Background: Following detection of receptors for ghrelin and growth hormone (GH) in the cardiovascular system, different clinical trials have used ghrelin or GH for the treatment of cardiac patients. While some of these trials reported improvements in the patients' situation, others reported deterioration. Objectives: To clarify the contradictory outcomes, we designed this study to evaluate the circadian rhythms of acylated ghrelin, GH, and the related factors [Insulin-like Growth Factor-1 (IGF-1), Insulin-like Growth Factor Binding Proteins 1 and 3 (IGFBP-1 and IGFBP-3)], and leptin in patients with reduced ejection fraction (rEF). Patients and Methods: Ten patients with rEF and an equal number of healthy control subjects matched for age and gender participated in this study according to inclusion criteria. All participants were hospitalized in the cardiac care unit (CCU), under identical conditions during collection of blood (every 2 hours). Primary processing of samples was carried out immediately and the plasma was stored at -20oC until evaluation of the aforementioned parameters using ELISA methods. Results: Evaluation of the collected data showed that among aged participants only circulating leptin is gender-dependent, while the patients had significantly (P<0.001) lower ghrelin, GH, IGF-1, and IGFBP-1, but a higher level of IGFBP-3 compared to the control group. In addition, except for GH that showed a mild circadian rhythm, the parameters we examined did not have a significant circadian rhythm. Correlation analysis of the data showed a positive correlation between ghrelin and GH or IGF-1, and significant negative or positive correlations between leptin and IGFBP-1, or IGFBP-3, respectively, in both groups. Conclusions: Here, for the first time, we show that circulating ghrelin, GH, and IGF-1 levels are reduced in the patients with rEF, and the condition of patients is deteriorated not only due to reduced IGF-1 but also due to reduction of IGFBP-1 or increase of IGFBP-3, which may be influenced by circulating leptin. Finally, disturbance of the balance between ghrelin/GH/IGF-1 and leptin may be the cause of rEF, and thus evaluation of these parameters could provide diagnostic as well as prognostic tools for the treatment of these patients.

Insulin growth factor protein 3 (IGFBP-3) is a member of the binding protein family which is known as the main carrier of insulin-like growth factors in human serum. Through the existence of multiple IGFBP-3 binding partners such as insulin growth factors (IGFs), transmembrane receptor 219 (TMEM219) protein, retinoid X receptors (RXRs), and other proteins, in IGF-dependent and IGF-independent cell signaling pathways, IGFBP-3 exerts the various key roles associated with physiological processes such as cell growth prevention and differentiation, apoptosis induction and have several metabolic activities such as regulating blood glucose, lipid metabolism, regulating bone, and chondrocyte growth as well. Moreover, IGFBP-3 plays an important role in the pathophysiology of a variety of human diseases including ischemia, Alzheimer’s disease, diabetes mellitus, asthma, and cancer. Therefore, in this current study, we intend to describe the IGFBP-3 role depending on its effect on the pathophysiology of human illnesses.

Prolonged exercise increases plasma insulin growth factor binding protein-1 (IGFBP-1) in response to a decline in plasma insulin and glucose. In a previous study, it was speculated that factors of exercise per se might also regulate IGFBP-1 secretion, as values increased despite euglycaemia under carbohydrate feeding. Therefore, to determine the effect of exercise per se on circulation of IGFBP-1, the present study undertook prolonged exercise during hyperglycemic and hyperinsulinemic clamps. Eight trained male cyclists cycled at 70% VO2max for 120 min on two separate occasions under either an intravenous glucose clamp (G) at 10 mmol/l, or a glucose (10 mmol/l) and insulin clamp (GI) at 40 mU/sqm/min. Fasting venous blood samples taken at rest both before and after clamp and also during exercise were analyzed for IGFI, IGFBP-1 and IGFBP-3 using specific radio immunoassay. Plasma glucose was maintained at 10 mmol/l in both trials. Plasma insulin averaged 32±7.3 and 102±16.6 mU/ml during exercise in G and GI trials respectively. Plasma IGFBP-1 was not changed 30 min after either clamps, but significantly decreased after 60 min and 120 min exercise in both trials (P<0.001). It would appear from these findings that the high levels of exogenous glucose and insulin completely suppress IGFBP-1 secretion during the exercise and/or enhance IGFBP-1 clearance from the circulation. We conclude that insulin is the primary regulator of IGFBP-1 and that there is no effect of exercise on IGFBP-1 regulation.