The biochemistry of Laron Syndrome Mutated Growth Hormone Receptors inhibit bindingLaron Syndrome or Primary Growth Hormone Insensitivity is characterised by high serum Growth Hormone (GH) Levels and defective Growth Hormone Receptors resulting in a lack of stimulation of insulin-like growth factor 1 (IGF-1). GH, secreted from the pituitary gland, has essential roles in growth, cell division and metabolism (Bethesda, 2015). Usually, Growth Hormone Receptors (GH receptors) found on the surface of liver cells mediate GH effects directly through tyrosine kinase activation as well as indirectly through stimulating the release of an associated hormone – insulin-like growth factor 1 (IGF-1) (Brooks and Waters, 2010). Fig 1 shows how GH is released from the pituitary gland resulting in its binding to GH receptors and consequent stimulation of IGF-1 production (Junnila et al. 2013). When Laron Syndrome was initially discovered by Zvi Laron in the 1950s, it was initially thought that the short stature and related symptoms of Laron Syndrome were due to a lack of GH, but in 1963 it was found that the GH in blood serum levels were astonishingly high. In the 1980s, it was found that the GH receptors were mutated and binding couldn’t take place, therefore IGF-1 wasn’t stimulated (Taubes, 2013) this discovery of this mechanism is highlighted in Figure 2. To read more about the mutations and genetic elements of this disease click hereFigure 2 Timeline from the discovery of Laron Syndrome and understanding its biochemical mechanism Information from (Taubes,2013) Low IGF-1 levels reducing pro-ageing signals and cancer riskReduced IGF-1 signalling found in Laron Syndrome has been associated with longevity and reduced cancer risk in humans. Patients with Laron Syndrome have a much lower risk of cancer and diabetes compared to unaffected relatives as shown in Figure 3 illustrating causes of death and mortality of both groups. 17% of unaffected relatives died from cancer compared one non-lethal malignant cancer case in the GHRD (Growth Hormone Receptor Deficiency) group representing the individuals with Laron Syndrome in Figure 3D. A possible explanation for reduced cancer incidences could be due to the protective functions of low IGF-1 serum levels and increased apoptosis (Guevara-Aguirre et al., 2011).Increased apoptosis due to low IGF-1 signalling has been implicated with reducing the cancer risk in Laron Syndrome patients. Normally, through IGF-1 binding, the IGF-1 receptor (like other tyrosine kinase receptors including GH receptors) mediates the hormone’s effects through the activation of the tyrosine kinase resulting in the autophosphorylation of the receptor. IGF-1 signals then trigger a complex network of intracellular lipids and kinases responsible for cell division, tissue differentiation and protection from apoptosis (Laviola, Natalicchio and Giorgino, 2007). The IGF-1 pathway has been proposed to promote ageing and genomic instability and have a role in the development and progression of cancer, paradoxically due to its anti-apoptotic function as well as the promotion of age-dependent mutations leading to oncogenes and consequently proto-oncogenes (Guevara-Aguirre et al., 2011). The suppression of apoptosis in order to regulate cell growth along with the stimulation of cell proliferation optimizes tumour growth hence increasing cancer risk. This is in line with the fact that high IGF-1 concentrations have been found in breast, prostate, lung and colorectal cancers (Yu, 2000). The paradox of Obesity and Reduced Diabetes Risk Laron Syndrome patients, despite their marked obesity and high percentage of body fat, as shown in Figure 4, have an increased insulin-sensitivity and decreased insulin resistance compared to with their age and BMI-matched control relatives. Aguirre-Guevara proposed this increase in body fat is due to the lack of binding of GH to its GH receptor resulting in the elimination of the counter-regulatory effects and direct metabolic effects of GH which includes interactions with insulin, gluconeogenesis and glycogenolysis ((Guevara et al. 2015), (Vijayakumar, Yakar and LeRoith, 2011). Insulin therefore is unopposed promoting the uptake of circulating lipids and causing increased triacylglycerol breakdown from which, glycerol and free fatty acids can easily enter adipocytes resulting in an increase in body fat percentage in Laron Syndrome patients (Guevara et al. 2015). A common symptom of Laron Syndrome is hypoglycaemia (lowered glucose levels) however and this may be disadvantage of patients lacking GH’s counter-regulatory effects.Aguirre-Guevara measured the levels of HOMA-IR as an indicator of insulin resistance and found that it was lower in Laron Syndrome patients compared to age, gender and BMI-matched controls as shown in Figure 4H, indicating GH has a role in determining insulin resistance. Insulin is very important in the uptake of glucose, amino acids and fatty acids into cells, and it is well known insulin resistance eventually leads to hyperglycaemia and is a major risk factor for type 2 diabetes. However it seems that the association between diabetes and obesity is dependent on an intact GH receptor signal and hence the binding of GH. It is also noted that low secretion of insulin (as shown in Figure 4G) can also lead to the development of diabetes due to raised glucose levels, however due to the lack of GH and its counter-regulatory effects, Laron Syndrome patients have enough insulin to control blood-glucose levels, further reducing their risk of diabetes (Guevara et al. 2015).
September 8, 2019 0 Comments