Assessing insulin sensitivity and resistance in syndromes of severe short stature.

Individuals affected with two genetic syndromes identified in Ecuador have severe short stature and diminished insulin secretion, along with essentially different GH counterregulatory effects on insulin action, which leads to the appearance of opposing metabolic phenotypes. In the case of Laron syndrome, subjects have enhanced insulin sensitivity and diminished incidence of type 2 diabetes mellitus. In the other clinical entity, individuals have innate insulin resistance, a varying degree of carbohydrate metabolism disturbances, glucose intolerance, and eventually insulin-resistant diabetes mellitus. Since both groups have diminished insulin secretion, the standard homeostatic minimal models for assessment of insulin sensitivity and resistance were used to see if they could properly identify the metabolic status, especially considering that these methodologies are simple and non-invasive procedures. METHODS: Fasting insulin concentrations, fasting glucose/fasting insulin ratio and various minimal models were determined in individuals from the two syndromic cohorts, as well as in a control group made of first-degree normal relatives of the insulin-resistant phenotype subjects. RESULTS: The metabolic characteristics of enhanced insulin sensitivity in one of the syndromes and innate insulin resistance in the other could not be properly ascertained by the selected methodology. Furthermore, results were confusing and even discrepant with the clinical findings. CONCLUSIONS: The standard homeostatic minimal models could not properly identify or discriminate insulin sensitivity and resistance in subjects with inherently diminished secretion. It is thereby suggested that these models should be used with caution in clinical situations where reduced secretion of the metabolic peptide is found or suspected.

Whole exome sequencing in a child with acute disseminated encephalomyelitis, optic neuritis, and periodic fever syndrome: a case report.

BACKGROUND: Acute disseminated encephalomyelitis is generally preceded by an infection, and it is usually self-limiting and non-recurrent. However, when there are multiple attacks of acute disseminated encephalomyelitis followed by optic neuritis, it is defined as acute disseminated encephalomyelitis-optic neuritis. To the best of our knowledge, there are no previous reports of acute disseminated encephalomyelitis and optic neuritis preceded by autoinflammation, triggered by periodic fever syndrome. We report on a case of acute disseminated encephalomyelitis with optic neuritis and periodic fever syndrome in a 12-year-old Ecuadorian Hispanic boy with several relapses over the past 10 years, always preceded by autoinflammatory manifestations and without evidence of infectious processes. Whole exome sequencing was performed, and although the results were not conclusive, we found variants in genes associated with both autoinflammatory (NLRP12) and neurological (POLR3A) phenotypes that could be related to the disease pathogenesis having a polygenic rather than monogenic trait. CONCLUSION: We propose that an autoinflammatory basis should be pursued in patients diagnosed as having acute disseminated encephalomyelitis and no record of infections. Also, we show that our patient had a good response after 1 year of treatment with low doses of intravenous immunoglobulin and colchicine.

Velocidad de crecimiento en pacientes con síndrome de Turner que recibieron hormona recombinante de crecimiento / Growth rate in patients with Turner syndrome who received recombinant growth hormone

El síndrome de Turner (ST) afecta a uno de cada 2000-2500 recién nacidos vivos y tiene una prevalencia de 50 por cada 100 000 mujeres. Las manifestaciones clínicas son variables, dependiendo del tipo de alteración cromosómica y de la edad de presentación. Una de las características más prevalentes y sobresalientes del síndrome es su estatura extremadamente baja. La hormona de crecimiento humana recombinante (rh-GH) se ha usado para aumentar el crecimiento y la estatura final en las niñas que tienen el síndrome de Turner. Para valorar los efectos de la hormona de crecimiento recombinante en las niñas y adolescentes con ST, hemos tomado en cuenta el efecto de la hGH, considerando la velocidad en la talla de crecimiento como un punto importante del estudio observacional retrospectivo. Resultados principales: El uso de rh-GH tiene una relación estadísticamente significativa (p0.049 <0.05), que se asocia con un factor de influencia positiva en relación con la velocidad de crecimiento, como variable principal. Al comparar a las pacientes que recibieron la hormona de crecimiento con las que no la recibieron, en las primeras existe la tendencia a acercarse a la curva del percentil 10 en comparación con la de aquellas que no recibieron la rh-GH, que estuvieron más lejos de la curva.

Turner syndrome (TS) affects about one in 1500 to 2500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Recombinant human growth hormone (rh-GH) has been used to increase growth and final height in girls who have Turner syndrome. To assess the effects of recombinant growth hormone in children and adolescents with TS we have evaluated the effect of HGH considering growth rate as an important point through a retrospective observational study. Main results: The use of rh-GH has a statistically significant relationship (p0.049 <0.05) that is associated with an influencing factor in favor of the use of rh-GH in relation to the variable growth rate. When comparing the patients who received growth hormone with those who did not receive, there is the tendency to arrive closer to the 10th percentile curve compared to the curve of the patients who did not receive rh-GH, which is further away.

GH and GHR signaling in human disease.

Along with its inherent properties in growth promotion, cell division and regeneration, growth hormone (GH) exerts a variety of miscellaneous and widespread actions on the human body after binding to its receptor (GHR). Indeed, GH influences the metabolism of carbohydrates, lipids and proteins; shapes body composition, influences cardiovascular profile, quality of life, and induces other direct and indirect physiologic effects. Besides this salutary actions, GH and its derived peptide insulin-like growth factor-I (IGF-I), main product of the GH/GHR interaction, have been implicated in the genesis of diseases such as cancer and insulin-resistant diabetes. The effects of these peptides are difficult to discern in healthy individuals but can be better evaluated in disease states in which their action in target tissues is abnormal. In consequence, we selected acromegaly and Laron syndrome due to GH receptor deficiency (GHRD) as models for excess and absence of GH action, and focused in the role of GH/GHR signaling in the genesis of cancer and diabetes. Considering that malignancy has been linked at epidemiological level to type 2 diabetes and high body mass index, suggesting that hyperinsulinemia is an independent contributor to cancer genesis and progression, we propose that the GH-derived IGF-I is also an independent influence for progression to neoplasia since its absence associates with less DNA damage, diminished mutagenesis and efficient apoptosis. Regarding development of type 2 diabetes, we support the notion that GH, by influencing insulin sensitivity via its counter-regulatory properties on carbohydrate metabolism, is an important contributor for development of this disease.

Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives.

In the present pandemics of obesity and insulin resistant diabetes mellitus (DM), the specific contribution of etiological factors such as shifts in nutritional and exercise patterns, genetic and hormonal, is subject of ongoing research. Among the hormonal factors implicated, we selected obesity-driven insulin resistance for further evaluation. It is known that growth hormone (GH) has profound effects on carbohydrate metabolism. In consequence, we compared the effects of the lack of the counter-regulatory effects of GH, in a group of subjects with GH receptor deficiency (GHRD) due to a mutated GH receptor vs. that of their normal relatives. It was found that, despite their obesity, subjects with GHRD, have diminished incidence of diabetes, lower glucose and insulin concentrations, and lower values of indexes indicative of insulin resistance such as HOMA-IR. The GHRD subjects were also capable of appropriately handling glucose or mixed meal loads despite diminished insulin secretion. These observations allow us to suggest that the association of obesity with increased risk for diabetes appears to be dependent on intact growth hormone signaling.

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.

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.

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.

Latin American consensus: children born small for gestational age.

BACKGROUND: Children born small for gestational age (SGA) experience higher rates of morbidity and mortality than those born appropriate for gestational age. In Latin America, identification and optimal management of children born SGA is a critical issue. Leading experts in pediatric endocrinology throughout Latin America established working groups in order to discuss key challenges regarding the evaluation and management of children born SGA and ultimately develop a consensus statement. DISCUSSION: SGA is defined as a birth weight and/or birth length greater than 2 standard deviations (SD) below the population reference mean for gestational age. SGA refers to body size and implies length-weight reference data in a geographical population whose ethnicity is known and specific to this group. Ideally, each country/region within Latin America should establish its own standards and make relevant updates. SGA children should be evaluated with standardized measures by trained personnel every 3 months during year 1 and every 6 months during year 2. Those without catch-up growth within the first 6 months of life need further evaluation, as do children whose weight is ≤ -2 SD at age 2 years. Growth hormone treatment can begin in SGA children > 2 years with short stature (< -2.0 SD) and a growth velocity < 25th percentile for their age, and should continue until final height (a growth velocity below 2 cm/year or a bone age of > 14 years for girls and > 16 years for boys) is reached. Blood glucose, thyroid function, HbA1c, and insulin-like growth factor-1 (IGF-1) should be monitored once a year. Monitoring insulin changes from baseline and surrogates of insulin sensitivity is essential. Reduced fetal growth followed by excessive postnatal catch-up in height, and particularly in weight, should be closely monitored. In both sexes, gonadal function should be monitored especially during puberty. SUMMARY: Children born SGA should be carefully followed by a multidisciplinary group that includes perinatologists, pediatricians, nutritionists, and pediatric endocrinologists since 10% to 15% will continue to have weight and height deficiency through development and may benefit from growth hormone treatment. Standards/guidelines should be developed on a country/region basis throughout Latin America.