2.4 The benefits of a proof of concept study-

2.4.1 Testing the hypothesis-

The proposed proof of concept study aims to test the hypothesis of the insulin stress response theory with the aim to establish this theory as a fundamental component of the stress response to injury, This would represent a transformation in our understanding of the role of Insulin as a stress response hormone. The insulin stress response theory proposes a number of features which have potential benefits for patients in terms of new therapies to improve outcomes following life threatenig tissue injuyr. This research also demonstrates a model to study the stress response to injury and to understand the underlying mechanisms that control this important integrated physiological response. 

2.4.2 A vision of the future management for life threatening tissue injury-

This research aims to confirm a new concept in metabolic and endocrine physiology following tissue injury that has potential benefits across a wide range of medicine. As outlined in the section the knowledge gap that this research addresses, this knowledge is relevant to surgery, trauma, sepsis, myocardial infarction, stroke and many other areas of medical practice. In particular, this research provides a mechanistic framework to consider new therapies for stress hyperglycaemia following life threatening tissue injury. Confirmation of these underlying mechanisms by the proof of concept research study would lead to a range of new therapeutic options to target stress hyperglycaemia in the different settings that it occurs. This includes predicting its occurrence from baseline medical parameters in the elective surgical setting, as well as treatment with insulin, GIP agonists and visfatin/NAMPT in subjects where the trajectory of these mediators are deficient or dysregulated. In addition this model also highlights underlying endocrine mechansims that demonstrate how diabetic subjects develop increased complications following life threatening tissue injury.  

For example, a vision for the future is for patients undergoing (major) surgery to have a metabolic assessment prior to surgery as part of the pre-assessment process. Simple metabolic parameters would be performed including anthropometric measurements as well as fasting serum metabolic mediators (incretins, insulin and adipokines). Following pre-assessment these parameters would  predict the metabolic stress response characteristics for individual patients. This includes predicting insulin stress response responders and non-responders. This would highlight potential therapeutic options including insulin or GIP therapies to prevent stress hyperglycaemia. 

 2.4.3 New Endocrine Stress Pathways-

The insulin stress response proposes two separate endocrine pathways that mediate increases in insulin secretion following life threatening injury. These two pathways represent new endocrine stress mechanisms within the human body. Both these pathways are fundamentally new concepts within clinical medicine and aid our understanding of the body's response to physical stress.

2.4.4 An incretin endocrine pathway-

The first pathway is an incretin pathway involving the hormone GIP that regulates insulin secretion following life threatening injury. This proof of concept study would establish new knowledge of the role of incretins within the stress response to injury. This research proposes a strong link between the secretion of the hormones GIP, insulin and leptin, where the activation of these hormones share common patterns in their response to injury. These common features include a paradoxical response in subjects who have high unstressed concentrations of these hormones.

This model is designed to represent the underlying mechanisms of the stress response to life threatening injury highlights important human stress mechanisms which include the role of the resting unstressed concentration in regulating both the GIP and the insulin response to injury. This analysis illustrates how both GIP and insulin respond to injury is determined in part by the unstressed resting concentrations of these hormones. These mechanisms highlight the importance of the unstressed concentrations of these hormones for human health. If these unstressed concentrations are high the host has no reserve to increase the secretion of these hormones in response to injury. In cases where the unstressed concentrations are highest this results in a large decrease in the secretion of these hormones- a paradoxical response. This mechanism is postulated to explain the poor prognosis that is known to occur in subjects without diabetes who experience stress hyperglycaemia following life threatening injury. 

2.4.5 An adipokine endocrine pathway-

The second endocrine pathway identified links visceral adipose tissue with the secretion of the adipokine visfatin/NAMPT in the stress response to injury. The aim of this proof of concept study is to demonstrate this mediator as an important regulator that integrates the metabolic and immune responses to life threatening injury.This research would also confirm the dual endocrine functions of visfatin/NAMPT that mediate both insulin secretion as well as insulin resistance. These contradictory functions are explicable during the host response to injury; in these circumstances, increases in insulin secretion are considered a stress response that functions to increase glucose delivery to the wound and cells of the immune system. This is also a new paradigm in considering the role of visceral adipose tissue in the stress response to injury. Importantl;y, this research identifies these functions as stress mechanisms and highlight this role only during the response to injury . This explains why previous research in humans has failed to identify a role for this adipokine in the regulation of insulin secretion.

2.4.6 Wider benefits of the proof of concept study- 

Finally the benefits of this proof of concept study are not limited to new knowledge relating to the stress response to injury. These stress mechanisms are relevant to many common human diseases where pathophysiological mechanisms involve both insulin and adipose tissue. In particular, the identification of these stress mechanisms offer the hope of identifying new causative mechanisms for many of the common metabolic diseases. For example these mechanisms provide a model to understanding how obesity is associated with an wide range of different metabolic sequelae including insulin resistance and elevated levels of insulin secretion. This would place both these endocrine stress pathways involving GIP and visfatin/NAMPT as important pathophysiological mechanisms of the adverse metabolic sequelae associated with obesitry.