The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal–regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity

The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice

FTO (fat mass and obesity associated) was identified as an obesity-susceptibility gene by several independent large-scale genome association studies. A cluster of SNPs (single nucleotide polymorphism) located in the first intron of FTO was found to be significantly associated with obesity-related traits, such as body mass index, hip circumference, and body weight. FTO encodes a protein with a novel C-terminal α-helical domain and an N-terminal double-strand β-helix domain which is conserved in Fe(II) and 2-oxoglutarate-dependent oxygenase family. In vitro, FTO protein can demethylate single-stranded DNA or RNA with a preference for 3-methylthymine or 3-methyluracil. Its physiological substrates and function, however, remain to be defined. Here we report the generation and analysis of mice carrying a conditional deletion allele of Fto. Our results demonstrate that Fto plays an essential role in postnatal growth. The mice lacking Fto completely display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density than control mice, but their body compositions are relatively normal. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of IGF-1. Moreover, despite the ubiquitous expression of Fto, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nerve system to regulate postnatal growth

Acromegaly : irreversible clinical consequences

This thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the considerable prevalence of diverse morbidity in these patients, during the active phase of the disease but even more so after 17 years of disease cure, we suggest the screening of acromegalic patients on highly frequent comorbidities, such as osteoarthritis, vertebral fractures, colonic polyps, and colonic diverticulae. It is of great concern to recognize the long-term consequences of the disease in order to offer the patients adequate follow-up and multidisciplinary care. The aim should be to control the persisting complex morbidity as much as possible in order to prevent the patients from a further decrease in quality of life. The patients__ physician as well as the patient itself should be aware of the long-term consequences of acromegaly in order to eliminate surreal expectations concerning recovery of certain comorbidities.Novartis, Novo nordisk, Sandoz, Pfizer, Ipsen, Genzyme, Astra Zeneca, Ferring, Zambon, TramedicoUBL - phd migration 201

Studies of GH Receptor Signalling and Antagonism in the setting of Growth Hormone Deficiency and Acromegaly.

MD (res)Conditions of GH excess and deficiency cause significant morbidity and mortality. Treatments for both situations have evolved considerably in recent years, but heterogeneity in therapeutic responses remains poorly understood. An improved understanding of the role of the growth hormone receptor’ (GHR) has the potential to advance future clinical management. Deletion of exon 3 in the GH receptor (d3- GHR) has been linked to enhanced rhGH responsiveness in children; the effect in adults with GH deficiency and acromegaly in adults is less well understood. Pegvisomant, a GHR antagonist is a highly effective treatment for acromegaly but monitoring of treatment is limited by the potential imprecision of IGF-I as the sole marker of response. The aim of this work was two-fold; to investigate the effect of the d3-GHR in determining an individual’s response to GH in GH deficiency and acromegaly and to investigate the effect of supraphysiological doses of pegvisomant on IGF-I and the physiological markers of GH activity in patients with acromegaly. 194 GHD patients and 79 acromegaly patients were genotyped for d3-GHR and results correlated with clinical and biochemical response to GH. Homozygosity for d3-GHR confers a marginal increase in GH responsiveness in GH deficiency and acromegaly but without significant clinical effects. Both d3 alleles are required to achieve this response; given that only 10% of the population are d3 homozygotes, d3-GHR does not explain heterogeneity in GH responsiveness. Investigation of supra-physiological doses of pegvisomant revealed unexpected and previously unpublished findings; despite two to four fold increases in dose, six of the nine patients failed to achieve target subnormal IGF-I levels. The absence of a significant role for d3-GHR in determining GH response and the unexpected difficulty in causing GH deficiency with high dose GH receptor antagonism highlights the need for further study of the GHR in determining an individual’s response to GH

Adult growth hormone deficiency: clinical advances and approaches to improve adherence

Introduction: There have been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration. Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that non-adherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence. Expert opinion: This article summarizes recent clinical advances in rhGH replacement therapy, the biological and molecular aspects that may influence rhGH action, and offers practical strategies to enhance adherence in adults with GHD

An investigation into the underlying genetic determinates in obesity using the candidate-gene association approach and microarray technology

Introduction: (1) Ghrelin is a peptide and has been suggested involved in energy metabolism. (2) Physical activity plays an important role in the regulation of body fat. Generally, the body composition of obese people tend to be resistant to negative energy balance. Little is known, however, with respect to the molecular mechanism and basis underlying the differences of responsiveness between obese and non-obese humans. Methods: This study consists of two parts: ( 1) Genetic association of 3 single nucleotide polymorphisms (SNPs) in the ghrelin precursor gene (GHRL) with obesity phenotypes in the NL population ( 1182 subjects); (2) A global gene expression study of abdominal subcutaneous adipose tissue (ASAT) and comparison between lean and obese young men (10 subjects) in response to a 7-day aerobic exercise protocol using whole genome mRNA microarrays. Results: No significant association of any of the variant sites and body compositions or serum lipids was found in allele, genotype and haplotype analyses. In microarray experiment, the discoveries include, and to our knowledge the first time reported the differential regulations: 1) 6 inflammatory-related genes (SMPD3, CERK, ASAH2, ST3GAL5, ILJRIJ, and AGTRJ) within obese ASAT; 2) the genes in the lipolytic pathway (PRKACA, SLC27A6, ADCY6, ADCYAPJ, PPPJCB, DGAT2, and VLDLR); 3) the genes in the protein tyrosine phosphatase (PTP) pathway (PTPNJJ, PTPRD, and PTPN3) related to insulin sensitivity; 4) PPARA and PPRCJ that may favourably control energy metabolism in lean individuals, while not in obese. Conclusion: ( 1) The SNPs investigated within GHRL were not significantly associated with the variations of body composition and lipids in the NL population; (2) The genome-wide mRNA microarray expression study revealed many major differences of ASA T between obese and nonobese at the molecular level, with respect to the regulation of inflammation, lipolysis and insulin sensitivity