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Scientific Reports Oct 2015Laron syndrome is a rare disease caused by mutations of the growth hormone receptor (GHR), inheriting in an autosomal manner. To better understand the pathogenesis and...
Laron syndrome is a rare disease caused by mutations of the growth hormone receptor (GHR), inheriting in an autosomal manner. To better understand the pathogenesis and to develop therapeutics, we generated a miniature pig model for this disease by employing ZFNs to knock out GHR gene. Three types of F0 heterozygous pigs (GHR(+/4bp), GHR(+/2bp), GHR(+/3bp)) were obtained and in which no significant phenotypes of Laron syndrome were observed. Prior to breed heterozygous pigs to homozygosity (GHR(4bp/4bp)), pig GHR transcript with the 4 bp insert was evaluated in vitro and was found to localize to the cytoplasm rather than the membrane. Moreover, this mutated transcript lost most of its signal transduction capability, although it could bind bGH. GHR(4bp/4bp) pigs showed a small body size and reduced body weight. Biochemically, these pigs exhibited significantly elevated levels of GH and decreased levels of IGF-I. These results resemble the phenotype observed in Laron patients, suggesting that these pigs could serve as an ideal model for Laron syndrome to bridge the gaps between mouse model and human.
Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Gene Knockout Techniques; Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Receptors, Somatotropin; Swine; Swine, Miniature
PubMed: 26511035
DOI: 10.1038/srep15603 -
Journal of Pediatric Endocrinology &... 2013There are different opinions concerning changes in glucose metabolism in patients with Laron syndrome. In this paper we discuss the treatment results of our patient with...
There are different opinions concerning changes in glucose metabolism in patients with Laron syndrome. In this paper we discuss the treatment results of our patient with Laron syndrome who developed diabetes during late adolescence. A 19-year-old boy with Laron syndrome was referred to our clinic for follow-up. He had been diagnosed with Laron syndrome (LS) at 4 years old and rIGF-1 therapy was initiated. After 4 months the treatment was discontinued. At the age of 17, rIGF-1 therapy was restarted. A height gain of 8.8 cm. was observed during the 2-year treatment period. He was admitted to our hospital at the age of 19 years following discontinuation of the therapy. At that time, his height was 142 cm, and weight for height was 136%. His blood glucose was 85 mg/dL (4.72 mmol/L), insulin was 26.39 pmol/L, and HbA1c was 5.4%. At the age of 20, when he has not been receiving IGF-1 therapy for 1 year, his weight for height was 143 cm. Laboratory evaluation revealed that fasting blood glucose was 176 mg/dL (9.77 mmol/L), fasting insulin was 29.86 pmol/L, and HbA1c was 7.5%. Primary insulin therapy was then initiated. His parents both had a diagnosis of type 2 diabetes. Insulin therapy was switched to oral antidiabetic (OAD) therapy at the end of the second year because of a normal C-peptide level of 0.8 nmol/L under insulin therapy. After 6 months of OAD, HbA1c was 5.7%. The treatment was then switched to IGF-1 therapy, but his blood glucose profile was impaired and OAD therapy was restarted. In conclusion, we observed that genetic susceptibility and abdominal obesity caused type 2 diabetes in this patient. We believe that oral antidiabetic agents and life-style changes may be the appropriate approach when diabetes is developed in LS patients.
Topics: Adult; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Monitoring; Humans; Hypoglycemic Agents; Insulin; Insulin-Like Growth Factor I; Laron Syndrome; Male; Metformin; Obesity, Abdominal; Recombinant Proteins; Treatment Outcome; Young Adult
PubMed: 23729552
DOI: 10.1515/jpem-2012-0411 -
Nihon Rinsho. Japanese Journal of... Feb 2002Laron syndrome, characterized by a short stature with raised serum levels of growth hormone but extremely low levels of insulin-like growth factor I, is caused by... (Review)
Review
Laron syndrome, characterized by a short stature with raised serum levels of growth hormone but extremely low levels of insulin-like growth factor I, is caused by genetic defects of growth hormone receptor, including loss of functions of growth hormone receptor and abnormal growth hormone receptor acting in a dominant negative manner. This chapter focused on loss of functions of growth hormone receptor causing disruption of growth hormone binding and intracellular signalling. Most mutations and deletions have been found in extracellular domains of growth hormone receptor. Serum levels of growth hormone binding protein, cleaved from the extracellular portion of the growth hormone receptor, are typically decreased in most patients but are normal or high in some patients.
Topics: Dwarfism, Pituitary; Humans; Mutation; Receptors, Somatotropin
PubMed: 11857918
DOI: No ID Found -
The American Journal of the Medical... Jun 2018
Topics: Fanconi Anemia; Humans; Laron Syndrome
PubMed: 29891047
DOI: 10.1016/j.amjms.2018.02.004 -
Growth Hormone & IGF Research :... Feb 2018Along with its inherent properties in growth promotion, cell division and regeneration, growth hormone (GH) exerts a variety of miscellaneous and widespread actions on... (Review)
Review
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.
Topics: Diabetes Mellitus; Human Growth Hormone; Humans; Insulin Resistance; Neoplasms; Receptors, Somatotropin; Signal Transduction
PubMed: 29395968
DOI: 10.1016/j.ghir.2017.12.006 -
The Israel Medical Association Journal... Jan 2017
Topics: Humans; Insulin-Like Growth Factor I; Laron Syndrome; Neoplasms
PubMed: 28457105
DOI: No ID Found -
Growth Hormone & IGF Research :... Feb 2018Specific phenotypic features of subjects affected with genetic syndromes depend on peculiarities of expression of each discrete mutation and on extent of its divergence... (Review)
Review
Specific phenotypic features of subjects affected with genetic syndromes depend on peculiarities of expression of each discrete mutation and on extent of its divergence from normal physiology. In this context, and when studying the GH/IGF-I axis of subjects with two different syndromes that include severe short stature (SSS), we noticed different metabolic phenotypes in each cohort. Subjects with Laron syndrome (LS), who have GH insensitivity (GHI), display obesity, increased body fat, enhanced insulin sensitivity and diminished incidence of diabetes mellitus. Subjects with a new syndrome (NS), who have normal GH signaling, display intrauterine growth retardation (IUGR), normal to slightly elevated body fat content, insulin resistance and early onset type 2 diabetes mellitus (T2DM). In consequence, we were able to observe the clinical consequences of different GH counter-regulation status on carbohydrate metabolism, especially considering that subjects with either syndrome most likely have diminished pancreatic reserve.
Topics: Cohort Studies; Diabetes Mellitus, Type 2; Dwarfism; Growth Disorders; Human Growth Hormone; Humans; Insulin Resistance; Laron Syndrome; Obesity
PubMed: 29306561
DOI: 10.1016/j.ghir.2017.12.012 -
Endocrine-related Cancer Oct 2023The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and... (Review)
Review
The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.
Topics: Humans; Growth Hormone; Acromegaly; Insulin-Like Growth Factor I; Human Growth Hormone; Insulin; Neoplasms
PubMed: 37428642
DOI: 10.1530/ERC-22-0402 -
Growth Hormone & IGF Research :... Jun 2016
Topics: Congresses as Topic; Ecuador; Growth Hormone; Human Growth Hormone; Humans; Laron Syndrome; Peptides; Universities
PubMed: 27113157
DOI: 10.1016/j.ghir.2016.04.002 -
Endocrine-related Cancer May 2023Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced... (Review)
Review
Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.
Topics: Male; Female; Rats; Mice; Humans; Animals; Growth Hormone; Insulin-Like Growth Factor I; Neoplasm Recurrence, Local; Human Growth Hormone; Carcinoma
PubMed: 36826838
DOI: 10.1530/ERC-22-0403