Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency.

BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

Cancer in growth hormone excess and growth hormone deficit.

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.

Cancer in Ecuadorian subjects with Laron syndrome (ELS).

Meta-analyses from 2018-2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.

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.

Growth hormone receptor deficiency in humans associates to obesity, increased body fat percentage, a healthy brain and a coordinated insulin sensitivity.

BACKGROUND: We have shown that subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) and their relatives have comparable brain structure and function; moreover, the brain of individuals affected with GHRD appears like those of younger people. While the functionally absent growth hormone receptor and the diminished concentrations of the insulin-like growth factor-I have been associated to these findings, the role of the insulin-glucose axis is emerging as an unavoidable consideration when determining the aetiology of these observations. In consequence, we decided to search for the potential and discrete associations between the neurological findings and several parameters of carbohydrate metabolism that might exist in the subjects affected with GHRD. SUBJECTS AND METHODS: Individuals affected with GHRD were compared to relative controls. Besides standard measures of anthropometry, body composition and brain characteristics, the elements of the carbohydrate metabolism (CHO), including glucose, insulin, triacylglycerol and the free insulin growth factor binding protein 1 (IGFBP1) concentrations were determined. In addition, the correlations existing between the parameters of CHO and brain characteristics were established. RESULTS: Besides the phenotypical characteristics of GHRD subjects, including those of brain structure and function, enhanced insulin sensitivity, and other minor, we observed that the insulin-regulated IGFBP1 had a consistent negative correlation with the main elements of the carbohydrate metabolism only in the individuals affected with the disease, and not in their relatives. CONCLUSIONS: When compared to their relatives, subjects with GHRD who lack the counter-regulatory effects of GH on the insulin axis, despite their increased risk factor profile due to obesity and increased body fat percentage, have a healthy and younger looking brain associated to an enhanced and coordinated insulin sensitivity. Furthermore, it was observed that in the GHRD subjects IGFBP1 negatively correlates, in a constant and systematic manner, with the main elements of the CHO metabolism. These observations suggest a direct relationship between an efficient insulin sensitivity and a healthy brain.