Serum ghrelin concentrations are increased in children with growth hormone insensitivity and decrease during long-term insulinlike growth factor-I treatment.

BACKGROUND: Ghrelin increases food intake, body weight, and growth hormone (GH) secretion. Serum concentrations of ghrelin are low in obese hyperinsulinemic persons, are reduced by infusion of insulin into normal-weight subjects, and are increased in underweight hypoinsulinemic patients with anorexia nervosa. Laron syndrome is an autosomal recessive disorder of GH insensitivity that results in decreased insulinlike growth factor-I (IGF-I) synthesis and growth failure. These patients have elevated GH levels, excess adipose tissue, and are insulin resistant. Because IGF-I has insulinlike actions and patients with GH insensitivity syndrome (GHIS) exhibit excess adiposity, we sought to determine whether ghrelin levels were elevated in these patients and potentially regulated by IGF-I replacement. METHODS: Thirteen children with GHIS and 20 normal control children matched for age, sex, and body mass index underwent complete physical examination and a fasting blood draw at baseline. The GHIS subjects then underwent follow-up fasting blood draws during therapy with human recombinant IGF-I (80-120 mug/kg, given subcutaneously twice daily). Fasting glucose, insulin, and IGF-I concentrations were measured at the time of collection. Fasting total ghrelin levels were measured on stored serum samples. RESULTS: The GHIS subjects had 2-fold higher fasting ghrelin levels (2926 +/- 1869 pg/mL) compared with the normal control children (1492 +/- 493 pg/mL; P = 0.009), and mean ghrelin values were reduced 56% during 6.4 +/- 0.2 years of IGF-I replacement (P < 0.05). CONCLUSIONS: Growth hormone resistance and low IGF-I levels are associated with elevated ghrelin levels, which may potentiate GH secretion and adiposity in these children. Suppression of ghrelin during IGF-I treatment suggests a novel mechanism potentially regulating ghrelin levels.

Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity.

CONTEXT: Children with severe IGF-I deficiency due to congenital or acquired defects in GH action have short stature that cannot be remedied by GH treatment. OBJECTIVES: The objective of the study was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency. DESIGN: Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design. SETTING: The study was conducted at general clinical research centers and with collaborating endocrinologists. SUBJECTS: Entry criteria included: age older than 2 yr, sd scores for height and circulating IGF-I concentration less than -2 for age and sex, and evidence of resistance to GH. INTERVENTION: rhIGF-I was administered sc in doses between 60 and 120 microg/kg twice daily. MAIN OUTCOME MEASURES: Height velocity, skeletal maturation, and adverse events were measured. RESULTS: Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%). CONCLUSIONS: Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.

A novel mutation (E767K) in the second extracellular loop of the calcium sensing receptor in a family with autosomal dominant hypocalcemia.

Autosomal dominant hypocalcemia resulting from gain-of-function mutations of the calcium sensing receptor (CASR) is a rare familial disorder that can become evident at any age. We report a novel mutation (E767K) of the CASR in a family with autosomal dominant hypocalcemia. Ten members of the family had a history of hypocalcemia. The index case exhibited marked hypocalcemia and seizures in the newborn period, while her father who also has hypocalcemia, was largely asymptomatic except for a myocardial infarction-like event at 21 years of age, a new presentation of the disorder. The E767K mutation, which resides in the second extracellular loop adjacent to the fifth transmembrane domain, co-segregated with hypocalcemia in these two individuals. Both subjects are heterozygous for the mutation. The proband is also heterozygous for the previously reported CASR polymorphism of G990R in the intracellular domain, while her father is homozygous. The co-segregation of this naturally occurring mutation with autosomal dominant hypocalcemia supports the previously reported experimental model in which it was proposed that the three acidic residues (767, 758, and 759) in exo-loop 2 in CASR help maintain an inactive conformation of the receptor.

Role of the insulin-like growth factor I decline in the induction of atrogin-1/MAFbx during fasting and diabetes.

In catabolic conditions, atrogin-1/MAFbx, a muscle-specific ubiquitin-ligase required for muscle atrophy, is increased, and concentrations of IGF-I, a growth factor known to have antiproteolytic action, are reduced. To define the relationship between the decline in IGF-I and the induction of atrogin-1/MAFbx, we studied the effect of IGF-I replacement on atrogin-1/MAFbx mRNA in rats fasted for 51 h and in rats made diabetic with streptozotocin (STZ). Fasting produced a 5.8-fold increase in atrogin-1/MAFbx (P < 0.001). This was attenuated to a 2.5-fold increase by injections of IGF-I (P < 0.05 vs. fasting). Animals with STZ-induced diabetes experienced a 15.1-fold increase in atrogin-1/MAFbx (P < 0.001). Normalization of their circulating IGF-I concentrations by IGF-I infusion blunted the induction of atrogin-1/MAFbx to 6.3-fold (P < 0.05 vs. STZ diabetes without IGF-I). To further delineate the regulation of atrogin-1/MAFbx by IGF-I, we studied a model of cultured muscle cells. We observed that IGF-I produced a time- and dose-dependent reduction of atrogin-1/MAFbx mRNA, with a 50% effective dose of 5 nm IGF-I, a physiological concentration. The degradation rate of atrogin-1/MAFbx mRNA was not affected by IGF-I, suggesting that the reduction of atrogin-1/MAFbx mRNA by IGF-I is a transcriptional effect. Exposure of muscle cells in culture to dexamethasone increased atrogin-1/MAFbx mRNA with a 50% effective dose of 10 nm, a pharmacological concentration. In the presence of dexamethasone, IGF-I at physiological concentrations retained its full inhibitory effect on atrogin-1/MAFbx mRNA. We conclude that IGF-I inhibits atrogin-1/MAFbx expression and speculate that this effect might contribute to the antiproteolytic action of IGF-I in muscle.

Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome.

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an autosomal recessive disorder characterized by diabetes mellitus (DM), progressive sensorineural deafness, and thiamine-responsive anemia. Mutations in the SLC19A2 gene encoding a high-affinity thiamine transporter protein THTR-1 are responsible for the clinical features associated with TRMA syndrome. We report an African-American female with TRMA-syndrome associated with thyroid disease and retinitis pigmentosa caused by a novel mutation in the SLC19A2 gene. The patient presented at 12 months of age with paroxysmal atrial tachycardia and hepatosplenomegaly. One month later, she developed DM requiring intermittent insulin therapy. At 2-1/2 years of age, profound sensorineural hearing loss was discovered. By 4 years of age, daily insulin therapy (0.5 U/kg/day) was instituted and her insulin requirement gradually increased to 1.0 U/kg/day by 9 years of age. She developed optic atrophy, retinitis pigmentosa, and visual impairment by 12 years of age with severe restriction of peripheral vision by 16 years. At age 19, a thiamine-responsive normocytic anemia was discovered. She was diagnosed with autoimmune thyroiditis at 20 years and she experienced a psychotic episode associated with a mood disorder at age 21. With oral thiamine therapy, her insulin requirement decreased by 30% over a 20 month period. Molecular analysis revealed that the patient is homozygous for a missense mutation (C152T) in exon 1 of the SLC19A2 gene.

Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study.

GH replacement therapy has been shown to improve abnormalities in body composition, bone mineral density (BMD), lipid profile, and other changes resulting from GH deficiency (GHD) in adults. There is, however, need to determine appropriate dosing in young adults who were treated for GHD as children, to bridge the interval between childhood (in which relatively high doses are used) and older adulthood (in which only lower doses are tolerated). This multicenter, randomized, double-blind, placebo-controlled study compares the safety and efficacy of two doses of GH (25 and 12.5 microg/kg.d) with placebo, maintained for 2 yr, in adults with GHD who were treated as children and were off GH for at least 1 yr (mean, 5.6 yr). The 64 treated subjects were less than 35 yr of age (mean, 23.8 yr) and had maximum serum GH responses, on retesting less than 5 microg/liter (mean, 0.7 micro g/liter). At baseline, 22% had spine BMD below -2 SD, 59% were overweight or obese, and 45% had serum total cholesterol more than 200 mg/dl. A significant dose response was seen for percent increase in spine BMD at 24 months (mean of 1.3%, 3.3%, and 5.2% in the placebo, 12.5-, and 25- microg/kg.d groups, respectively, P = 0.018). Both GH-treated groups had similar changes in body composition at 6 months (decreased fat mass, increased lean mass); however, some gains were subsequently lost in the lower dose group. A significant decrease in low-density lipoprotein cholesterol was seen only in the higher GH dose group. Significant changes were not observed in quality of life and echocardiographic measures. The groups were similar with regard to adverse events and laboratory measurements, except for a higher incidence of edema in the GH-treated groups. We conclude that this dose-response study confirms the benefits of GH-replacement therapy in GHD adults and indicates that, to achieve treatment goals in younger adults, higher doses may be needed than those generally used in older adults.

Divergent regulation of proteasomes by insulin-like growth factor I and growth hormone in skeletal muscle of rats made catabolic with dexamethasone.

Insulin-like growth factor I (IGF-I) and growth hormone (GH) exert their anabolic actions by increasing protein synthesis, but only IGF-I has been reported to impede protein breakdown. Using a model of myofibrillar catabolism produced by dexamethasone (Dex) we have reported that IGF-I down-regulates Dex-induced mRNAs for Ubiquitin (Ub) and Ub-conjugating enzymes (E2) in skeletal muscle, whereas GH had no significant effect. In the present study, we used the same model to determine whether IGF-I (0.35 mg/100 g BW) and/or GH (0.3 mg/100 g BW) have effects on proteasome subunit mRNAs in skeletal muscles of rats treated with Dex (0.5 mg/100 g BW) for 3 days. Dex caused significant increases in C-2, -3, and -8 proteasome subunit mRNAs (6.0-, 4.0-, and 6.6-fold increases, respectively). Injections of IGF-I in Dex-treated animals caused significant suppression of transcripts for C-2, -3, and -8 (32%, 42%, and 40%, respectively). GH restored the serum IGF-I levels in Dex treated animals, but caused further increases in proteasome subunit mRNAs (C-2, 35%; C-3, 34.5%; C-8, 33%; C-6, 42%; C-5, 32%; C-9, 37%). Administration of IGF-I in the Dex/GH-treated animals decreased the mRNAs of proteasome subunits in a manner and degree similar to those observed in the Dex/IGF-I group. Surprisingly, injection of GH alone in normal animals increased proteasome subunit mRNAs in skeletal muscle (C-2, 85%; C-3, 109%; C-8, 91%). This effect of GH on proteasome subunit mRNAs was also observed in liver. These findings suggest, therefore, that suppression of Dex-induced expression of proteasome subunit mRNAs in skeletal muscle is one of the mechanisms by which IGF-I exerts its antiproteolytic activity in catabolic states. On the other hand, the biological function of GH in regulating proteasome subunits needs further investigation.

Hepatic reduction of insulin-like growth factor (IGF)-I and IGF binding protein-3 that results from fasting is not attenuated in genetically obese rats.

Fasting or caloric restriction causes substantial reductions in serum IGF-I in normal weight humans and animals, and reductions of liver IGF-I and IGFBP-3 mRNAs in animals. Obese humans, however, have attenuated and delayed decrements in IGF-I in serum when subjected to caloric restriction. Obese Zucker rats show a clear tendency to preserve body protein during fasting. To determine whether obesity opposes the effects of fasting on IGF-I and IGFBP-3, and thereby contributes to preservation of lean tissue, we have examined the effect of 72 h of fasting on IGF-I and IGFBP-3 in lean and obese Zucker rats. We observe that between lean and obese animals, fasting for 72 h produces similar decrements in body weight, serum IGF-I, liver IGF-I mRNA, serum IGFBP-3 and liver IGFBP-3 mRNA. Our finding that the reduction of IGF-I and IGFBP-3 in liver that results from 72 h of fasting is not attenuated in obese Zucker rats raises the possibility that conservation of lean tissue in these animals during fasting is not related to the hepatic production of IGF-I and IGFBP-3.

Primary growth hormone insensitivity syndrome - A case reporte

Aproximadamente 230 casos da síndrome de insensibilidade ao GH (síndrome de Laron) foram descritos até o presente, e destes, dois o foram no Brasil. Esta síndrome caracteriza-se por achados clínicos de deficiência severa de hormônio do crescimento, associados à níveis séricos elevados de GH. Estamos relatando o terceiro paciente brasileiro, o primeiro do mundo com descendência portuguesa, que se apresentou com quadro clínico e laboratorial típicos da doença.