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.

A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.

CONTEXT: CDKN1C, a cyclin-dependent kinase inhibitor and negative regulator of cellular proliferation, is paternally imprinted and has been shown to regulate ß-cell proliferation. CDKN1C mutations are associated with growth disorders, including Beckwith-Wiedemann syndrome and IMAGe syndrome. OBJECTIVE: To investigate the genetic basis for a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. DESIGN, SETTING, AND PARTICIPANTS: Genomic DNA samples (15 affected and 26 unaffected from a six-generation pedigree) were analyzed by genome-wide single nucleotide polymorphism arrays, whole exome and Sanger sequencing, and multiplex ligation-dependent probe amplification. MAIN OUTCOME MEASURE(S): Subjects were assessed for height, weight, adrenal gland size, ACTH, diabetes status, and testis volume. Linkage and sequence analyses were performed, and the identified genetic variant was functionally evaluated in reconstitution studies. RESULTS: The pedigree followed a paternally imprinted pattern of inheritance, and genetic linkage analysis identified a single significant 2.6-megabase locus on chromosome 11p15, within the imprinting center region 2. Multiplex ligation-dependent probe amplification did not detect copy number variants or methylation abnormalities. Whole exome sequencing revealed a single novel variant in the proliferating cell nuclear antigen-binding region of CDKN1C (c.842G>T, p.R281I) that co-segregated with affected status and, unlike variants found in IMAGe, did not entirely abrogate proliferating cell nuclear antigen binding. Clinical assessments revealed that affected individuals had low testicular volume but normal adrenal function. CONCLUSIONS: We report a novel CDKN1C mutation associated with features of IMAGe syndrome, but without adrenal insufficiency or metaphyseal dysplasia, and characterized by early-adulthood-onset diabetes. Our data expand the range of phenotypes observed with CDKN1C defects and suggest that CDKN1C mutations may represent a novel monogenic form of diabetes.

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.

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.

Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 µU/ml versus 4.4 µU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.

Comparison of oral insulin spray and subcutaneous regular insulin at mealtime in type 1 diabetes.

BACKGROUND: The aim of this study was to compare the glucose pharmacodynamics after oral spray insulin (Oral-lyn , Generex Biotechnology, Toronto, ON, Canada) and subcutaneous (sc) injection of regular insulin in 10 subjects with type 1 diabetes mellitus (T1DM). METHODS: Basal therapy was twice-daily insulin glargine. Preprandial (30 min) regular insulin was given for 3 days, followed by 9 days of Oral-lyn, eight to 12 puffs immediately pre- and postprandially. Adjustments for glycemia were made using standard snacks and additional regular insulin or Oral-lyn. Peripheral glucose measurements were self-monitored in duplicate. Serum concentrations of fructosamine and hemoglobin A1c (HbA1c) were determined at the start and the end of the study period. RESULTS: Average glucose concentrations (in mmol/L) for the 3-day regular insulin and 9-day Oral-lyn periods, respectively, were: pre-breakfast (B), 5.06 and 3.89; 1-h post-B, 8.39 and 7.67; post-B, 6.00 and 6.33; pre-lunch (L), 5.50 and 4.72; 1-h post-L, 7.83 and 7.89; 2-h post-L, 5.89 and 6.33; pre-dinner (D), 5.61 and 5.17; 1-h post-D, 7.22 and 7.83; and 2-h post-D, 6.11 and 6.67. Areas under the curve for both treatments were not significantly different (P = 0.6875). Fructosamine (mean +/- SD, 338.7 +/- 77.4 micromol/L and 321.7 +/- 63.4 micromol/L), and HbA1c (mean +/- SD, 7.5 +/- 1.5% and 7.2 +/- 1.2%) did not change significantly. CONCLUSIONS: Regular insulin and Oral-lyn had similar glucodynamic effects in subjects with T1DM receiving twice-daily insulin analogue as baseline therapy. Intensive monitoring and timely corrections with additional snacks, additional sc regular insulin, or Oral-lyn puffs resulted in appropriate glycemic control as assessed by individual daily glycemic responses and, especially, normal preprandial glycemia. Protein glycation decreased, but not significantly.

Effects of heterozygosity for the E180 splice mutation causing growth hormone receptor deficiency in Ecuador on IGF-I, IGFBP-3, and stature.

CONTEXT & OBJECTIVE: The Ecuadorian GH receptor deficiency (GHRD)/Laron syndrome population is the only large cohort with a single GHR mutation (E180 splice), permitting identification of numerous carrier and noncarrier first-degree relatives, to ascertain effects of heterozygosity on GH-dependent IGF-I and IGFBP-3 concentrations and on growth. DESIGN: First-degree relatives (n=212) of GHRD patients had specimens taken for IGF-I, IGFBP-3, and GHR genotyping. Normal statured (n=40) and short statured (n=40) unrelated controls had measurement of IGF-I, IGFBP-3, and stature. RESULTS: There were no significant differences between heterozygous and homozygous normal relatives in IGF-I or IGFBP-3 standard deviation scores (SDS). Heterozygous relatives had lower mean height SDS than did homozygous normals, but with extensive overlap between genotype groups in both child and adult relatives. Height SDS in general did not relate to IGF-I or IGFBP-3 concentrations. CONCLUSIONS: GH-dependent IGF-I and IGFBP-3 secretion is not affected by heterozygosity for the E180 splice mutation that causes GHRD/Laron syndrome in the Ecuadorian population. Heterozygosity is associated with reduction in mean statural SDS, but this is not sufficient to be clinically important and not mediated through measurable differences in circulating IGF-I or IGFBP-3 related to genotype.

Absence of hypoglycemia in response to varying doses of recombinant human insulin-like growth factor-I (rhIGF-I) in children and adolescents with low serum concentrations of IGF-I.

AIM: To determine whether recombinant human insulin-like growth factor-I (rhIGF-I) administration to children with low IGF-I and relatively low insulin-like growth factor binding protein-3 (IGFBP3) serum concentrations would result in hypoglycemia. METHODS: Eighteen children age 11-19 y with serum levels of IGF-I< -2 SDS and IGFBP3< 0 SDS were randomly assigned to receive rhIGF-I at 80 microg/kg body weight daily (n = 6), 40 microg/kg twice daily (n = 6), or 80 microg/kg twice daily (n = 6). After a 10-d dose escalation and 15 d of treatment at the specified dosage, a 25-h pharmacokinetic/pharmacodynamic profile was obtained, which included 22 blood glucose measurements. Regular meals and snacks were provided. RESULTS: No signs or symptoms of hypoglycemia were noted throughout the study. There were no differences in mean blood glucose concentrations among the three dosage groups. The lowest glucose value recorded, 3.44 mmol/l, was 15 min after a morning injection of 80 microg/kg IGF-I, and promptly rose. Although subjects were selected on the basis of low concentrations of IGF-I to represent proposed candidates for rhIGF-I therapy, the mean and range of SDS for height were not different from those of previously studied normal Ecuadorian controls. CONCLUSION: In normal individuals with low serum concentrations of IGF-I and relatively low concentrations of IGFBP3, the administration of therapeutic doses of rhIGF-I, while maintaining reasonable food intake, does not result in hypoglycemia.