Why has the insulin stress response remained unrecognised within clinical medicine?

2.3 The reasons why the insulin stress response has remained unrecognised within clinical medicine are multifactorial. These are outlined below and are listed in order of importance in terms of the sequence of steps that are required to understand this theory- 

1. The counterintuitive endocrine argument- the actions of counterregulatory stress hormones directly oppose many of the actions of insulin and also inhibit insulin secretion. Therefore the role of insulin during the stress response to injury is limited by these factors and this hormone cannot function as a stress response hormone. These assumptions represent current accepted knowledge on the role of insulin following life threatening injury. 

The first step in understanding the insulin stress response theory challenges these long held assumptions. This theory proposes novel unrecognised functions of insulin which include the requirement to increase glucose delivery to the immune system and the wound to generate the inflammatory response to life threatening injury. 

In this context the insulin stress response theory postulates increases in glucose stimulated insulin secretion (GSIS) following injury. This is coupled with the actions of the counter regulatory stress hormones to mediate insulin resistance and increased glucose production. These are mechanisms to switch glucose delivery to tissues that have a critically important requirement for glucose following life threatening injury. This occurs when transitioning from the unstressed to the stressed state, where the insulin stress response highlights the role of insulin as a hormone that transports glucose across the cell membrane. These actions divert glucose delivery from insulin sensitive tissues (the liver, adipose and muscle tissues) to the immune system which has significantly increased glucose requirements following activation of the innate immune system. 

The insulin stress response is postulated to have additional functions within the systemic inflammatory response firstly by inhibiting pro-inflammatory mediator release (through the actions of leucocyte PPAR alpha receptors) and secondly through the actions of growth factors secreted during the resolution phase of the inflammatory response.

2. Fasting insulin concentrations- it is necessary to measure fasting insulin concentrations to demonstrate the insulin stress response. This is to eliminate insulin secretion that may occur in response to an external caloric load. The ideal experimental conditions to measure the insulin stress response should eliminate factors that may influence insulin secretion other than the response to injury. 

There are significant practical and ethical difficulties in measuring fasting insulin concentrations in response to injury. Nutrition is essential for recovery following life threatening injury; limiting caloric intake even for short periods may have deleterious consequences for the patient. The requiement to measure fasting insulin concentrations also limits clinical research studies to planned tissue injuries, for example, following planned elective surgery. This response cannot be studied in subjects with emergency or unplanned tissue injuries.

3. The absolute delta value (ΔV)- analysing the change in fasting insulin concentration from the unstressed to the stressed state most accurately demonstrates the changes in insulin concentration that occur in response to injury. The delta value is superior to absolute insulin concentrations in demonstrating this pattern of response.  As unstressed fasting insulin concentrations are highly variable between individuals, using the absolute delta value to measure the insulin stress response eliminates this variability within the analysis. 

4. The paradoxical insulin stress response- the paradoxical inslin stress response results in a highly variable insulin secretory response to injury. In these circumstances a proportion of subjects with high unstressed insulin values will experience a fall in insulin values following injury. This contrasts with the normal regulated response which consists of an increase in insulin values from the unstressed to the stressed state. Due to these contrasting insulin responses within a group of subjects this may result in minimal changes in absolute values of insulin from the unstressed to the stressed state. (see slideshow 2 slides 1-6)

5. It is postulated that a paradoxical insulin stress response represents a dysregulated response which occurs in subjects with insulin, leptin and GIP resistance. This paradoxical response may result in a precipitous fall in insulin secretion in subjects with significantly elevated fasting insulin values. Consequently, as the incidence of insulin resistance within the population has increased in tandem with rates of obesity, a significant proportion of subjects may experience a paradoxical insulin response. This results in a large range of absolute insulin concentrations following injury which has clouded the regulated insulin stress response that occurs in response to injury.

6. Mathematical modelling techniques are required to most accurately measure the relationships between mediators within this complex integrated physiological response. With these techniques it is possible to analyse the endocrine roles of different mediators in the regulation of the stress response following injury. Such a model measuring incretin (GIP) and adipokine (Visfatin/NAMPT) mediators is required to demonstrate their functions in regulating GSIS from beta cells of the pancreas. This includes the regulation of both the change in fasting insulin concentration (regulated by GIP) as well as absolute values of insulin concentrations (regulated by visfatin/NAMPT) in the blood.

The role of insulin within the blood has been investigated in the setting of major trauma and has been demonstrated to exhibit a highly variable response to injury. However, this highly variable response was not demonstrated to have any identifiable pattern following injury. The study of insulin secretion following tissue injury has also previously involved measuring insulin secretion in animal models with the assumption that these mechanisms apply to humans-these assumptions still feature in current review articles on the stress response to injury.  This section discusses the areas that remain uncertain in terms of the insulin stress response theory. 

2.3.1 A Historical Perspective

The first published reports by Cuthbertson of the endocrine components of the stress response to injury were a major advance in our understanding of the pathophysiological response to injury [76]. These reports highlighted the role of the hypothalamic pituitary adrenal axis as a key endocrine stress pathway activated following injury. Cuthbertson and other researchers at this time also highlighted the increases in basal metabolic rate that occurred following life threatening injury. The role of insulin as an anabolic hormone within the highly catabolic stress response was considered to be less significant in contrast to the roles of the counter regulatory hormones epinephrine, cortisol and glucagon. During the 1970s and 80s this assumption was supported by research reporting that insulin secretion was inhibited following life threatening injury [26,27,77–79]. These  assumptions for the role of insulin following life threatening injury have remained to the present time and are a feature of review articles on this topic[17,80]. 

2.3.2 Advances in biomedical science and the stress response to tissue injury-

Advances in biomedical science have resulted in improved understanding of the underlying mechanisms of the stress response to life threatening injury. These advances have occurred in many areas of medical science including endocrinology, immunology and biochemistry, leading to improvements in our knowledge of the integrated nature of this physiological response. For example, the discovery of incretin endocrine mediators has led to significant advances in our understanding of how insulin secretion in regulated by the pancreas. In addition, our understanding of the endocine functions of adipose tissue have also highlighted previously unkown roles for adipose tissue. This is important in relation to visceral adipose tissue and its association with fasting insulin secretion which have resulted in major advances in  our understanding of metabolic diseases. 

Advances in laboratory medicine have also contributed to improved understanding of the underlying mechanisms of the stress resposne. Modern laboratory analytical methods have revolutionised bioassay techniques enabling multiple peptide mediators to be simultaneously analysed from a single blood sample. Coupled with modern data analysis techniques, these technologies allow a more detailed analysis of the complex endocrine mechanisms underlying the stress response to injury. These advances allow detailed analysis necessary to investigate multiple potential endocrine regulatory mechanisms involving immune, metabolic and endocrine mediators within the stress response to injury. 

2.3.3 Counter-regulatory hormones antagonise the functions of insulin-

The stress response to injury involves the release of counter-regulatory hormones into the bloodstream producing a metabolic state that antagonises many of the actions of insulin. The combined actions of these counter regulatory hormones  including cortisol, epinephrine, norepinephrine, glucagon and cytokines produce a profoundly catabolic state which directly opposes the actions of insulin. These counter regulatory endocrine actions are considered a defining feature of the metabolic response to injury resulting in increases in the basal metabolic rate as well as profound muscle and adipose tissue breakdown. Therefore, the role of insulin within this response is assumed to be diminished where the functions of counter regulatory hormones dominate over the actions of insulin. 

The counter regulatory endocrine hormones mediate changes in cell metabolism within insulin sensitive tissues that directly oppose the actions of insulin. The actions of these hormones are mediated by specific receptor mediated effects that activate signal transduction pathways resulting in an array of changes in cell function. These changes in cell function may include altered receptor sensitivity, changes in enzyme activity or adaptations in gene expression depending on the underlying mechanims of these hormones. For example, the actions of the counter regulatory hormones mediate insulin resistance in insulin sensitive tissues which inhibits the actions of insulin due to phosphorylation of insulin receptor subunits. Insulin resistance has an important function within the stress response to injury where inhibtion of insulin in these tissues results in increases in the availability of glucose to the vital organs and the wound following injury. Whilst Insulin resistance has a beneficial role following injury, in certain circumstances high levels of insulin resistance following life threatening injury have been linked with stress hyperglycaemia and increases in morbidity and mortality following life threatening injury.  This subject is explored in more detail in the section 

2.3.4 Counter regulatory hormones and inflammatory mediators inhibit insulin secretion-

The above assumptions regarding the role of insulin within the metabolic response to injury are supported by research indicating that insulin secretion from the pancreas is inhibited following life threatening injury. This research includes both human  and laboratory studies which indicate that insulin secretion by the pancreas is inhibited by the actions of catecholamines (epinepthrine) and cytokines  [26,27,77–79]. 

These assumptions were investigated in research carried out in trauma patients by Heath and  by Frayn et al . who studied insulin concentrations in the blood in trauma patients admitted to specialist trauma units. These studies concluded that plasma insulin concentrations following trauma showed a highly variable range of responses, and particularly In the most severe cases of trauma, the insulin response appeared to be inhibited in relation to plasma glucose concentrations. In these severe trauma cases this relative lack of insulin was associated with stress hyperglycaemia and supported these mechanisms that inhibited insulin secretion following life threatening injury. 

These research findings have supported the notion that the role of insulin following life threatening injury is limited by the actions of the counter regulatory hormones and also by the relative inhibition of insulin secretion by the pancreas. Stress hyperglycaemia following life threatening tissue injury is considered to result from a combination of these two factors. The clinical significance of stress hyperglycaemia is increasingly recognised to play an important role in terms of excess morbidity and mortality following tissue injury.. This is discussed in more detail in the section stress hyperglycaemia. An overview of the stress response to injury .   

2.3.4 Additional Practical and Ethical Considerations-

Practical and ethical factors have also contributed to the insulin stress response remaining unrecognised within clinical medicine. As Insulin concentrations in the blood are altered in response to any caloric input (either enterally or parenterally) this limits the ability to measure the insulin secretory response to injury. Fasting insulin concentrations provide a suitable measure of insulin secretion that is not altered by recent caloric input. However, following injury the ability to measure fasting insulin concentrations is limited due to the importance of providing nutritional support to patients following life threatening injury.  In order to accurately measure the insulin response to injury the requirement to obtain fasting mediator concentrations limits our ability to investigate this response. Ethical considerations limit fasting blood samples following life threatening injury and are only justifiable where recommended nutritional input has been achieved by subjects and where early morning fasting samples are performed after a period of sleep.

In addition, practical considerations also limit comparisons of host insulin concentrations between the unstressed and stressed states. This comparison is more accurately made by measuring unstressed values prior to life threatening injury, rather that following recovery from injury. In many circumstances it is not practical to obtain fasting insulin measurements prior to acute tissue injury in emergency medical scenarios. Elective surgery therefore represents one of the few settings in which fasting insulin concentrations can be measured both prior to and immediately following injury. The setting of elective surgery is one of the few settings in which to study the metabolic response to injury. 

Finally, fasting insulin concentrations vary significantly between individuals where normal values for healthy individuals are difficult to define [85]. For this reason fasting insulin concentrations are rarely measured in routine clinical practice as the interpretation of these measurements is unclear.  Therefore following life threatening injury values of fasting insulin concentrations will reflect both the response to injury as well as other factors that result in this variation (eg metabolic factors ). The component reflecting the insulin stress response to injury is likely to be "hidden" within these different factors and is more accurately reflected by measuring the change in concentration from pre-injury values. 

Overall the use of fasting insulin concentrations requires a number of assumptions to interpret these values with accuracy in the setting of life threatening injury. These include the need to fast for 6 hours prior to measuring this mediator in the blood. Fasting insulin concentrations are a practical method of estimating insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA IR) [33,34] The use of fasting insulin concentrations to analyse insulin secretion by the pancreas represents a practical method of estimating insulin resistance. More accurate methods to measure insulin resistance involve invasive procedures that are challenging in subjects undergoing elective joint replacement surgery. Measurement of insulin resistance using the insulin clamp technique is the gold standard method of analysing this important response, however, in the setting of acute tissue injury these measurements entail practical difficulties.