The GH/IGF-1 system during surgery and catabolism : focus on metabolism and heart function

Sammanfattning: GH plays a role in both anabolism and catabolism. The anabolic properties of GH are mediated by circulating (endocrine) and locally secreted (paracrine) IGF-1. It is thus the IGF-1 response after increased GH secretion that determines whether metabolism will be anabolic or catabolic. IGF-1 synthesis is particular dependent on an adequate energy and protein supply and is stimulated by both GH and insulin. Rapidly decreasing circulating IGF-1 is seen during starvation. Physical stress, such as surgery, infections and critical illness, all of which are associated with catabolism, is also associated with low circulating levels of IGF-1 and increased GH secretion. Furthermore, the metabolic activity of IGF-1 at the cellular level is influenced by circulating and tissue specific binding proteins, IGFBPs, of which six have so far been identified. The short-lived IGFBP-1 is considered to be the most important binding protein for control of the amount of free IGF-1 available for signalling. The overall aim of this thesis was to investigate whether different treatment procedures during surgery and critical illness could affect the somatotropic axis in a more anabolic direction and/or lead to a change in glucose homeostasis after surgery. To attain this goal, we performed three randomised clinical studies in which we investigated: whether various modes of anaesthesia influenced the physiology of the GH-IGF-1 axis (paper I); whether peroperative GIK-infusion influenced the pattern of GH, IGF-1, IGFBP-1, insulin and glucose during and after elective coronary artery by-pass surgery (paper II); whether peroperative infusion of amino acids influenced the pattern of IGF-1, IGFBP-1 and glucose homeostasis after elective hysterectomy and whether starting this infusion ahead of anaesthesia made a difference (paper III). In the fourth paper of this thesis, we examined whether an augmented GH dose in two critically ill moribund catabolic patients with dilated cardiomyopathy could improve cardiac function via IGF-1 and an improved nitrogen balance (paper IV). The studies (I, II, III) demonstrate that the reduction in IGF-1 found during major surgery is a general phenomenon seen during orthopaedic, abdominal and cardiac surgery and that it is not influenced by the type of anaesthesia used. One important general observation was that variations between individuals in a surgical population were greater than the variations within individuals caused by surgery and the interventions themselves. This is a novel observation and should be considered in future studies. In paper I the rapid decrease in IGF-1 during hip replacement surgery correlated to the increase in blood glucose and insulin during surgery. In addition, regional anaesthesia accelerated the recovery of IGF-1 after surgery and abolished hepatic insulin resistance, as reflected by depressed IGFBP-1 levels, during the night following surgery. GIK-infusion during elective coronary artery bypass surgery substantially diminished the prompt release of IGFBP-1 after extracorporeal circulation and accelerated the recovery of IGF-1 after surgery. The glucose homeostasis of patients subjected to cardiac surgery was more severely disrupted both before and after surgery compared to that of the other patients undergoing surgery. An amino acids infusion during abdominal surgery attenuated the decline in IGF-1 and diminished diabetes of injury after surgery. Starting the amino acid infusion one hour before anaesthesia appeared to be favourable with regard to glucose homeostasis, but had a slightly inferior effect in terms of diminishing the decrease in IGF-1. Finally, an augmented GH dose in two critically ill catabolic patients with dilated cardiomyopathy improved cardiac function. This improvement in cardiac function was vital and corresponded to both an increase in IGF-1 and an improved nitrogen balance. Altogether, the above novel findings illustrate that it is possible to improve the somatotropic axis and glucose homeostasis after surgery by means of different interventions during surgery. These findings also challenge the old paradigm that it is not worthwhile to give nutrition during surgery.