Decreased insulin response to glucose in islet cell antibody-negative siblings of type 1 diabetic children.

Measurement of beta-cell function is an important marker of progression to diabetes in individuals at risk for the disease. Although the peak incidence for the disease occurs before 17 years of age, normal values for insulin secretion were not available in this age group. We performed a simplified intravenous glucose tolerance test in 167 normal children, and in 98 islet cell antibody (ICA)-negative and 12 ICA-positive siblings of diabetic patients. Their age range was 1-16 yr. The first phase of insulin secretion, evaluated as the sum of plasma insulin concentrations at 1 and 3 min, increased with age and was significantly lower in ICA-negative siblings (86 +/- 6 microU/ml, P < 0.002) than in normal controls (115 +/- 6 microU/ml). This difference was not apparent before 8 yr of age. None of the ICA-negative siblings developed diabetes after an average of 4.5 yr. ICA-positive siblings at first study had a first phase insulin response similar to that of ICA negative siblings, but significantly lower than that of the normal controls (74 +/- 13 microU/ml, P < 0.02). The reason for the decreased insulin secretion in ICA-negative siblings is unknown, but could involve a defect in the growth of beta-cell mass or insulin secretion that could be part of the multifactorial pathogenesis of type 1 diabetes.

Lipid transport in the human newborn. Palmitate and glycerol turnover and the contribution of glycerol to neonatal hepatic glucose output.

Free fatty acid (FFA) transport was measured in 11 and glycerol turnover in 5 newborns with continuous tracer infusion of [1-(13)C]palmitate or [2-(13)C]glycerol, respectively. In addition, simultaneous determination of glucose production in the latter group with [6,6-(2)H(2)]glucose tracer and measurement of the appearance rate of [(13)C]glucose derived from [(13)C]glycerol allowed calculation of gluconeogenesis from glycerol.The average FFA inflow rate was 11.5+/-1.7 mumol kg(-1)min(-1), 2.5-4.5 h after the last feeding, and 16.7+/-2.8 mumol kg(-1)min(-1), 5-12 h after the last meal. These rates are comparable to those found in adults only after 8-16 h and approximately 72 h of fasting, respectively. FFA inflow in the newborn was directly correlated with time of fasting, plasma FFA level, and plasma glycerol level. Palmitate clearance and fractional removal were inversely related to palmitate level. Glycerol flux averaged 4.4+/-0.5 mumol kg(-1)min(-1), a value three- to fourfold that of the postabsorptive adult. Approximately 75% of transported glycerol was converted to glucose and represented 5.0+/-0.6% of hepatic glucose production. Furthermore, there was a direct relationship between glycerol turnover and the fraction of glucose coming from glycerol. Despite the absolutely elevated neonatal FFA and glycerol transport rates, these were quantitatively similar to values found in adults with comparable elevated substrate levels. Furthermore, other similarities with the adult in the relationships between inflow transport and substrate values, and between transport and fractional removal suggest that the regulatory aspects of lipid transport in man are already well developed by the first day of life.

Ketone body transport in the human neonate and infant.

Using a continuous intravenous infusion of D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3 +/- 1.4 mumol kg-1 min-1 in the neonates, a value not different from that of 20.6 +/- 0.9 mumol kg-1 min-1 measured in the older infants. This rate was accelerated to 32.2 mumol kg-1 min-1 in the diabetic and slowed to 5.0 mumol kg-1 min-1 in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased. Compared with the adult, however, ketone body turnover rates of 12.8-21.9 mumol kg-1 min-1 in newborns fasted for less than 8 h, and rates of 17.9-26.0 mumol kg-1 min-1 in older infants fasted for less than 10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate's basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans.

Glycerol production and utilization during the early phase of human obesity.

To study the initial period of fat deposition in human obesity, we measured glycerol turnover in 12 children of 135-253% ideal body weight, who had continuously gained weight since the onset of obesity 2-9 yr previously. Hyperinsulinemia developed in these children depending on obesity duration (r = 0.74, P less than 0.01). Whole-body glycerol production was twofold greater in the obese children (311 vs. 156 mumol.min-1, P less than 0.01) and correlated with body fat (r = 0.67, P less than 0.005). Normalization of glycerol flux to fat mass revealed that the rate of triglyceride hydrolysis was in fact lower in the adipose tissue of obese children (9.4 vs. 17.7 mumol.min-1/kg body fat) and correlated with plasma insulin (r = 0.64, P less than 0.005). Euglycemic insulin clamps showed that the response of glycerol production to a unit increment in plasma insulin concentration was increased in obese children, suggesting increased insulin sensitivity of adipose tissue. As a direct consequence (r = 0.67, P less than 0.025) of their elevated plasma glycerol concentration (65 +/- 4 vs. 37 +/- 2 microM, P less than 0.05) obese children had an increased glycerol utilization by the whole body, as well as per unit of lean body mass (9.1 +/- 1 vs. 6.5 +/- 0.9 mumoles.min-1.kg lean body mass-1, P less than 0.025).

Time course of increased lipid and decreased glucose oxidation during early phase of childhood obesity.

To determine the time course of metabolic dysfunctions in recent active obesity, we studied basal energy expenditure and lipid and glucose oxidation in 31 obese children (duration of obesity 1-11.5 yr), compared with 14 lean age-matched control subjects. Using indirect calorimetry in basal overnight fasting conditions, we found that obese children produced 15% more energy than control subjects. Obese children oxidized twice as much lipid (56 +/- 4 mg/min) as normal children (25 +/- 5 mg/min, P < 0.0005), so that lipid oxidation provided 61 +/- 6% of overall energy production (vs. 33 +/- 3% in control subjects, P < 0.0005). This increase of lipid oxidation was already present in the earlier stages of obesity. Glucose oxidation was diminished in the obese (93 +/- 6 mg/min) compared with the control children (136 +/- 6 mg/min, P < 0.0005) and accounted for only 39 +/- 3% of energy production (67 +/- 6% in control subjects, P < 0.0005). This decrease was not present initially and appeared after approximately 4 yr and worsened with obesity duration (r = 0.72, P < 0.0005). The results were similar when lipid and glucose oxidation were normalized to body surface area or lean body mass. We hypothesize that increased lipid oxidation is one of the earlier dysfunctions observed in recent-onset obesity and that lipid oxidation may induce a progressive decrease of glucose oxidation, insulin resistance, and increased fasting insulin secretion.

Cyclosporin A suppresses insulin autoantibodies and heterologous insulin antibodies in type I diabetic children.

We report that cyclosporin A (CsA) suppresses the insulin autoantibodies that are present before insulin therapy in the sera of one-third of studied type I (insulin-dependent) diabetic children. CsA also reversibly blocks the production of antibodies after exogenous insulin injection, whereas high titers of heterologous insulin antibody are observed in all type I patients not receiving CsA.

Increased basal glucose production and utilization in children with recent obesity versus adults with long-term obesity.

To characterize the abnormalities of glucose homeostasis and insulin action early in the course of human obesity, we studied in vivo glucose kinetics in seven children who were recently massively overweight. At time of study they were gaining weight at a rate of 13.5 +/- 1.4 kg/yr. They were compared with six age-matched control subjects. Six adults with long-term obesity and five normal adults were studied in parallel. The obese children and adults were normoglycemic and hyperinsulinemic. We found that glucose production and utilization were remarkably higher in obese children (295 +/- 18 mg/min; 7.6 mg.kg-1 lean body mass.min-1) than in control children (129 +/- 13 mg/min; 4.4 mg.kg-1 lean body mass.min-1, P less than .01) and obese adults (151 +/- 8 mg/min; 3.1 +/- 0.3 mg.kg-1 lean body mass.min-1, P less than .01). Obese adults had normal rates of glucose production and utilization. Insulin- and non-insulin-mediated glucose uptake, estimated with somatostatin-induced suppression of endogenous insulin secretion, contributed almost equally to the excess glucose utilization observed in the obese children. When studied with the euglycemic-hyperinsulinemic clamp, obese children could not increase glucose disposal to the same extent as normal children and were not able to adequately suppress their endogenous glucose production. Recently obese children are therefore characterized by an increased basal glucose turnover rate and an already established insulin resistance of the liver and probably the skeletal muscles.

Circulating leptin in normal children and during the dynamic phase of juvenile obesity: relation to body fatness, energy metabolism, caloric intake, and sexual dimorphism.

In 112 obese compared with 42 lean children, we found that serum leptin is elevated early in the evolution of childhood-onset obesity (28.4 +/- 1.4 vs. 4.5 +/- 0.4 ng/ml in lean children, P < 0.0001) and correlates with adiposity. Obese children also had higher serum leptin normalized to fat mass. Despite high serum leptin, obese children ingested 2-3 times more calories than did lean control subjects (P < 0.0001) and gained weight rapidly (10.2 +/- 0.3 vs. 2.9 +/- 0.1 kg/year in control subjects, P < 0.0001). Girls had higher leptin levels than did boys, in obese as well as in nonobese children, and showed a closer correlation between adiposity and serum leptin. Elevation of serum leptin was comparable before and after puberty in obese boys, but puberty further increased leptin levels in obese girls (36 +/- 3 ng/ml), resulting in a clear sexual dimorphism with pubertal obese boys (22 +/- 5 ng/ml, P < 0.005). In conclusion, increased serum leptin reflects but does not halt fat deposition in childhood obesity. After normalization to body adiposity, leptin was found to be increased independently by obesity status, female sex, and female sexual maturation.

Long-term results of early cyclosporin therapy in juvenile IDDM.

In juvenile IDDM patients, immunosuppression with cyclosporin A allows partial beta-cell function recovery and transient remissions of insulin dependency. The effects of this therapeutic approach, however, have not been evaluated in the long-term, since no reported trial exceeded 1 year. Here we analyze 130 diabetic children followed at our institution during the first years of their disease. Cyclosporin was given to 83 of them at an initial dose of 7.2 +/- 0.1 mg.kg-1.day-1, which was decreased stepwise then interrupted after 6-62 months, depending on the response to therapy. A total of 47 diabetic children, who served as control subjects in two trials, were pooled for comparison. Over 4 years, the cyclosporin-treated group kept plasma C-peptide approximately twice as high as the control group (P < 0.02). It took 5.8 +/- 0.6 years for C-peptide secretion stimulated by glucagon to become undetectable in the cyclosporin group versus 3.2 +/- 0.6 years in the control group (P < 0.02). Average insulin dose remained lower by 0.2-0.4 U.kg-1.day-1 and glycated hemoglobin by approximately 1% in cyclosporin-treated patients (P < 0.02), who also had less hypoglycemia than the diabetic control subjects (P < 0.05). After 4 years, differences between the groups became nonsignificant. We observed no significant secondary effects of cyclosporin. In conclusion, positive effects of low-dose cyclosporin in recently diagnosed clinical IDDM patients are prolonged beyond interruption of the drug. The magnitude and duration of the benefit, however, do not appear sufficient to justify this immunosuppressive treatment in clinical practice.

Glucose counterregulation in pre-school-age diabetic children with recurrent hypoglycemia during conventional treatment.

To determine whether immature or defective glucose counterregulation was responsible for the severe recurrent hypoglycemic episodes (3.6 per patient per year) observed during conventional therapy (CT) in six pre-school-age diabetic children, we investigated their metabolic and hormonal responses to insulin infusion (40 mU/kg i.v. for 60 min). Counterregulation was considered adequate because no patient experienced symptoms requiring discontinuation of the test, and blood glucose (BG) nadirs averaged 42 +/- 5 mg/dl. Glucose production rate decreased from 4.2 +/- 0.2 to 2.6 +/- 0.6 mg X kg-1 X min-1. Blood 3-hydroxybutyrate levels were elevated (approximately 3 mM) and did not change during insulin infusion. The responses of epinephrine (from 137 +/- 37 to 393 +/- 143 pg/ml), norepinephrine (from 145 +/- 33 to 347 +/- 152 pg/ml), and growth hormone (from 6.0 +/- 1.5 to 20.3 +/- 5.1 ng/ml) were normal for this age group. As previously observed in diabetic adults, glucagon response was deficient (from 117 +/- 30 to 114 +/- 18 pg/ml). The six children were subsequently treated with continuous subcutaneous insulin infusion (CSII), which resulted in a 20-fold decrease in the number of severe hypoglycemic reactions. Predisposition to severe hypoglycemia in this subset of diabetic children, which remains a refractory problem even after considerable efforts have been made to decrease them, may thus be sharply decreased with CSII therapy. During this therapy, a significant inverse correlation appeared between the individual frequency of BG values less than 40 mg/dl and BG nadir during the insulin infusion test (r = .94, P less than .001).

Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin.

Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before, a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms, less severe hyperglycemia, lower incidence of ketoacidosis, and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean +/- SE duration of 316 +/- 21 days (range 31-850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen, titer of autoantibodies, or progression of beta-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo, the patients who had a remission of insulin dependency had better glycemic control, lower insulin dosages, and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically, serum creatinine remained unchanged, and kidney biopsies performed at 18-24 mo of treatment were within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of ketosis during intensive insulin therapy in pre-school-age diabetic children.

The risk of ketosis and its relationship to the mode of insulin therapy were studied in a subset of pre-school-age diabetic children. These five children, who initially responded poorly to standard in-hospital diabetes management, were selected for a program of intensified therapy directed at achieving more stable blood glucose control. Optimized conventional therapy was first employed for 16 +/- 5 mo and did not improve substantially blood glucose level or stability. During this period, there was an average of almost one episode of ketonuria per patient per month, and three diabetic ketoacidosis episodes were observed. Because of its limited efficacy, the treatment was then changed to continuous subcutaneous insulin infusion. This mode of therapy had a rapid favorable effect on blood glucose control, with no concomitant increase of the frequencies of ketonuria or diabetic ketoacidosis, most of which occurred during the first months of insulin pump therapy. Deliberate cessation of either conventional or subcutaneous insulin infusion therapy for 7 h under close in-hospital control resulted in similar metabolic changes: a slight nonconstant increase of blood glucose, and an abrupt rise of blood 3-hydroxybutyrate to 3 mM, with massive ketonuria. The management of these young diabetic children with insulin pump therapy was thus not associated with an increased frequency or an accelerated rate of development of ketosis. However, the possible failures originating from the infusing device and the rapid increase of ketosis in young ages require special vigilance from the parents, based on twice-daily urine testing for ketones and appropriate insulin supplementation.

Improvement of diabetic control and acceptability of a three-injection insulin regimen in diabetic adolescents. A multicenter controlled study.

OBJECTIVE: To compare the effectiveness and acceptability of a three-injection insulin regimen with the conventional two-injection therapy in an unselected population of diabetic adolescents. RESEARCH DESIGN AND METHODS: Some 205 patients aged 10-18 yr with IDDM, who were previously treated with two daily insulin injections, were included without any selection into a randomized trial. They were either switched to three (regular prebreakfast, regular prelunch, and [regular+ultralente] predinner) or remained on two ([regular+intermediary] prebreakfast and predinner) subcutaneous injections. They were evaluated after 1 yr of treatment. The major criteria of outcome of efficacy were the concentration of GHb, the frequency of severe hypoglycemia and DKA, and body weight. RESULTS: Of the patients, 82% accepted the three-injection regimen, and 83% accepted the two-injection regimen. At entry into the trial, no significant differences appeared between the two treatment groups nor among patients refusing the allocated regimen. Significant explanatory variables predicting initial diabetes control were duration of disease and adherence to diet. GHb, decreased from 9.8 +/- 0.1 to 9.3 +/- 0.2% (P < 0.05) in the three-injection group, whereas it increased from 9.5 +/- 0.3 to 9.8 +/- 0.3% (P < 0.05) in the two-injection group, resulting in a modest (0.75%) but significant difference (P < 0.05) between GHb change in the two groups. The difference reached 1.4% (P < 0.0002) in patients with GHb > 11.2% at entry. The frequency of hypoglycemia and DKA was similar in the two groups. None of the parameters known to potentially influence glycemic control changed during the trial, and, therefore, the improvement of GHb could be attributed to the pattern of daily insulin distribution per se. CONCLUSIONS: In the general diabetic adolescent population, the efficacy of a three-injection regimen is somewhat superior to that of a conventional two-injection regimen, particularly in patients previously poorly controlled. The acceptability of this regimen being excellent, its increased use should be considered in this age-group.

Factors associated with glycemic control. A cross-sectional nationwide study in 2,579 French children with type 1 diabetes. The French Pediatric Diabetes Group.

OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.

Growth hormone treatment of children with short stature increases insulin secretion but does not impair glucose disposal.

Pediatricians willing to administer GH to non-GH-deficient children with short stature are concerned about the potential adverse effects of this hormone on glucose homeostasis and insulin action. This study was designed to determine the effects of GH therapy on carbohydrate metabolism in 10 prepubertal non-GH-deficient children with short stature. After 12 months of treatment with 0.3 U GH/kg BW.day, which resulted in an increase in height velocity from 4.0 +/- 0.3 (+/- SE) to 11.0 +/- 0.4 cm/yr, glucose tolerance was not impaired in these children. Not only were their fasting and postprandial plasma glucose concentrations unchanged from the pretreatment values, but basal glucose turnover did not vary; it was 0.53 +/- 0.04 before and 0.64 +/- 0.06 mmol/m2.min after GH treatment. Using the euglycemic clamp technique, the dose-response curves describing the effects of insulin on glucose disposal were comparable before and after GH treatment. There was a consistent 1.5- to 2-fold increase in plasma insulin and C-peptide concentrations during GH treatment, in both the basal and postprandial states, and after oral glucose or iv glucagon stimulation. We conclude that the GH regimen employed was remarkably effective in increasing growth velocity and devoid of detectable diabetogenic effects during a 1-yr treatment period in these non-GH-deficient children. (glucose, 1 mmol/L = 18 mg/dL; insulin, 1 pmol/L = 0.139 microU/mL; C-peptide, 1 pmol/L = 0.003 ng/ml).

Glucose metabolism in hyperinsulinemic infants: the effects of fasting and sodium DL-beta-hydroxybutyrate on glucose production and utilization rates.

Glucose metabolism was investigated in four infants aged 3-32 months with persistent hypoglycemia and hyperinsulinism of neonatal onset. Fasting hypoglycemia was found to be due both to an insulin-induced decrease in hepatic glucose output to 3.95 +/- 0.30 (SEM) mg/kg X min, a value about two thirds of normal, and to a glucose utilization rate of 4.25 +/- 0.32 mg/kg X min, which exceeded glucose production by about 8%. Simultaneously, and despite hypoglycemia, fasting plasma D-beta-hydroxybutyric acid concentrations were inappropriately low: 406 +/- 146 microM, presumably the result of elevated circulating insulin levels. The infusion of sodium DL-beta-hydroxybutyrate resulted in an increase of plasma glucose (48 +/- 7 vs. 32 +/- 7 mg/dl, P less than 0.01) and lactate (1704 +/- 217 vs. 964 +/- 149 microM, P less than 0.005), without detectable changes in insulin secretion estimated from circulating C-peptide values. Unexpectedly, the increase of plasma glucose was due to the restoration of glucose production up to 6.7 +/- 0.2 mg/kg X min. The individual increments of plasma lactate and glucose production rate were linearly correlated (P less than 0.01). These results together with the known inhibitory effect of ketone bodies on pyruvate dehydrogenation, suggest both increased production of lactate from peripheral recycling of glucose carbon and an increased conversion of this gluconeogenic precursor into glucose.

Effects of hypopituitarism and growth hormone replacement therapy on the production and utilization of glucose in childhood.

Glucose metabolism during fasting was investigated in 10 children aged 1.5 month-11.5 yr with deficiency of GH with or without other pituitary hormone deficiencies. After 10-16 h of fasting, mean plasma glucose was 56 +/- 4 (SEM) mg/dl, the result of decreased hepatic production of glucose (3.3 +/- 0.3 mg kg-1 min-1) insufficient to match glucose utilization (3.6 +/- 0.4 mg kg-1 min-1). The diminution of plasma glucose and of glucose production was similar whether ACTH deficiency was present (3.2 +/- mg kg-1 min-1) or not (3.5 +/- 0.6 mg kg-1 min-1). These results indicate that the lack of GH was the primary cause of hypoglycemia. Fasting plasma alanine (212 +/- 41 mumol/liter) and lactate (1222 +/- 136 mumol/liter), the main gluconeogenic substrates, were normal and did not correlate with the decrease of hepatic glucose release. Both plasma FFA (552 +/- 35 microM) and beta-hydroxybutyrate (654 +/- 158 microM) were in the low normal range, and neither correlated with the rate of glucose utilization. hGH replacement therapy resulted in a normalization of fasting plasma glucose concentration (78.5 +/- 6 mg/dl, P less than 0.005) and hepatic glucose production (6.1 +/- 1.2 mg kg-1 min-1). No significant changes occurred in the plasma concentrations of gluconeogenic or lipid substrates. These results, together with the known stimulatory effects of GH on carbohydrate-induced insulin secretion and storage of hepatic glycogen, suggest that the changes in glucose production in untreated and GH treated patients reflect the degree of hepatic glycogen replenishment.

Glucose metabolism in experimental hyperthyroidism: intact in vivo sensitivity to insulin with abnormal binding and increased glucose turnover.

The characteristics of the dose response of insulin on the glucose turnover rate and erythrocyte insulin binding parameters were determined in five normal men before and during experimentally induced hyperthyroidism [L-T4 (2 micrograms kg-1 day-1) for 4 weeks with additional L-T3 (1 microgram kg-1 day-1) for the following 3 weeks]. Hyperthyroidism was characterized by significant rises in T3 from 1.92 +/- 0.17 (+/- SEM) to 3.66 +/- 0.17 nmol/liter (P less than 0.01) and resting metabolic rate from 39 +/- 0.7 to 48 +/- 1 watt/m2 (P less than 0.001). While the subjects received a diet adapted to the metabolic rate, blood glucose rose from 3.8 +/- 0.07 to 4.46 +/- 0.11 mmol/liter (P less than 0.05) without a significant change in plasma insulin. During the insulin dose-response study, glucose infusion rates were unaltered by hyperthyroidism, and neither the maximum effect nor the sensitivity to insulin was altered. Glucose turnover rate, measured using [6,6-2H2]glucose as tracer, was determined in the basal state and during the 0.4 mU kg-1 min-1 insulin infusion. In the basal state, it was significantly increased by hyperthyroidism (control, 2.3 +/- 0.1; hyperthyroidism, 3.7 +/- 0.1 mg kg-1 min-1). During the insulin infusion, hepatic glucose production was totally suppressed before T4 and T3 treatment, but was 0.96 +/- 0.39 mg kg-1 min-1 during T4 and T3 treatment. A marked decrease in the insulin binding affinity to erythrocytes was found without a change in the insulin receptor number. In conclusion, glucose metabolism in experimental hyperthyroidism is characterized by 1) increases in basal glucose production and utilization; 2) antagonism between the effect of insulin and hyperthyroidism at the hepatic level; and 3) lack of peripheral insulin resistance in spite of marked alteration in erythrocyte insulin binding affinity.

Lack of effect of GnRH agonists on final height in girls with advanced puberty: a randomized long-term pilot study.

GnRH agonists improve final height in girls with "true" precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 +/- 0.1 yr), a variant of normal called "advanced" puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 +/- 4.3 cm (+0.6 SDS) in group I, 136.1 +/- 4.2 cm (+0.8 SDS) in group II, with target height 157.6 +/- 4.3 cm (group I) and 157.8 +/- 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 +/- 3.9 cm and 155.2 +/- 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 +/- 4.0 cm) and untreated girls (156.1 +/- 5.3 cm) (NS).

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.