1.1 An introduction to the insulin stress response theory-
The insulin stress response theory combines both clinical and basic science principles to bring together a novel hypothesis to explain the functions of the hormone insulin following life threatening injury. This theory proposes a specific insulin secretory response to the physical stress associated with life threatening injury. The concept of the anabolic hormone insulin functioning as a stress response hormone is a fundamentally new approach to understanding the role of this hormone within the human body. This is the basis of the insulin stress response theory which challenges current knowledge of the role of insulin in response to injury.
The insulin stress response theory proposes an increase in glucose stimulated insulin secretion (GSIS) by the pancreas that is mediated in response to any serious tissue injury. This response is postulated to have a number of beneficial functions for the host following injury to promote wound healing and host recovery. These beneficial functions occur across different components of the host stress response to life threatening injury and include the metabolic response the injury, the activation of the innate immune system and tissue regeneration at the site of injury.
The insulin stress response theory proposes a specific change in (GSIS) following life threatening injury that has characterisitc features of a stress response similar to other stress hormones. Preliminary research carried out by this team has demonstrated highly regulated changes in fasting insulin concentrations following life threatening injury ( Preliminary Clinical Research ) These results also indicate that changes in fasting insulin concentrations are highly correlated with two important endocrine mediators that are known to mediate changes in GSIS. These correlations indicate that insulin secretion following life threatening injury is highly regulated by these endocrine mediators during the first 24-72 hours following injury. The insulin stress response theory utilises measurements of the change in fasting insulin concentrations between the pre-injury unstressed state and the post-injury stressed state to quantify this response. The comparison of changes in fasting insulin concentrations between the unstressed to the stressed state is the key to demonstrating the highly regulated changes in insulin secretion following injury.
Within this website are different sections outlining relevant medical scientific knowledge of the stress response to life threatening injury. The aim is to provice a comprehensive review of this novel scientific theory and how it is integrated within the stress response to injury. A detailed description of the insulin stress response theory is outlined in the section The Insulin Stress Response to injury . A summary of relevant current knowledge of the stress response to injury is outlined in the section An overview of the stress response to injury. Finally, A summary of where we are now: outlines the next stages in establishing this theory within clinical medicine practice.
1.2 The importance of the insulin stress response theory-
Life threatening tissue injury occurs in many different medical conditions that are highly relevant to medical practice; this knowledge is also applicable to both the developed and developing areas of the world. These medical conditions include trauma, heamorrhage, surgery, sepsis, myocardial infarctionn and stroke which collectively contribute to a significant proportion of hospital inpatient admissions. [1–5] All these conditions have tissue injury as a common feature which requires the host to activate a stress response to injury to achieve tissue healing and recovery. The stress response to injury is the term describing the combined actions of the host endocrine, immune and autonomic nervous systems that are required to activate an inflammatory response at the site of life threatening tissue injury .[6]
The stress response to injury is a fundamental biological response observed throughout the animal kingdom which promotes survival following life threatening injury [7]. This response is activated immediately following any life-threatening injury and produces changes in the function of all the principal physiological systems of the body. These physiological changes aim to protect the host by promoting tissue healing and recovery from the injury. [8–10] This is achieved in part by utilising the hosts metabolic reserves, where the metabolic response to injury generates temporary energy consuming metabolic pathways that are required for wound healing and ultimately host survival . These stress mechanisms therefore have the net effect of depleting the hosts metabolic reserves, creating temporary metabolic deficits that are restored following recovery from the injury. However, the process of activating the stress response to injury has the effect of leaving the host vulnerable during the immediate post injury period with a compromised physiological and metabolic status.
The stress response to injury may be considered as a double edged sword where the benefits of healing and host survival are achieved at a cost for the host in terms of a temporary state of vulnerability. These competing host priorities are central to the stress resposne to injury and become more important with increasing severity of injury. The metabolic requirements of the stress response to injury increase with increasing severity of injury leaving the host more vulnerable to life threatening complications during the immediate post injury period. This "double edged sword" analogy of the stress resposne to injury is dicussed further in the section An overview of the stress response to injury
The insulin stress response theory proposes that failure to activate an appropriate insulin response to injury results in a dysregulated stress response to injury. This may be associated with stress hyperglycaemia, poor tissue healing and increased morbitdity and mortality[11–14]. Common medical diseases where an impaired ability to activate an insulin stress response include diabetes, obesity. and malnutrition. This theory highlights a component of the stress response to injury that has remained undetected within clinical medicine. The reasons why the insulin stress response has not been recognised are multifactorial and outlined in the section Why has the insulin stress response remained unrecognised within medicine?
1.3 The knowledge gap that this research addresses-
The insulin stress response theory proposes a fundamental change in our understanding of the metabolic response to injury. Current established medical knowledge of the body's response to serious injury asserts that insulin is not a stress response hormone[5,15,16]. Current knowledge of the endocrine components of the stress response to injury includes a range of counter regulatory hormones that are secreted into the bloodstream following injury.[17–19] These hormones include cortisol, epinephrine, glucagon and growth hormone that have essential functions following injury and collectively mediate actions which directly oppose many of the functions of insulin. For example, the actions of these hormones raise blood glucose concentrations in the blood as well as mediating insulin resistance in peripheral tissues of the body. The function of these hormones mediate the breakdown of stored glycogen, fat and muscle within the body to supply ATP, glucose and other metabolic substrates for a range of functions required by the host following injury. Current knowledge of the stress response to tissue injury assumes that the actions of these counter regulatory hormones imply that insulin plays a limited role in the stress response to tissue injury.[20–23]
The above assumptions concerning the limited role of insulin following life threatening injury have remained for many years and were supported by clinical research indicating that insulin secretion from the pancreas is inhibited by a number of factors following injury[24]. The release of catecholamines into the circulation following injury mediates specific inhibitory effects on the secretion of insulin from the pamcreas [20,25,26]. In addition, the actions of high levels of cytokines including Il-6 also inhibit insulin secretion[27]. The inhibition of insulin secretion (or relative inhibition) is considered to be a defining feature of the body's metabolic response to injury[2,8]. A key feature of the stress response to injury is the range of endocrine actions that create a metabolic response that is "resistant" to the actions of insulin[23,28].
The results of the preliminary research indicate that insulin secretion into the blood has characteristic features of a stress response hormone following life threatening injury. Set against this background it is important to answer some important questions concerning the metabolic response to injury. How can increases in GSIS following life threatening injury be of benefit to the host? What functions does the insulin stress response achieve given the opposing actions of counter regulatory hormones that are released into the blood? Given the highly catabolic nature of the stress response to injury why is there an anabolic insulin stress response?
The insulin stress response theory directly challenges current understanding of the role of insulin following injury. These questions are addressed in different sections of this website that outline the highly regulated insulin response to life-threatening injury. This website also explains the functions of the insulin stress response to injury in terms of why glucose becomes the principal energy substrate for both the wound and the innate immune system The metabolic response to injury . The underlying endocrine stress mechanisms that regulate this response are outlined and are postulated to increase glucose supply to these tissues. In addition, these endocrine stress mechanisms regulate the release of key inflammatory mediators of the innate immune system and stimulate tissue growth and regeneration within the wound. As insulin is an important anabolic hormone this new theory highlights potential anabolic functions of insulin following life threatening injury that are required for tissue repair and regeneration.
This theory postulates new underlying mechanisms for stress hyper- and hypoglycaemia following life threatening injury. These mechanisms are described in the section outlining the preliminary clinical research. The regulation of plasma glucose following life threatening injury and its important association with both wound healing and survival has been highlighted by multiple research studies [5,15,29–32] . The role of insulin in regulating plasma glucose highlights the potential importance of these mechanisms that represent advances in our understanding of stress hyperglycaemia and its association with poor outcomes following injury. The insulin stress response theory outlines potential mechanisms for stress hyperglycaemia and how it is an important indicator of both impaired tissue healing and complications following life threatening injury. These underlying mechanisms have remained unclear and the insulin stress response theory provides a basis to explain these important pathophysiological mechanisms. This new knowledge also highlights potential novel therapeutic strategies to prevent these poor outcomes associated with stress hyperglycaemia following life threatening injury.
1.4 The development of the insulin stress response theory-
The principal event that conceived the insulin stress response theory was preliminary clinical research carried out by members of this research team when investigating the stress response to injury in patients undergoing elective surgery. This clinical research was a small preliminary study designed to lead onto a larger more confirmatory research study. It is important to note that the results of this preliminary study were obtained using post hoc analysis and therefore these results need to be confirmed by a priori clinical research. Elective surgery provides suitable conditions where insulin secretion may be studied following tissue injury. In particular, the clinical setting of elective surgery allows for the comparison between unstressed conditions with stressed conditions occurring immediately following surgery.
