William B. Zipf

Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome

Prader-Willi syndrome is characterized by dramatic hyperphagia and morbid obesity, and is associated with a deficiency in basal and meal-stimulated serum pancreatic polypeptide (PP) levels. Intravenous infusions of pancreatic polypeptide (90 min, 50 pmol/kg/h) restored normal serum PP levels, and a regimen of morning and afternoon PP infusions was found to significantly reduce food intake in Prader-Willi subjects. Food intake was evaluated in a 60-min free-feeding test that shows high reliability and validity. Basal food intake during saline infusions was striking (approximately 60 chicken sandwich quarters), and this intake was reduced overall by approximately 12% during PP infusions. This reduction was apparent only for female subjects, and may have reflected enhanced satiation rather than an overall suppression of food intake. No differences were apparent across subjects, in either basal food intake or the PP-related decrease in food intake, in the presence or absence of the widely recognized chromosomal marker for this syndrome [deletion of 15(q11-q13)]. More specific gene defects as recently reported in these subjects, however, suggest that the Prader-Willi syndrome may represent an important model for the study of food intake regulation.

Growth Hormone Treatment of Adults with Prader-Willi Syndrome and Growth Hormone Deficiency Improves Lean Body Mass, Fractional Body Fat, and Serum Triiodothyronine without Glucose Impairment: Results from the United States Multicenter Trial

CONTEXT GH replacement in Prader-Willi syndrome (PWS) children has well-defined benefits and risks and is used extensively worldwide. Its use in PWS adults has been limited by documentation of benefits and risks, as determined by larger multisite studies. OBJECTIVES Our objective was to evaluate the effectiveness and safety of GH in GH-deficient genotype-positive PWS adults. DESIGN We conducted a 12-month open-label multicenter trial with 6-month dose-optimization and 6-month stable treatment periods. SETTING The study was conducted at outpatient treatment facilities at four U.S. academic medical centers. PATIENTS Lean and obese PWS adults with diverse cognitive skills, behavioral traits, and living arrangements were recruited from clinical populations. INTERVENTION Human recombinant GH (Genotropin) was initiated at 0.2 mg/d with monthly 0.2-mg increments to a maximum 1.0 mg/d, as tolerated. MAIN OUTCOMES MEASURES Lean body mass and percent fat were measured by dual-energy x-ray absorptiometry. RESULTS Lean body mass increased from 42.65 +/- 2.25 (se) to 45.47 +/- 2.31 kg (P < or = 0.0001), and percent fat decreased from 42.84 +/- 1.12 to 39.95 +/- 1.34% (P = 0.025) at a median final dose of 0.6 mg/d in 30 study subjects who completed 6-12 months of GH. Mean fasting glucose of 85.3 +/- 3.4 mg/dl, hemoglobin A1c of 5.5 +/- 0.2%, fasting insulin of 5.3 +/- 0.6 microU/ml, area under the curve for insulin of 60.4 +/- 7.5 microU/ml, and homeostasis model assessment of insulin resistance of 1.1 +/- 0.2 were normal at baseline in 38 study initiators, including five diabetics, and remained in normal range. Total T(3) increased 26.7% from 127.0 +/- 7.8 to 150.5 +/- 7.8 ng/dl (P = 0.021) with normalization in all subjects, including six (20%) with baseline T(3) values at least 2 sd below the mean. Mildly progressive ankle edema was the most serious treatment-emergent adverse event (five patients). CONCLUSIONS This multicenter study demonstrates that GH improves body composition, normalizes T(3), and is well tolerated without glucose impairment in PWS genotype adults.

Growth hormone treatment and adverse events in Prader–Willi syndrome: data from KIGS (the Pfizer International Growth Database)

Objective  To evaluate the response to recombinant GH treatment and adverse events in children with Prader–Willi syndrome (PWS) from KIGS, the Pfizer International Growth Database.

Predictors of First-Year Growth Response to a Fixed-dose Growth Hormone Treatment in Children Born Small for Gestational Age: Results of an Open-Label, Multicenter Trial in the United States

BACKGROUND Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

Splanchnic uptake of leucine in healthy children and in children with cystic fibrosis.

Interpretation of tracer studies of amino acid kinetics in the fed state is dependent on knowledge of splanchnic uptake of diet-derived amino acids. We studied five healthy control children and five children with cystic fibrosis (CF). After an overnight fast, the children ingested, hourly, a formula diet for 11 h. 5,5,5-[2H3]Leucine was added to the feedings during the last 6 h, and an i.v. infusion of 1-[13C]leucine was administered during the last 2 h of the formula feeding. The mean rate of splanchnic uptake of leucine was similar in the CF and control group, 23.8 ± 24.0 and 21.5 ± 21.2 µmol·kg-1·h-1, respectively. Fractional splanchnic uptake of leucine was not significantly different in the patients with CF (0.16 ± 0.112 mean ± SD) compared with the control children (0.244 ± 0.256-1). The rate of whole body protein breakdown was not significantly different between the groups (CF versus control) with (159 ± 18 versus 135 ± 28 µmol·kg-1·h-1) or without (135 ± 14 versus 114 ± 20 µmol·kg-1·h-1) correction for splanchnic leucine uptake. However, for the 10 cases combined, protein breakdown corrected for splanchnic leucine uptake (147 ± 26 µmol·kg-1·h-1) was 18% greater than uncorrected protein breakdown (124 ± 20 µmol·kg-1·h-1) (p = 0.009). The data suggest that companion studies of splanchnic uptake might enhance the interpretation of leucine kinetics in the fed state.

Pancreatic Polypeptide: Identification of Target Tissues Using an In Vivo Radioreceptor Assay

The definitive function of pancreatic polypeptide in mammalian physiology remains unknown. The identification of specific PP target tissues should be helpful to further investigations into the possible regulatory actions of this peptide. An in vivo radioreceptor assay was used in the rat to locate potential binding sites of I(125) bovine PP. In vitro, high concentrations of unlabeled hormone competitively inhibit binding to receptors by low concentrations of labeled hormone. In vivo studies showed that, in the presence of concentrated unlabeled pancreatic polypeptide, labeled PP distributes between the plasma and interstitial fluid. When excess unlabeled PP is replaced with saline in the companion animals, the labeled peptide appears to distribute in a volume that exceeds the combined plasma volume and interstitial fluid volume of the tissue. Using this in vivo receptor assay, the distribution volume that exceeds the anatomic extracellular volume has been identified as the receptor compartment. With this assay we demonstrated in the rat specific and displaceable PP binding to the ductus choledochus, duodenum, ileum, and adrenal gland. The NVV determined in the adrenal gland of experimental animals was 3.9 times greater than that found in the control group. Binding was rapid and was displaced only by excess unlabeled pancreatic polypeptide. Neither excess insulin nor excess neuropeptide Y significantly reduced this binding.

EFFECTS OF SPLANCHNIC UPTAKE (SU) OF LEUCINE (LEU) ON THE MEASUREMENT OF WHOLE BODY PROTEIN BREAKDOWN (B) IN HEALTHY CHILDREN (HC) AND IN CHILDREN WITH CYSTIC FIBROSIS (CF). † 710

EFFECTS OF SPLANCHNIC UPTAKE (SU) OF LEUCINE (LEU) ON THE MEASUREMENT OF WHOLE BODY PROTEIN BREAKDOWN (B) IN HEALTHY CHILDREN (HC) AND IN CHILDREN WITH CYSTIC FIBROSIS (CF). † 710

458 BLUNTED PANCREATIC POLYPEPTIDE RESPONSES IN CHILDREN WITH OBESITY OF PRADER-WILLI SYNDROME

Pancreatic polypeptide (PP) has been shown to mitigate the hyperphagia of genetically obese mice. These animals have low concentrations of PP. Patients with Prader-Willi Syndrome (P-W,S) are characterized by obesity and hyperphagia. Serum levels of PP, glucose, insulin and gastroinhibitory polypeptide (GIP) were obtained at 15 min. intervals for 180 min. after a 300 calorie meal in 7 pts with P-W,S and were compared to responses obtained in 10 normal and 13 obese controls. P-W,S had a mean (X) age of 12.3 years (y) (range 7-16Y) and a X body weight (wt) 230% of ideal. Obese controls had a X age of 30.5y (17-44y) and a X body wt 200% of ideal. Normal controls had a X age of 34.ly (19-64y) and X body wt 106% of ideal. Basal and peak responses of glucose, insulin and GIP for pts with P-W,S were slightly but significantly less when compared to normal or obese controls. No significant differences in basal or peak PP responses were noted between normal and obese controls (basal, 103±30 vs 111±19: peak, 561±140 vs 603±107 pg/ml, X ± SE). All 7 pts with P-W,S had abnormal PP responses. Five failed to show significant PP release after the stimulation; one had a peak response to 130 pg/ml while the 7th pt had a supernormal response to > 2000 pg/ml. The 6 pts with low or no response had basal PP values of 62±12 pg/ml and a X peak response of 78±15 pg/ml. This observation of blunted PP response in a human model of hyperphagia and obesity suggests that PP may have a significant role in appetite control.