2.1.1 The Insulin Stress Response Theory-

The insulin stress response theory postulates two novel endocrine stress pathways that regulate the secretion of the hormone insulin following life threatening tissue injury. The preliminary research presented in the next section indicates that fasting serum insulin concentrations display a highly regulated response  to life threatening injury. This highly regulated response over time following life threatening injury is postulated to result from a specific secretory response by the pancreas to the physical stress of tissue injury. 

The changes in fasting serum insulin concentration described below are highly correlated with serum concentrations of endocrine mediators that are known to mediate changes in GSIS. The observed changes in fasting serum insulin concentration over time following injury also display a number of features which indicate they display a characteristic stress response to the physical injury. The insulin stress response theory proposes that these changes in fasting insulin concentration over time represent a temporary and reversible change in GSIS by the pancreas in response to life threatening injury. When the fasting serum insulin concentration time curve is measured following life threatening injury a characteristic pattern is observed which represents a specific stress response to injury (slideshow 1 slide 2) 

The insulin stress response theory proposes novel endocrine stress pathways that regulate changes in GSIS following life threatening injury. This endocrine stress response varies between individuals depending on a number of regulatory factors outlined below. These proposed regulatory stress mechanisms mediate a characteristic pattern in fasting insulin concentrations following life threatening injury. Importantly, this pattern is most accurately demonstrated when fasting serum insulin concentrations are analysed by comparing the change from pre-injury (unstressed) to the immediate post-injury (stressed) state- the delta value ΔV. When this comparison is measured between the unstressed to the stressed states the highly regulated nature of the insulin secretory response to tissue injury can be demonstrated.  

Following life threatening injury there are four principal features that indicate a specific insulin secretory stress response to life threatening injury. 

1. Following life threatening injury a change in fasting insulin concentration can be measured in the blood from the unstressed to the stressed state.  Within any group of subjects there is a wide range of changes in fasting insulin concentration observed between the unstressed to stressed states. 

2. The change in fasting insulin concentration from the unstressed to the stressed state is accompanied by a corresponding change in endocrine mediators that are known to regulate GSIS by the pancreas. Strong correlations are observed between the endocrine mediators including the incretin (Glucose dependent insulinotropic peptide-GIP) and the adipokine (visfatin/ NAMPT) peptides outlined below. 

3. Following the transition from the unstressed to the stressed state described above, an equal and opposite change in fasting insulin concentration over time is observed during the transition to return from stressed to the unstressed state following recovery from injury. Within a group of subjects, when the changes in fasting insulin concentration from the unstressed to the stressed state are compared with the corresponding changes from the stressed back to the unstressed state. a highly inverse correlation is observed between these measurements. This is postulated to represent a characterisitc stress response pattern in the secretion of insulin into the blood.

4. During this recovery period there are also corresponding changes in the concentrations of the same incretin and adipokine mediators that return back to their unstressed state concentrations. The transition from the stressed state to the unstressed state shows a reverse of these concentration changes. The changes in fasting insulin concentrations are similarly correlated with changes in these endocrine mediators.    

Fasting serum insulin concentrations measured during unstressed (resting) conditions are known to vary considerably between subjects depending on metabolic factors such as adiposity, nutritional status, and diabetes. The insulin stress response theory postulates that due to this variation in fasting insulin concentrations, the ability of the host to meet the metabolic demands of the stress response to injury are more accurately reflected by the change in fasting insulin concentration from the unstressed to the stressed state. This change in fasting insulin concentration (delta value ΔV) represents a more clinically significant measurement compared to absolute values of fasting serum insulin concentrations in the stressed state. For example, a subject with high fasting insulin concentrations under unstressed conditions has a limited ability to increase fasting insulin concentration in response to injury compared to a subject with normal unstressed fasting insulin concentrations. This is the key to understanding the insulin stress response to injury, where the change in fasting insulin concentrations over time more accurately identifies the response to injury compared to absolute fasting insulin concentrations. 

The characreristic pattern of fasting insulin concentrations includes an initial change from the unstressed state to reach a point of maximal change in concentration in the stressed state. Over time this is followed by an equal and opposite change in fasting insulin concentration to return the the unstressed state following recovery from the injury, The postulated concentration time curve of fasting insulin concentration over time following life threatening injury is displayed in Slideshow 1 slide 2.

When the change in fasting insulin concentrations from the unstressed to the stressed state is measured over time there are also corresponding correlations with changes in endocrine mediators that are known to regulate glucose stimulated insulin secretion from the pancreas. These endocrine mediators include the incretin hormone GIP and the adipokine visfatin/NAMPT. These correlations indicate that the change observed in fasting insulin concentrations are in part mediated by these two endocrine mediators which are both stress response endocrine mediators with key metabolic or immune functions following life threatening injury.

Therefore, the insulin stress response theory proposes that changes in the fasting concentration of insulin from the unstressed state to the stressed state following injury occur in part due to a change in GSIS mediated by both the incretin and the adipokine mediators. In addition, the nature of this response over time, where these mediators are observed to exhibit an equal but opposite change in concentration from the stressed state back to the unstressed state, further supports a stress response pattern of these mediators activated by life threatening injury.  

In addition, within a group subjects an important and hitherto unrecognised feature of the change in fasting insulin concentration following injury includes a range of values from a large increase to a large decrease. During the transition from the unstressed to the stressed state, some subjects exhibit a fall in fasting insulin concentrations whilst others may exhibit an increase; at the extreme range of these changes fasting insulin values may change by many multiples of their respective unstressed concentrations . The change in fasting insulin concentration from the unstressed to the stressed state is determined by changes in the concentration of both GIP and visfatin/NAMPT that are postulated to regulate insulin secretion following life threatening injury. 

In subjects that experience a fall in fasting insulin concentrations this is accompanied by a corresponding fall in GIP concentrations in the blood which indicates a decrease in pancreatic GSIS in response to injury. In these subjects the underlying pattern of the response to injury remains where the change from the unstressed to the stressed state (ie a fall in fasting insulin concentrations) is accompanied by an equal and opposite change from the stressed state back to the unstressed state (ie a rise in fasting insulin concentrations) . Therefore, despite the clearly dysregulated nature of the insulin stress response in these subjects, the underlying pattern of response to life threatening injury measured by temporary and reversible changes in fasting insulin concentrations remains.