63 +/- 1.8 mg/dl) in adults). The late glucose decrease stimulated a rise in plasma epinephrine levels that was twofold higher in children than in adults (2260 +/- 289 vs 1031 +/- 147 pmol/L (407 +/- 52 vs 186 +/- 26 pg/ml), p < 0.01) and a significant increase in hypoglycemic symptom scores in children (p < 0.01), but not in adults. During control experiments, in which six of the healthy children ingested a sugar-free drink, there were no significant changes in plasma glucose levels, hormone concentrations, or hypoglycemic symptom scores. During the hypoglycemic clamp, P300 potentials did not change in any of eight adult subjects until the plasma glucose concentration was lowered to 3.0 mmol/L (54 mg/dl), whereas similar changes in P300 potentials were observed in six of seven children at glucose levels 3.6 to 4.2 mmol/L (65 to 75 mg/dl). CONCLUSION: Enhanced adrenomedullary responses to modest reductions in plasma glucose concentration and increased susceptibility to neuroglycopenia may be important contributing factors to adverse behavioral and cognitive effects after sugar ingestion in healthy children.

Effect of growth hormone treatment on hyperinsulinemia associated with Turner syndrome.

To determine whether the insulin resistance in patients with Turner syndrome, which may be exaggerated by treatment with human growth hormone, leads to excessive insulin secretion, we applied the hyperglycemic glucose-clamp technique to produce a standard hyperglycemic stimulus (6.9 mmol/L, or 125 mg/dl, greater than fasting plasma glucose level for 120 minutes) in seven patients with Turner syndrome and in seven healthy children. These studies were repeated in the patients after 6 to 12 months of therapy with growth hormone. Fasting plasma levels of insulin were comparable in control subjects and patients before therapy but increased significantly in the patients after 6 to 12 months of treatment with growth hormone. Despite identical glucose increments in the two groups during the glucose-clamp procedure, both first- and second-phase insulin responses were significantly greater in the patients than in the control subjects. Moreover, the hyperinsulinemic responses to glucose were markedly exaggerated in the patients after their treatment with growth hormone, reaching values (first phase 474 +/- 100 pmol and second phase 826 +/- 100 pmol; p less than 0.02 vs pretreatment values) that were almost threefold greater than those in control subjects (p less than 0.001). Nevertheless, the rate of insulin-stimulated glucose metabolism during the last 60 minutes of the clamp procedure was similar in all three groups of studies. Glycosylated hemoglobin, total cholesterol level, and blood pressure remained normal in patients after therapy with growth hormone. We conclude that glucose-stimulated insulin response is increased in patients with Turner syndrome and that these alterations are further exaggerated by treatment with growth hormone. These hyperinsulinemic responses appear to compensate for reductions in insulin sensitivity.

Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity.

Recent studies have suggested that insulin action is reduced during puberty in normal children. To determine whether such resistance leads to excessive insulin secretion, we used the hyperglycemic clamp technique to produce a standard hyperglycemic stimulus (125 mg/dl above fasting levels for 120 minutes) in 9 preadolescent and 14 adolescent healthy children and in 14 normal adults. Fasting plasma insulin and C-peptide concentrations were higher in adolescents than in preadolescents and adults (p less than or equal to 0.02). Despite identical glucose increments during the glucose clamp procedure, both first- and second-phase plasma insulin and C-peptide responses were also markedly greater in adolescents than in preadolescents or adults (p less than 0.01 vs. other groups). Despite sharply increased insulin responses in adolescents, the amount of exogenous glucose required to maintain hyperglycemia was similar in all three groups. Insulin responses in the children were directly correlated with fasting plasma levels of insulin-like growth factor I (r = 0.60 to 0.70, p less than 0.01). We conclude that glucose-stimulated insulin secretion is normally increased during puberty, a response that may compensate for puberty-induced defects in insulin sensitivity.

Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children.

To determine whether children with insulin-dependent diabetes mellitus (IDDM) might have exaggerated hormonal responses to hypoglycemia, the euglycemic-hypoglycemic glucose clamp procedure was used to provide a uniform hypoglycemic stimulus (plasma glucose kept at 90 mg/dL for 2 hours, then reduced to 50 to 55 mg/dL for 1 hour) in children and adults with and without IDDM. The chidren with IDDM showed an exaggerated rise in plasma epinephrine levels (625 +/- 112 pg/mL) compared with adults with IDDM (259 +/- 57 pg/mL, P less than 0.02); the same was true for children and adults without IDDM (811 +/- 100 vs 458 +/- 85 pg/mL, P less than 0.05). Among the children, the increase in epinephrine during hypoglycemia was similar in prepubertal and pubertal patients. Children with IDDM showed a greater rise in plasma norepinephrine than did adults with IDDM (P less than 0.001), and both diabetic groups failed to mount a glucagon response. Growth hormone and cortisol responses were unaffected by either childhood or diabetes. Enhanced secretion of epinephrine, induced by mild reductions in plasma glucose, may contribute to the management difficulties characteristically observed in the young patient with diabetes.

Prospective clinical trial of human growth hormone in short children without growth hormone deficiency.

Ten unselected, apparently healthy short children who were capable of normal growth hormone secretion were given human growth hormone (0.1 U/kg 1M thrice weekly) for 6 months to determine whether such treatment might lead to an increase in growth velocity. During treatment, all patients increased their growth rate (from 4.3 +/- 0.3 cm/yr to 7.4 +/- 0.5 cm/yr P less than 0.001). No adverse effects were detected. During the four-day IGF generation test, IGF I and IGF II levels rose significantly from 0.32 +/- 0.04 U/ml to 0.62 +/- 0.13 U/ml and from 279 +/- 36 ng/ml to 434 +/- 49 ng/ml, respectively. However, the growth response was not predicted by either the acute rise in IGF I or that in IGF II. Human growth hormone in standard doses may be capable of inducing accelerated growth in some short children without growth hormone deficiency. Measurements of IGF I and II cannot be used to predict which children will respond.

Effect of intensive insulin treatment on linear growth in the young diabetic patient.

Although impaired growth is a well-recognized complication of uncontrolled diabetes, it has not been established whether less severe metabolic derangements commonly seen with conventional treatment adversely affected growth potential. To examine this question, growth velocity was measured in nine type 1 diabetic patients (age 14 +/- 3 years) before and after six months of intensive insulin treatment either with the insulin pump or with multiple injections, which lowered mean plasma glucose concentration from 270 +/- 96 to 105 +/- 55 mg/dl and total glycosylated hemoglobin from 12.4 +/- 3.0 to 8.4 +/- 1.5% (mean +/- SD). During conventional treatment, growth velocity (5.3 +/- 2.2 cm/year) was within the range of normal despite elevations in plasma glucose concentrations. However, growth velocity increased sharply during intensive treatment (to 9.4 +/- 3.9 cm/year, P less than 0.005), reaching values in excess of normal in seven patients. The increase in growth velocity observed during intensive treatment was associated with a twofold rise in plasma somatomedin-C values. Skeletal maturation, previously normal or slightly delayed, did not advance excessively. These data indicate that the metabolic changes accompanying intensive treatment may enhance growth in diabetic children, even in those with apparently normal growth velocity during conventional therapy.

Juvenile rheumatoid arthritis in children with diabetes mellitus.

Seven children with insulin-dependent diabetes mellitus were found to have juvenile rheumatoid arthritis; six of these children had the polyarticular form of the disease. All six had positive serology (rheumatoid factor and/or antinuclear antibody) and clinical or serologic evidence of autoimmune diseases usually ascribed to the thyrogastric cluster. Five expressed HLA antigens associated with increased risk for both diabetes and rheumatoid arthritis in adults. Evidence of B cell hyperactivity and impaired T cell response was found in some, but immunoregulatory function was normal in all. The association of these two diseases may be the result of factors other than chance alone, and may be more common than previously suspected.