Cotherapy with recombinant human insulin-like growth factor I and insulin improves glycemic control in type 1 diabetes. RhIGF-I in IDDM Study Group.

OBJECTIVE: To study the effects of 12 weeks of cotherapy with recombinant human IGF-I (rhIGF-I) and insulin on glycemic control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study population consisted of 223 patients who ranged in age from 11-66 years and were randomized in a double-blind study to receive 12 weeks of treatment with twice-daily subcutaneous injections of placebo (n = 54), or rhIGF-I at a dose (A.M/P.M) of 40/40 micrograms/kg (n = 56), 80/40 micrograms/kg (n = 57), or 80/60 micrograms/kg (n = 56), while continuing to receive standard insulin therapy. Patients were instructed to test blood glucose levels four times daily and adjust insulin doses to optimize blood glucose control. HbAlc, insulin requirements, body weight, and parameters of the IGF-IGF-binding protein axis were assessed before and during treatment. RESULTS: All groups were comparable at baseline with respect to mean age, gender distribution, duration of diabetes, HbAlc, and BMI. Cotherapy with rhIGF-I/insulin produced a mean decrease in HbAlc of 1.2%, compared with a 0.7% decrease in HbAlc for patients receiving intensified insulin therapy alone (P < or = 0.01). Subjects receiving rhIGF-I/insulin cotherapy also decreased their daily insulin usage by 11-19%, compared with a 7% increase in insulin usage reported by the placebo group. Moreover, the incidence of hypoglycemia was similar in subjects treated with rhIGF-I/Insulin cotherapy compared with those treated with insulin alone, despite the better glycemic control of the former group. The 40/40 dose of rhIGF-I was well tolerated. Higher doses of rhIGF-I did not further improve efficacy yet were associated with unacceptable levels of adverse events, including edema, jaw pain, and early worsening of retinopathy. CONCLUSIONS: These results demonstrate that rhIGF/insulin cotherapy improves glycemic control in patients with type 1 diabetes better than optimized insulin management alone; longer-term trials would be required to determine an acceptable benefit-risk profile.

Behavior change after growth hormone treatment of children with short stature.

OBJECTIVES: To measure the prevalence of behavioral and learning problems among children with short stature and to assess the effect of growth hormone (GH) treatment on such problems. STUDY DESIGN: A total of 195 children with short stature (age range 5 to 16 years, mean age 11.2 years) were tested for intelligence, academic achievement, social competence, and behavior problems before beginning GH therapy and yearly during 3 years of treatment. Children were classified as having growth hormone deficiency (GHD) when GH responses to provocative stimuli were <10 ng/mL (n = 109) and as having idiopathic short stature (ISS) when >10 ng/mL (n = 86). A normal-statured matched comparison group was tested at the baseline only. RESULTS: Seventy-two children in the GHD group and 59 children in the ISS group completed 3 years of GH therapy and psychometric testing. Mean IQs of the children with short stature were near average. IQs and achievement scores did not change with GH therapy. Child Behavior Checklist scores for total behavior problems were higher (P < .001) in the children with short stature than in the normal-statured children. After 3 years of GH therapy these scores were improved in patients with GHD (P < .001) and ISS (P < .003). Also, there was improvement in the scores of children in the GHD group in the internalizing subscales (withdrawn: P < .007; somatic complications, P < .001; anxious/depressed, P < .001) and on the 3 components of the ungrouped subscales (attention, social problems, and thought problems, each P = .001). Larger effects were observed in the GHD group than in the ISS group. CONCLUSIONS: Many referred children with short stature have problems in behavior, some of which ameliorate during treatment with GH.

Reduced concentration of serum growth hormone-binding protein in children with idiopathic short stature. National Cooperative Growth Study.

One possible explanation for the growth failure in children with idiopathic short stature (ISS) is reduced peripheral responsiveness to GH. In Laron syndrome, growth retardation is caused by GH resistance due to GH receptor (GH-R) defects, which are associated in most cases with absent or low serum concentrations of the GH-R-related GH-binding protein (GHBP). We tested the hypothesis that some children with ISS have reduced serum concentrations of GHBP and that this may reflect decreased sensitivity to GH. A ligand-mediated immunofunctional assay was used to measure biochemically active GHBP in serum from 1549 children, including 773 controls, 573 with ISS, 107 with GH deficiency (GHD), and 96 with Turner syndrome (TS). Ages ranged from 1-17 yr. Serum GHBP concentrations in children with GHD, ISS, and TS were converted to SD scores and compared to controls by analysis of variance. In male and female ISS subjects, approximately 90% had GHBP concentrations below the age- and sex-adjusted mean for controls, and 20% had GHBP concentrations below the normal range. The mean serum GHBP SD score was lower in both males and females with GHD (-0.6) or ISS (-1.2) than in controls (both P < 0.005). The mean for ISS males was significantly lower than that for GHD males (P < 0.0001). The mean GHBP SD score for girls with TS (-0.3) did not differ significantly from that of the control females. The decreased levels of serum GHBP in some children with idiopathic short stature suggest that these children could have a defect at the level of the GH-R.

Academic achievement and psychological adjustment in short children. The National Cooperative Growth Study.

Limited information is available on the educational and behavioral functioning of short children. Through 27 participating medical centers, we administered a battery of psychologic tests to 166 children referred for growth hormone (GH) treatment (5 to 16 years) who were below the third percentile for height (mean height = -2.7 SD). The sample consisted of 86 children with isolated growth-hormone deficiency (GHD) and 80 children with idiopathic short stature (ISS). Despite average intelligence, absence of significant family dysfunction, and advantaged social background, a large number of children had academic underachievement. Both groups showed significant discrepancy (p < .01) between IQ and achievement scores in reading (6%), spelling (10%), and arithmetic (13%) and a higher-than-expected rate of behavior problems (GHD, 12%, p < .0001; ISS, 10%, p < .0001). Behavior problems included elevated rates of internalizing behavior (e.g., anxiety, somatic complaints) and externalizing behavior (e.g., impulsive, distractable, attention-seeking). Social competence was reduced in school-related activities for GHD patients (6%, p < .03). The high frequency of underachievement, behavior problems, and reduced social competency in these children suggests that short stature itself may predispose them to some of their difficulties. Alternately, parents of short, underachieving children may be more likely to seek help. In addition, some problems may be caused by factors related to specific diagnoses.

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans.

To examine the effects of repeated administration of recombinant human insulin-like growth factor-I (rhIGF-I) on IGF-I levels, free IGF-I pharmacokinetics, glycemic response, and IGF-binding proteins (IGFBP), we administered rhIGF-I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF-I, glucose, insulin, and IGFBP. Total IGF-I was measured by RIA after acid/ethanol extraction. Free IGF-I was separated from binding protein-complexed IGF-I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF-I increased significantly from 0-24 h after administration on day 1 (mean +/- SD, micrograms/L: 120 +/- 44 to 166 +/- 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 +/- 51 to 178 +/- 62) or from 0-24 h on day 5 (178 +/- 62 to 209 +/- 89). The area under the total IGF-I concentration curve was greater on day 5 than day 1 (311 +/- 99 min.g/L vs. 249 +/- 77, P = 0.0001). There were no significant differences in free IGF-I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF-I administration (day 1 baseline: 53 +/- 11 pmol/L, nadir: 18 +/- 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 +/- 15 pmol/L, nadir: 16 +/- 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30-kilodalton band which migrates in a manner similar to IGFBP-1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF-I administration, and diminished by 480-600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF-I increased the level of total circulating IGF-I without changing free IGF-I disposition or glycemic response. A 30-kilodalton IGFBP band, most likely IGFBP-1, appeared transiently following rhIGF-I administration, probably as a result of suppression of insulin levels. IGFBP-2, -3, and -4 were unaffected.

Effects of acute right ventricular ischemia on ventricular interactions during prosthetic left ventricular support.

Systolic ventricular interactions may be partially responsible for right ventricular failure that sometimes occurs during clinical use of prosthetic left ventricular assist devices. In this hypothesis, it is proposed that the left ventricular assist device reduces left ventricular pressure and its contribution to right ventricular performance, thus impairing right ventricular output. On the other hand, these effects may be small compared with other causes of right ventricular failure such as ischemia. To test the systolic interaction hypothesis in the normal and ischemic right ventricle, we used a left ventricular assist device to pressure unload the left ventricle of anesthetized pigs, and we compared its effect on right heart function before and after 2 minutes of acute right coronary artery occlusion as a model of right heart failure. Pigs were instrumented for measurements of septal to left ventricular and right ventricular free wall dimensions with ultrasonic crystals, ventricular chamber pressures, and cardiac output with a pulmonary artery blood flow probe. Without right ventricular ischemia, the left ventricular assist device produced an 80% +/- 6% reduction in left ventricular pressure-time integral while maintaining aortic pressure. This resulted in a leftward septal shift with an 11.6% +/- 1.8% decrease in left ventricular septal-to-free wall dimension and a 12.5% +/- 2.4% increase in right ventricular septal-to-free wall dimension, with no changes in right ventricular cardiac output or stroke work. In contrast, right coronary artery occlusion alone produced right heart failure, with a 50% +/- 6% reduction in right ventricular global stroke work and 26% +/- 6% and 27% +/- 3% reductions in cardiac output and right ventricular peak systolic pressure, respectively. This right heart failure persisted during left ventricular unloading with the left ventricular assist device, which resulted in further leftward septal shifting and unchanged but still depressed stroke work and flow output. These findings support the hypothesis that a preexisting pathologic condition is the dominant factor in determining right ventricular function during prosthetic left ventricular support and that direct anatomic interactions play a minor role.

Growth hormone treatment in the United States: demographic and diagnostic features of 2331 children.

Demographic, diagnostic, and baseline clinical data were collected for a large cohort (N = 2331) of children who started treatment with biosynthetic human growth hormone (GH) between October 1985 and October 1987. Eighty-one percent met classic criteria for GH deficiency and were classified as having idiopathic GH deficiency (59%), organic GH deficiency (18%), or septo-optic dysplasia (4%). The remaining 19.8% had short stature of varied causes. Height standard deviation score at diagnosis, maximum GH response to stimulation, and heights of parents were examined according to gender, race, age at diagnosis, and previous treatment history. The predominance of boys in all subgroups except septooptic dysplasia, and the observation that girls with idiopathic GH deficiency were comparatively shorter than boys at diagnosis, suggest ascertainment bias. Black children with idiopathic GH deficiency were shorter than white children at diagnosis, and their low overall representation (6.0%) compared with their percentage in the at-risk population (12.9%) also suggest ascertainment bias among races. These data provide a profile of GH deficiency as it is currently defined and expose possible inherent biases in the diagnostic process. Now that GH supply is no longer limited, criteria for its use should be formulated to avoid apparent underascertainment or late diagnosis of GH deficiency in girls and black children.

Bridge to cardiac transplantation: successful use of prosthetic biventricular support in a patient awaiting a donor heart.

A 33-year-old man with dilated cardiomyopathy was successfully "bridged" to cardiac transplantation, with the use of left and right prosthetic ventricles. The prostheses supported the pulmonary and systemic circulations for 87 h, at which time they were removed and orthotopic transplantation was performed. Heart transplantation is the only viable long-term therapy for end-stage dilated cardiomyopathy. In the case of sudden decompensation in a patient who requires cardiac transplantation, if a suitable allograft is not immediately available, a system of prosthetic ventricles can be used to provide hemodynamic support until a donor organ is located. In addition, the use of a prosthetic ventricle or ventricles does not preclude the possibility of recovery of ventricular function, an option that is removed if a total artificial heart is used.

Right ventricular function in an operating room model of mechanical left ventricular assistance and its effects in patients with depressed left ventricular function.

Approximately 20% of patients who receive left ventricular assist devices (LVADs) for refractory cardiac failure after open heart surgery have had complications of right ventricular failure. To evaluate this problem in the diseased heart we simulated an LVAD in the operating room by bypassing and unloading the left ventricle with the heart-lung machine before routine open heart surgery. Right ventricular function was assessed in 12 patients with preoperative left ventricular ejection fractions of less than 0.55 (poor left ventricular function) (mean +/- SEM 0.40 +/- 0.03) and 10 patients with ejection fractions greater than 0.55 (normal left ventricular function) (0.63 +/- 0.02). Measurements before and during left ventricular bypass in the normal left ventricular function group revealed no change in cardiac output (from 5.7 +/- 0.6 to 5.8 +/- 0.4 liters/min), with a decrease in right ventricular end-diastolic pressure (from 8 +/- 2 to 6 +/- 1 mm Hg). However, in the poor left ventricular function group, cardiac output was increased significantly during left ventricular bypass from 4.5 +/- 0.2 to 5.3 +/- 0.4 liters/min and right ventricular end-diastolic pressure was decreased significantly from 13 +/- 2 to 8 +/- 2 mm Hg. During bypass there were significant reductions in mean pulmonary arterial pressure from 17 +/- 3 to 10 +/- 2 mm Hg in the normal left ventricular function group and from 27 +/- 3 to 12 +/- 2 mm Hg in the poor left ventricular function group. These measurements reflect passive changes in pulmonary pressures due to reductions in left ventricular filling pressure during left ventricular bypass.(ABSTRACT TRUNCATED AT 250 WORDS)

Right heart function during left heart assist and the effects of volume loading in a canine preparation.

A significant fraction of patients in whom mechanical left ventricular assist devices are implanted for refractory cardiac failure after open heart surgery have had the complication of right heart failure. To evaluate the effects of left ventricular assistance and pressure unloading on right ventricular function, we performed experiments in the normal hearts of open-chest, anesthetized, large mongrel dogs. We compared right ventricular function before and after left ventricular-to-aortic bypass with a roller pump at right atrial pressure levels of 1, 3, 5, and 7 mm Hg produced by volume loading. No significant changes were found in cardiac output or stroke volume over this range of right atrial pressures when comparing that before to that during left ventricular bypass, which at a right atrial pressure of 1 mm Hg reduced peak left ventricular pressure from 96 +/- 6 to 15 +/- 9 mm Hg and at a right atrial pressure of 5 mm Hg reduced it from 113 +/- 3 to 29 +/- 12 mm Hg, while maintaining aortic pressure. There was no evidence of right ventricular failure under these conditions: (from before to during bypass) at a right atrial pressure of 1 mm Hg cardiac output was 3.4 +/- 0.4 to 3.7 +/- 0.6 liter/min and stroke volume was 28 +/- 5 to 33 +/- 6 ml; during volume loading at a right atrial pressure of 7 mm Hg cardiac output was 5.6 +/- 0.6 to 5.7 +/- 0.7 liter/min and stroke volume was 47 +/- 5 to 52 +/- 5 ml.(ABSTRACT TRUNCATED AT 250 WORDS)