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

The reasons why the insulin stress response has remained unrecognised within clinical medicine are multifactorial and are outlined below. 

2.9 The counterintuitive endocrine argument- 

The counterintuitive argument states that the metabolic actions of counterregulatory stress hormones directly oppose many of the actions of insulin. This includes the role of these hormones to increase blood glucose concentrations whilst the actions of insulin lower blood glucose concentrations. As the actions of counter regulatory hormones are mediated through mechanisms that directly oppose the actions of insulin, the role of this anabolic hormone during the stress response to injury is limited and cannot function as a stress response hormone. 

The stress response to injury involves the release of multiple counter-regulatory hormones into the bloodstream producing a metabolic state that antagonises the actions of insulin. The combined actions of these counter regulatory hormones  including cortisol, epinephrine, norepinephrine, glucagon and inflammatory cytokines produce a profoundly catabolic state which directly opposes the anabolic actions of insulin. These counter regulatory endocrine actions are considered a defining feature of the metabolic response to injury resulting in increases in insulin resistance. In addition, the catabolic state produces increases in the host basal metabolic rate including 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. 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. 

However, whilst Insulin resistance has a beneficial role following injury, in certain circumstances high levels of insulin resistance following life threatening injury are considered to be linked with stress hyperglycaemia and increases in morbidity and mortality following life threatening injury. These assumptions represent current established knowledge of the metabolic actions of the stress response to injury. These assumptions imply that stress hyperglycaemia is primarily a result of excess insulin resistance mediated by host inflammatory and endocrine mechansims.  These assumptions hold that changes in insulin secretion by the pancreas following injury are not the primary pathogenic mechanism resulting in stress hyperglycaemia.  

The above assumptions regarding the role of insulin within the metabolic response to injury are also supported by research indicating that insulin secretion by 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]. 

Insulin secretion following tissue injury was investigated in research carried out in trauma patients by Heath and also by Frayn et al. who studied insulin concentrations in the blood in patients admitted to specialist trauma units. These studies concluded that plasma insulin concentrations following trauma showed a highly variable range of responses. 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 assumption 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 .   

The above assumptions represent current accepted knowledge on the role of insulin following life threatening injury and are directly challenged by the insulin stress response to injury theory. This theory proposes novel and previously unrecognised functions of insulin secretion following life threatening injury which include the requirement to increase glucose delivery to the immune system by the actions of insulin on leucocyte insulin receptors 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  to increase glucose metabolism (glycolysis) 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 increases the transport of 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 theory also postulates that increases in insulin secretion by the pancreas in response to life threatening injury has a range of addtional functions within the systemic inflammatory response. These include the inhibition of the release of the pro-inflammatory chemokine IP-10 (see preliminary research) and secondly through the actions of growth factors secreted during the resolution phase of the inflammatory response.

2.10 The requirement to measure fasting insulin concentrations- 

It is necessary to measure fasting insulin concentrations to investigate the insulin stress response to injury. Fasting insulin concentrations are required in order to eliminate insulin secretion that may occur in response to an external caloric load. The ideal experimental conditions to investigate the insulin stress response to injury should eliminate addtional factors that may influence insulin secretion from the pancreas such as nutrition, exogenous insulin and drugs that mediates changes in insulin secretion. 

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 limits clinical research studies on the regulation of insulin secretion following life threatening injury. For example, this response cannot be studied in subjects with emergency or unplanned life threatening injuries as fasting conditions cannot be guarenteed in these circumstances. Ethical considerations when conducting research studies in humans will permit periods of starvation where daily recommended nutritional input has been achieved by research participants and where early morning fasting samples are performed after a period of sleep. This has limited the scope to detect the insulin secretory 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 have until recently rarely been measured in routine clinical practice as the interpretation of these measurements is unclear.  Following life threatening injury values of fasting insulin concentrations will reflect both the response to injury as well as other metabolic factors that result in this variation (eg adiposity ). The component reflecting the insulin stress response to injury is likely to be "hidden" within these different factors.

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. However, whilst fasting insulin concentrations are a practical method of estimating insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA IR), their use in the post-injury state is less established [33,34] The use of fasting insulin concentrations to analyse basal insulin secretion by the pancreas represents a practical method of estimating insulin resistance in unstressed conditions. More accurate methods to measure insulin resistance involve invasive procedures that are challenging in subjects undergoing major elective 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.  

2.11 The delta insulin value (ΔV)- 

The insulin stress response theory postulates that 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 preliminary research indicates that the delta insulin 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 delta insulin value to measure the insulin stress response eliminates this variability within the analysis. 

Practical considerations limit comparisons of host insulin concentrations between the unstressed and stressed states. In many circumstances it is not practical to obtain fasting insulin measurements prior to acute tissue injury eg 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. 

2.12 The paradoxical insulin stress response- 

The paradoxical insulin stress response results in a decrease in fasting insulin concentrations in response to injury when compared to pre-injury (unstressed) fasting concentrations. The preliminary research indicates that this pattern of insulin response is typically observed in subjects with high pre-injury fasting insuin concentrations. Therefore, within a group of subjects undergoing major surgery, a proportion of subjects with high unstressed insulin values may experience a fall in fasting insulin values following injury. This contrasts with the presumed physiologically appropriate response which consists of an increase in GSIS from the unstressed to the stressed state.

The preliminary research indicates 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 pre-injury fasting insulin values. Consequently, as the incidence of insulin resistance within the surgical population has increased over time 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.

Due to the high variation firstly in fasting  unstressed insulin concentrations and secondly in the magnitude of the insulin response to injury, the net effect within a group of subjects is to produce smaller  changes in mean values of fasting insulin concentrations between the unstressed and the stressed states. (see slideshow 2 slides 1-6). However, within the group there may be changes in fasting insulin concentrations which have potentially clinically important consequences for the host. When the delta value is analyised this more accurately reflects the changes in insulin concentrations in response to injury.  

Statistical modelling techniques can measure the relationships between the serum concentrations of different endocrine mediators within this complex integrated physiological response. With these techniques it is possible to more accurately analyse potential 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 may form the basis 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. 

2.13 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]. 

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.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.  

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 endocrine functions of adipose tissue, including the discovery of the hormone leptin. This is also important in relation to the role of visceral adipose tissue as an endocrine organ that secretes a range of different adipokines. Recent important medical discoveries have identrified the role of visceral adipose tissue as a factor linked with metabolic diseases. Excess visceral adipose tissue is associated with elevated fasting insulin secretion and insulin resistance. 

2.14 Conclusions-

The above factors outline why the insulin stress response to life threatening injury has remained undetected by clinicians. For many years clinicians have understood that the stress response to injury produces a metabolic state with similarities to the pathophysiological state of diabetes where, for example, stress hyperglycaemia may be detected in trauma patients. This is referred to as the "diabetes of injury" and is assumed to arise due to a combination of increases in both glucose production and insulin resistance mediated by host counter-regulatory endocrine mechansims. This however, only recognises 2 of the 3 key metabolic components of the stress response to injury that increase glucose transmembrane flux in the post-injury state. The third component is the insulin stress response that enhances glucose flux across the cell membrane in cells that become insulin sensitive following injury. These cells have a increased requirement for glucose following life threatening injury. These mechanisms are also postulated to regulate blood glucose concentrations during the post injury state.