The mRNA-Binding Protein IGF2BP1 Restores Fetal Hemoglobin in Cultured Erythroid Cells from Patients with ß-Hemoglobin Disorders.

Sickle cell disease (SCD) and ß-thalassemia are caused by structural abnormality or inadequate production of adult hemoglobin (HbA, α2ß2), respectively. Individuals with either disorder are asymptomatic before birth because fetal hemoglobin (HbF, α2γ2) is unaffected. Thus, reversal of the switch from HbF to HbA could reduce or even prevent symptoms these disorders. In this study, we show that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is one factor that could accomplish this goal. IGF2BP1 is a fetal factor that undergoes a transcriptional switch consistent with the transition from HbF to HbA. Lentivirus delivery of IGF2BP1 to CD34+ cells of healthy adult donors reversed hemoglobin production toward the fetal type in culture-differentiated erythroid cells. Analogous studies using patient-derived CD34+ cells revealed that IGF2BP1-dependent HbF induction could ameliorate the chain imbalance in ß-thalassemia or potently suppress expression of sickle ß-globin in SCD. In all cases, fetal γ-globin mRNA increased and adult ß-globin decreased due, in part, to formation of contacts between the locus control region (LCR) and γ-globin genes. We conclude that expression of IGF2BP1 in adult erythroid cells has the potential to maximize HbF expression in patients with severe ß-hemoglobin disorders by reversing the developmental γ- to ß-globin switch.

Pupillometry shows the effort of auditory attention switching.

Successful speech communication often requires selective attention to a target stream amidst competing sounds, as well as the ability to switch attention among multiple interlocutors. However, auditory attention switching negatively affects both target detection accuracy and reaction time, suggesting that attention switches carry a cognitive cost. Pupillometry is one method of assessing mental effort or cognitive load. Two experiments were conducted to determine whether the effort associated with attention switches is detectable in the pupillary response. In both experiments, pupil dilation, target detection sensitivity, and reaction time were measured; the task required listeners to either maintain or switch attention between two concurrent speech streams. Secondary manipulations explored whether switch-related effort would increase when auditory streaming was harder. In experiment 1, spatially distinct stimuli were degraded by simulating reverberation (compromising across-time streaming cues), and target-masker talker gender match was also varied. In experiment 2, diotic streams separable by talker voice quality and pitch were degraded by noise vocoding, and the time alloted for mid-trial attention switching was varied. All trial manipulations had some effect on target detection sensitivity and/or reaction time; however, only the attention-switching manipulation affected the pupillary response: greater dilation was observed in trials requiring switching attention between talkers.

Psychosocial correlates of continuous glucose monitoring use in youth and adults with type 1 diabetes and parents of youth.

BACKGROUND: Continuous glucose monitoring (CGM) has been shown to improve glycemic control and reduce hypoglycemia with consistent use. Youth, however, are unlikely to use CGM consistently. We compared psychological characteristics of youth with type 1 diabetes, their parents, and adults with type 1 diabetes randomized to CGM or standard blood glucose monitoring (BGM). This study was an ancillary study, and participants completed the questionnaires at the 6-month visit of the main study. SUBJECTS AND METHODS: Participants enrolled at a single site of the Juvenile Diabetes Research Foundation CGM trial completed questionnaires and provided diabetes management data. Participants were randomized to the CGM or BGM group for 6 months. RESULTS: Parents in both groups reported more fear of hypoglycemia than youth in the corresponding groups. CGM youth and parents reported more negative affect around BGM than those in the BGM group. CGM youth reported more trait anxiety than BGM youth, whereas CGM adults reported less state and trait anxiety than BGM adults. CGM parent-proxy report of depression was significantly higher than that reported by BGM parents. CONCLUSIONS: Youth, their parents, and adults report different psychological impacts of CGM use. In some groups and with some variables, CGM use was associated with a positive psychosocial impact, whereas in others CGM use was associated with a negative psychosocial impact. Future research should explore the psychological consequences of CGM use.

Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene.

BACKGROUND/AIMS: Circulating growth hormone-binding protein (GHBP), in humans, is the proteolytic product of the growth hormone receptor (GHR). We investigated a prepubertal male subject who was of short stature, but who had a markedly elevated serum level of GHBP. METHODS: Serum and DNA from the patient and his mother were analyzed. RESULTS: Both the patient and mother had serum GHBP concentrations over 100-fold higher than normal, by assays, and Western and ligand blot analysis. Sequencing of the GHR gene revealed a novel heterozygous C>A transversion at position 785-3 in the acceptor splice site of intron 7. CONCLUSION: In silico analysis of the altered sequence suggested that 785-3(C>A) is a splicing mutation, with either retention of intron 7 or the skipping of exon 8. The consequence is a truncated GHR lacking the transmembrane domain (encoded by exon 8) and the cytoplasmic domain. We hypothesize that this GHR variant cannot anchor to the cell membrane, and the continual secretion into the circulation explains the elevated levels of serum GHBP detected in the patient and his mother. Despite this mutation, the presence of the wild-type GHR allele, presumably, permits some normality in GH-induced action.

Growth hormone (GH) insensitivity and insulin-like growth factor-I deficiency in Inuit subjects and an Ecuadorian cohort: functional studies of two codon 180 GH receptor gene mutations.

CONTEXT: Among more than 250 cases of GH insensitivity syndrome (GHIS) reported to date, the largest cohort was identified in southern Ecuador. In the Ecuadorian GHIS cohort, a sense mutation (GAA>GAG) at codon E180 of GH receptor [GHR (E180sp)] results in deletion of codons 181-188. No functional studies of this mutation have been performed, nor have different mutations at codon 180 been reported. OBJECTIVE: We now report identification of a novel GHR mutation, also within codon E180, in two distantly related GHIS subjects of Inuit origin and provide mechanistic insights into the defects caused by the Inuit and Ecuadorian GHR mutations. PATIENTS: The two Inuit subjects, with heights of -5 sd score and -7 sd score, respectively, had elevated circulating levels of GH but low levels of GH-binding protein, IGF-I, and IGF-binding protein-3. RESULTS: Both Inuit subjects carry the same novel nonsense homozygous GHR mutation at codon E180 (GAA->TAA, E180X). In vitro reconstitution experiments demonstrated that GHR (E180sp), but not GHR (E180X), could be stably expressed. GHR (E180sp), however, could not bind GH and could neither activate signal transducer and activator of transcription-5b nor induce -5b-dependent gene expression on GH treatment. Furthermore, the GHR (E180sp), which has a deletion of eight amino acid residues within the GHR dimerization domain, although retaining the ability to homodimerize, was defective in trafficking to the cell surface. CONCLUSIONS: The E180X mutation identified in two Inuit patients resulted in a truncated, unstably expressed GHR variant, whereas the E180 splicing mutation previously identified in the Ecuadorian cohort, affected both GH binding and GHR trafficking and rendered the abnormal GHR nonfunctional.

Primary growth hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene: genetic and functional studies of simple and compound heterozygous states.

CONTEXT: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. OBJECTIVE: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. PATIENTS: Patient 1 [height, -4.8 sd score (SDS)] and patient 2 (height, -5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (-5.0 SDS and -2.6 SDS, respectively) and IGF-binding protein-3 (-2.6 SDS and -2.0 SDS, respectively). RESULTS: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). CONCLUSIONS: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25).

IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [S(i)] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [K(ITT)] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S(i) and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S(i), sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans.

Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure.

CONTEXT: Primary IGF deficiency (IGFD) describes the condition in which serum concentrations of IGF-I are low in the face of normal to elevated GH production. Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans. OBJECTIVE: We investigated a case of IGFD in which serum IGF-I and IGFBP-3 were abnormally low, yet growth failure was modest (-2.1 sd score at 15.5 yr of age). RESULTS: The young male subject, from a consanguineous pedigree, had a postnatal growth profile consistently below the third percentile. The subject had a normal fasting GH level of 3.7 muU/ml and normal serum GH binding protein level (1258 pmol/liter; normal range 431-1892 pmol/liter), but serum IGF-I and IGFBP-3 were profoundly reduced (-5.8 and -7.2 sd score, respectively, at age 12.3 yr), even through puberty. A novel homozygous missense mutation was subsequently identified in the ALS gene, which resulted in severe deficiency of serum ALS (undetectable). CONCLUSIONS: ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.

Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b.

CONTEXT: The central clinical feature of GH insensitivity (GHI) is severe growth failure associated with elevated serum concentrations of GH and abnormally low serum levels of IGF-I. GHI can be the result of an abnormality in the GH receptor or aberrancies downstream of the GH receptor. OBJECTIVE: We investigated the GH-IGF-I axis in a young female GHI subject who presented with a height of 114 cm (-7.8 sd score) at age 16.4 yr. PATIENT: The subject, from a consanguineous pedigree, had circulating levels of GH and GH-binding protein that were normal to elevated, whereas IGF-I (7.2 ng/ml; normal, 242-600), IGF-binding protein-3 (543 ng/ml; normal, 2500-4800), and acid-labile subunit (1.22 microg/ml; normal, 5.6-16) levels were abnormally low and failed to increase during an IGF-I generation test. DESIGN: Dermal fibroblast cultures were established with the consent of the patient and family. Immunoblot analysis of cell lysates and DNA sequencing of her signal transducer and activator of transcription 5b (STAT5b), a critical intermediate of the GH-IGF-I axis, were performed. RESULTS: Sequencing of the STAT5b gene revealed a novel homozygous insertion of a single nucleotide in exon 10. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein. CONCLUSION: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.

Semantic feature knowledge and picture naming in dementia of Alzheimer's type: a new approach.

This study addresses continuing controversies concerning the nature of semantic impairment in early dementia of the Alzheimer type (DAT), and the relationship between conceptual knowledge and picture naming. A series of analyses of fine-grained feature knowledge data show that: (1) distinctive features of concepts were more vulnerable than shared; (2) the amount of attribute knowledge about a concept was associated reliably, and in a graded fashion, with the ability to name a picture of that item; (3) sensory features were differentially important in naming; and (4) the degree of disruption to different types of attribute knowledge did not vary between items from living and nonliving domains. These findings are discussed in the context of contemporary cognitive and computational models of semantic memory organisation.

Identification of the first patient with a confirmed mutation of the JAK-STAT system.

Growth hormone insensitivity (GHI) has been attributable, classically, to mutations in the gene for the GH receptor. After binding to the GH receptor, GH initiates signal transduction through a number of pathways, including the JAK-STAT pathway. We describe the first patient reported with a mutation in the gene for STAT5b, a protein critical for the transcriptional regulation of insulin-like growth factor-I.

Inconceivable? Deducting the costs of fertility treatment.

This Article considers whether infertile taxpayers can deduct their fertility treatment costs as medical expenses under Internal Revenue Code section 213 and whether they should be able to deduct them. Internal Revenue Code section 213 defines medical expenses as "amounts paid-for the diagnosis, cure, mitigation, treatment, or prevention of disease, or for the purpose of affecting any structure or function of the body." This definition is interpreted by reference to a baseline of normal biological functioning, which includes reproductive functioning. Most people conceive and bear children without having to incur expenses for fertility treatment. Expenses incurred to approximate the baseline of normal reproductive health are deductible, even if the taxpayer winds up better off, with a child, after the fertility treatment. The medical profession recognizes that infertility is a disease or condition. Infertility is a loss, just as a broken leg is a loss. Fertility treatment costs are thus medical expenses under section 213. In addition, given the existence of the medical expense deduction, taxpayers should be able to deduct the cost of fertility treatments, including IVF, egg donor, and surrogate procedures, under either an "ability-to-pay" or consequentialist normative approach. Reproduction is extremely important to most people. In addition, allowing taxpayers to deduct the costs of fertility treatment will encourage infertile taxpayers to elect the most effective treatment option and reduce the rate of risky multifetal pregnancies. This Article concludes that fertility treatment costs are deductible as medical expenses under current law and should be deductible as medical expenses.

Growth hormone insensitivity resulting from post-GH receptor defects.

Biochemical analysis indicates that the STAT-5b mutation affects signaling by both growth hormone (GH) and gamma-interferon. A patient with such a mutation thus manifests two new clinical disorders: (1) growth hormone insensitivity (GHI), which results from a post-receptor defect in GH signaling and (2) a new form of primary immunodeficiency. Given that the GH receptor is a member of the hematopoietin-receptor family, it seems reasonable to predict that additional cases of defects in GH signaling will be identified. The predicted phenotype would be GHI combined with defects in the immune system.

Reproducibility in patterns of IGF generation with special reference to idiopathic short stature.

BACKGROUND/AIM: Insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) generation tests are both sensitive and specific measures of growth hormone (GH) sensitivity. Recently, the question of reproducibility of IGF generation tests has been raised. We report our analysis of the correlation of low- and high-dose GH IGF-I and IGFBP-3 generation tests among patients with GH deficiency, GH insensitivity, and idiopathic short stature. METHODS: A total of 198 subjects were randomized to either high- or low-dose GH for 7 days; the alternate dose was received after a 2-week washout period. Samples were collected at baseline and on days 5 and 8 of GH administration. RESULTS: The serum concentrations of IGF-I and IGFBP-3 correlated significantly from one test to the other, regardless of the diagnosis. In normal subjects and patients with GH insensitivity and GH deficiency, the delta over baseline in IGF-I and IGFBP-3 in the low-dose test was highly predictive of the delta values in the high-dose test. The delta correlation was greatly diminished, however, in the patient population having idiopathic short stature. CONCLUSIONS: These observations support partial GH insensitivity effecting IGF-I generation specifically, as a possible etiology for idiopathic short stature, and thus such patients may warrant appropriate biochemical and/or molecular evaluation for partial GH insensitivity.

The impact of disrupted cortico-cortico connectivity: a long-term follow-up of a case of focal retrograde amnesia.

We report a long-term follow-up study of case JM, who demonstrated a focal retrograde amnesia (FRA) as a consequence of cerebral vasculitis. The present study showed that, several years post-onset, JM experienced considerable impairment in episodic retrograde memory, with normal anterograde autobiographical memory. Further investigations demonstrated that she showed no evidence of accelerated forgetting, unlike some other cases of FRA. Knowledge of people, pre- and post-illness, was also normal. Her ability to recall details of famous public events was good (though weaker for pre-illness events). JM's pattern of impairment is discussed in the context of other recent cases of FRA and developments in models of normal memory function.

Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by severe obesity, hyperphagia, hypogonadism, and GH deficiency. Unlike individuals with common obesity, who have low fasting-plasma ghrelin concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Treatment with octreotide, a somatostatin agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. This pilot study was performed to determine whether octreotide administration (5 microg/kg.d) for 5-7 d lowers ghrelin concentrations and affects body composition, resting energy expenditure, and GH markers in children with PWS. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P < 0.05). Meal-related ghrelin suppression (-35%; P < 0.001) was still present after intervention but was blunted (-11%; P = 0.19). Body weight, body composition, leptin, insulin, resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. In conclusion, short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. Further investigation is warranted to determine whether long-term octreotide treatment causes sustained ghrelin suppression, changes eating behavior, and induces weight loss in this population.

Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome.

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.

Leptin concentrations in GH deficiency: the effect of GH insensitivity.

Disorders of GH secretion are known to impair the physiological lipostat and to affect the secretion of leptin, a sensitive marker of regional fat accumulation and total body composition. In both children and adults with GH deficiency (GHD), leptin levels are increased proportionately with enhanced adiposity. In GHI, mutations of the GH receptor gene result in a phenotype similar to GHD, with increased adiposity and unfavorable lipid profiles. To examine the impact of different forms of growth disorders on leptin production, we measured leptin levels in 22 GHI patients homozygous for the E180 splice mutation (15 females and 7 males, aged 8-37 yr) and compared results with those obtained in 20 subjects heterozygous for the mutation (11 females and 9 males, aged 7-54), 17 idiopathic GHD patients (6 females and 11 males, aged 3-34), and 44 normal subjects (25 females and 19 males, aged 7-45). After the baseline evaluation, all subjects received two 7-d GH treatments at doses of 0.025 and 0.050 mg/kg x d in random order. Leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3) were assayed by specific immunoassays. IGF-I and IGFBP-3 levels were significantly lower (P < 0.0001) in homozygous GHI and GHD patients compared with either controls or GHI heterozygotes. Circulating leptin levels were significantly higher in homozygous GHI patients than in normal controls (20.7 +/- 4.2 vs. 8.7 +/- 1.4 microg/liter) as well as when compared with heterozygous GHI subjects (14.4 +/- 3.4 microg/liter) and GHD patients (9.8 +/- 1.6 microg/liter; P < 0.01). Similar results were obtained when leptin was normalized for body mass index. When subjects were subgrouped by gender, leptin levels were significantly higher (P < 0.05) in GHI females than in females of all other groups and were significantly increased in GHD males (P < 0.01 vs. control males). Within the study groups, females had significantly higher leptin levels than males in controls (12.7 +/- 2 vs. 3.3 +/- 1 microg/liter; P < 0.001) and homozygous GHI patients (28.7 +/- 5.3 vs. 6.9 +/- 2.3 microg/liter; P < 0.05), but not in heterozygous GHI (20.1 +/- 5.4 vs. 7.3 +/- 2.4 microg/liter; P < 0.06) and GHD (10.9 +/- 2.6 vs. 9.2 +/- 2.1 microg/liter) patients. By multivariate analysis, log-normalized leptin levels were best predicted by gender and body mass index in homozygous GHI patients as well as in normal subjects. During the 1-wk courses of GH therapy, serum IGF-I and IGFBP-3 levels significantly increased (P < 0.0001) in GHD patients, heterozygous GHI patients, and control subjects at both GH doses. Inversely, leptin levels did not change significantly during either course of GH administration in the groups examined. These data demonstrate that leptin is increased in patients affected with long-standing homozygous GHI, probably reflecting abnormalities of body composition and metabolism typical of this condition.