Divergent metabolic phenotypes in two genetic syndromes of low insulin secretion.

AIMS: We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS). METHODS: Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP). RESULTS: Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP. CONCLUSIONS: A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.

A half-century of studies of growth hormone insensitivity/Laron syndrome: A historical perspective.

UNLABELLED: A growth hormone (GH) dependent substance responsible for sulfate uptake by costal cartilage of hypophysectomized rats, labeled sulfation factor, was reported in 1957. In 1962 the radioimmunoassay for GH was described. The clinical picture of severe GH deficiency but with high serum concentrations of GH was reported in 3 siblings in 1966 and followed by a 1968 report of 22 patients belonging to 14 consanguineous oriental Jewish families in Israel. Defective sulfation factor generation was demonstrated in 15 of these individuals and in a 1971 report; FFA response to IV GH and growth response to GH injections suggested competitive saturation of peripheral tissue receptors by an abnormal GH. However, studies published in 1973 demonstrated normal fractionation of their circulating GH, and normal binding of GH from 22 patients to various antisera used for radioimmunoassay. In 1976, the Israeli investigators reported that circulating GH from 7 patients reacted normally in the recently developed radioreceptor assay for GH. In 1984, using hepatic microsome pellets, they demonstrated that the defect was a failure of GH binding to receptors. Characterization of the human GH receptor (GHR) gene, reported in 1989, included the initial description of a genetic defect of the GHR in 2 of 9 Israeli patients. At about the same time began the identification in Ecuador of what was to become the largest population of GH insensitivity in the world, ~100 individuals, and the only substantial population with a common mutation of the GH receptor. Treatment studies with recombinant IGF-I began in 1990. Growth response was modest compared to that of GH treated GH deficient subjects. The spectrum of GH insensitivity has expanded beyond GH receptor deficiency to include postreceptor abnormalities: IGF-I gene mutation (1996); IGF-I receptor mutation (2003); signal transducer and activator of transcription 5b mutation (2003); and mutation of the GH-dependent acid labile subunit (2004). CONCLUSION: Rare conditions of GH insensitivity caused by GH receptor and postreceptor abnormalities have provided insights into the processes of growth, body composition, and metabolism.

GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity.

CONTEXT: Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity. OBJECTIVE: We sought to determine the metabolic associations for this phenomenon. DESIGN: Four studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests. SETTING: Clinical Research Institute in Quito, Ecuador. SUBJECTS: Adults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C. RESULTS: Although GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P < .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P = .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater in GHRD (P = .0004 and P = .0128, respectively), and leptin levels were lower (P = .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, their mean glucose concentrations were lower, with mean insulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar. MAIN OUTCOME MEASURES: Measures of insulin sensitivity, adipocytokines, and energy metabolites. CONCLUSIONS: Without GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels, despite higher percentage body fat, suggest that obesity-associated leptin resistance is GH dependent. Elevated adiponectin levels not correlated with percentage body fat indicate that GH signaling is necessary for their typical suppression with obesity.

Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency.

Obesity with insulin-resistant diabetes and increased cancer risk is a global problem. We consider the alterations of metabolism attendant on the underlying pathogenic overnutrition and the role of the growth hormone (GH)-IGF-1 axis in this interaction. Obesity-induced insulin resistance is a determinant of diabetes. Excess glucose, and an elevated concentration of insulin acting through its own receptors along with complex interactions with the IGF-1 system, will add extra fuel and fuel signalling for malignant growth and induce anti-apoptotic activities, permitting proliferation of forbidden clones. In Ecuador there are ~100 living adults with lifelong IGF-1 deficiency caused by a GH receptor (GHR) mutation who, despite a high percentage of body fat, have markedly increased insulin sensitivity compared with age- and BMI-matched control relatives, and no instances of diabetes, which is present in 6% of unaffected relatives. Only 1 of 20 deceased individuals with GHR deficiency died of cancer vs 20% of ~1,500 relatives. Fewer DNA breaks and increased apoptosis occurred in cell cultures exposed to oxidant agents following addition of serum from GHR-deficient individuals vs serum from control relatives. These changes were reversible by adding IGF-1 to the serum from the GHR-deficient individuals. The reduction in central regulators of pro-ageing signalling thus appears to be the result of an absence of GHR function. The complex inter-relationship of obesity, diabetes and cancer risk is related to excess insulin and fuel supply, in the presence of heightened anti-apoptosis and uninhibited DNA damage when GHR function is normal.

Sudden death of a young woman attributed to diabetic ketoacidosis.

A young woman's death at home was attributed to new onset diabetic ketoacidosis with subsequent litigation supported by several expert consultants, despite a history and postmortem findings inconsistent with this diagnosis. More thorough tissue study of the heart and analysis of the circumstances led to a credible explanation of the entire scenario.

Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects.

CONTEXT: The maximum dose of IGF-I recommended for treatment of GH insensitivity is commonly used. OBJECTIVE: The aim was to test the hypothesis that a lower dose is as effective as a high dose of IGF-I in growth promotion and has fewer deleterious effects. DESIGN AND SETTING: Subjects were treated for 3 years with regular examinations including bone age and dual energy x-ray absorptiometry and for 1 year with abdominal ultrasound studies at a clinical research institute in Quito, Ecuador. SUBJECTS: The study included 21 subjects ages 3.2-15.9 years with GH insensitivity due to the same splice site mutation on the GH receptor gene. INTERVENTIONS: Subjects were allocated to receive 120 (n = 14) or 80 (n = 7) µg/kg IGF-I twice daily. MAIN OUTCOME MEASURES: Height velocity, osseous maturation, height SD scores (SDS), body composition, abdominal organ growth, and side effects were assessed. RESULTS: There were no differences in growth velocity or height SDS increment by dosage, and the SDS increase was greater than in other reported series. Osseous maturation over 3 years with the high dose was nearly twice as rapid as with the lower dose (P < .001) and correlated with an increase in percentage body fat (r = .64; P < .001) and with adrenal size increase over 1 year (r = .32; P = .03). The ratio of bone age to height age was lower in the high-dose group after 3 years of treatment (P = .007). CONCLUSIONS: The commonly used IGF-I dosage of 120 µg/kg twice a day is excessive in comparison to a dose of 80 µg/kg twice a day, disproportionately accelerating osseous maturation, probably from the combined effects of obesity and inappropriate adrenal growth, thus likely compromising adult height potential. Moreover, the lower dose decreases direct treatment cost by one-third.

Limited joint mobility in childhood diabetes: discovery, description, and decline.

CONTEXT: The discovery of limited joint mobility (LJM) as the earliest clinically apparent complication of diabetes in children and adolescents nearly 40 years ago provided insights into the mechanism of diabetes complications. RESULTS: LJM, due to periarticular connective tissue thickening and stiffness, varied from single joint involvement bilaterally to obvious hand deformity and limitation of movement of the spine. Thick, tight, waxy skin was apparent with more severe changes; biopsy indicated thickening of the dermis and epidermis with accumulation of collagen and loss of skin appendages. Substantial growth impairment was associated with all levels of LJM. Risk for microvascular disease over a 16-year period was actuarially increased nearly 4-fold by the presence of LJM. Long-term glycemic control influenced the onset of LJM; for every unit increase in average glycated hemoglobin from onset there was a 46% increase in the risk of LJM. Between 1976-78 and 1998, the prevalence of LJM decreased from 30 to 7%, and the portion with moderate to severe changes decreased from 33 to 14%, with the disappearance of severely affected individuals. Furthermore, growth data markedly improved for those with and without LJM; 30% without LJM and 77% with LJM had been less than the 25th percentile for height, whereas the more contemporary group had 22% without LJM and 33% with LJM in this quartile. CONCLUSIONS: The elucidation of LJM as a novel and informative early complication of pediatric diabetes has provided insights into the evolution of the severe long-term complications of diabetes. The marked decrease in the frequency of LJM and statural deficit in children and youth with diabetes in the 20 years between the late 1970s and 1990s can be attributed to improved metabolic control of children and adolescents. The prevalence of LJM in a population may serve as a measure of quality of diabetes control.

Inaccuracy of age assessment from images of postpubescent subjects in cases of alleged child pornography.

Despite frequent medical expert testimony authoritatively stating that images of individuals who are postpubescent indicate age less than 18 and therefore, child pornography, developmental experts have noted that a scientific basis for such estimation is lacking. In fact, recent studies have demonstrated a high degree of inaccuracy in such estimates, and that the stage of breast development often used as indicative of age under 18 years is present in a substantial percentage of adult women. Ten images of adult women from legitimate pornographic sites promoting youthful images were shown to 16 pediatric endocrinologists expert in evaluating maturation, who determined whether or not the individuals represented were under 18 years of age. They also provided information about what features were most important in their evaluations. Sixty-nine percent of the 160 estimates were that the images represented females under 18 years of age. There was wide variability in the designation of importance of the various features of maturation in reaching conclusions, with breast development and facial appearance considered most important. This study confirms that medical testimony, even by experts in adolescent development, can deem images of adult women selected for their youthful appearance to be under age 18 two thirds of the time. Thus, important as prosecuting users of child pornographic material may be, justice requires the avoidance of testimony that is not scientifically based.

Tanner stage 4 breast development in adults: forensic implications.

BACKGROUND AND OBJECTIVE: Forensic testimony in alleged child pornography cases commonly asserts that Tanner stage (TS) 4 breast development, characterized by secondary mounding of the areola that is obliterated in TS 5, is evidence of age <18 years. Clinical experience does not support this notion, but there are no relevant studies. We sought to estimate how frequently TS 4 might be interpreted from nonclinical images by individual forensic experts. METHOD: Published images of 547 adult women were independently examined by the authors and classified as having TS 4 or TS 5 breast development. RESULTS: There was concordance among all 4 of the examiners for 17 of the images, agreement of 3 of the examiners on another 36 images, of 2 examiners on 39 images, and 53 images were designated TS 4 by only 1 examiner, for a total of 153 (26.5%) images that could have been considered by a single forensic expert to represent TS 4. CONCLUSIONS: A substantial number of adults have persistent TS 4 breast development. This observation, and the frequent difficulty distinguishing TS 4 from TS 5, even by adolescent development specialists, especially in nonclinical images, renders testimony based on this distinction invalid. Without clinical relevance for distinguishing these advanced stages of breast development, they should both be considered indicative of full maturation. Testimony based on this inappropriate test of maturity should no longer be allowed.

Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship.

OBJECTIVE: To describe the clinical and biochemical features, and perform molecular analysis for candidate abnormalities in a novel familial syndrome of intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the 5th metacarpal-phalangeal joint, and adult-onset insulin-resistant diabetes unrelated to obesity or other manifestations of metabolic syndrome (MS). DESIGN: Detailed clinical history, auxological, biochemical, radiological, and molecular studies, including DNA analysis and in vitro study of the GH/IGF1 pathway. MATERIALS AND METHODS: Ten affected adults from two generations of five related families were studied in detail, and information obtained about nine other likely affected individuals. RESULTS: Height Z-scores ranged from -7.3 to -3.8. Unaffected parents of the older generation and frequency of confirmed and suspected instances of the syndrome in the two generations studied is consistent with autosomal recessive inheritance. Insulin resistance was uniformly present in seven subjects tested who were not taking insulin. Diabetes severity did not correlate with overweight. Subjects did not have other typical manifestations of MS such as substantial hyperlipidemia, osteoporosis, or hypertension. No biochemical abnormality in the GH/IGF1 axis or molecular defect was found. CONCLUSIONS: While the association of IUGR and adult MS, including diabetes, has been well documented, these subjects did not have typical manifestations of MS. Abnormalities in common components that could result in a combination of IUGR, severe postnatal growth, and insulin resistance have been ruled out. A mutation in an unidentified gene may affect intrauterine and postnatal growth, with insulin resistance directly affected or as a result of this growth phenomenon.

Hyperprolactinemia with antipsychotic drugs in children and adolescents.

There is increasing use of antipsychotic drugs in pediatric and psychiatry practice for a wide range of behavioral and affective disorders. These drugs have prominent side effects of interest to pediatric endocrinologists, including weight gain and associated metabolic risk factors and hyperprolactinemia. The drugs block dopamine action, thus disinhibiting prolactin secretion. Hyperprolactinemia is especially prominent with first-generation antipsychotics such as haloperidol and the second-generation drugs, most commonly risperidone, with some patients developing gynecomastia or galactorrhea or, as a result of prolactin inhibition of gonadotropin releasing hormone from the hypothalamus, amenorrhea. With concern about the long-term effects of antipsychotics on bone mass and pituitary tumor formation, it is prudent to monitor serum prolactin levels in antipsychotic drug-treated pediatric patients and consider treatment with an agent less likely to induce hyperprolactinemia.