Insulin resistance as a protective mechanism
If the muscle tissues of the heart are overwhelmed by nutrients, they run the risk of collapsing metabolically, and will no longer be able to do their job, which is to keep the heart beating. One hypothesis is therefore that cardiomyocytes develop insulin resistance to protect themselves against this fatal outcome (12, 13). Different degrees of insulin resistance may be induced in a similar manner in the liver, adipose tissue or skeletal muscle. When viewed thus, insulin resistance is not part of the pathogenesis of type 2 diabetes in the traditional sense, i.e. something which must be overcome by increasing doses of insulin, but rather a physiological defence mechanism against intracellular metabolic stress.
When insulin resistance is induced however, the beta cells respond by increasing insulin production to maintain blood glucose at a normal level. This enables the body to partition energy specifically between different organs, for example with increased relative insulin effect in adipose tissue and increased storage of energy, while the heart is better protected because increased exposure to insulin there is matched by reduced insulin sensitivity. For the body this is a choice between two evils, because the defence of the heart increases the burden on the other organs.
Although an insulin resistant heart is somewhat protected against caloric intoxication, the risk of cardiovascular disease is still elevated. This is due to the many other risk factors which are associated with metabolic disease, e.g. hypertension, dyslipidaemia and inflammation. These may cause atherosclerosis, which may lead to coronary disease, with an increased risk of myocardial infarction and cardiovascular death. Over time, metabolic overload may lead to ectopic storage of fat in the heart, so-called «fatty heart», which is harmful for its function. Furthermore, diabetic cardiomyopathy is associated with an increased risk of heart failure.
This pathogenesis contrasts with that of uncontrolled type 1 diabetes, in which there is also hyperglycaemia, relative hypertension and inflammation, and therefore increased risk of cardiovascular disease. In type 1 diabetes, however, the body does not suffer from caloric surplus and caloric intoxication, which is the case in type 2 diabetes. On the contrary, the cells are starving due to the absolute lack of insulin, and insulin resistance is therefore seldom observed.
Insulin resistance is controlled precisely by intracellular signalling mechanisms, and may be induced by many different conditions and stimuli, e.g. oxidative stress, glucocorticoids and hyperinsulinemia (18). There are several examples of insulin resistance being induced naturally in the body, such as during puberty and pregnancy, most likely due to prioritising energy for the development of the brain and the foetus respectively. It has been shown that reduced insulin sensitivity can be induced in healthy people of normal weight after only one month of overeating with a 40 % increase in caloric intake, and this happens before overweight is established (19). The condition is reversible upon subsequent caloric restriction, which shows that the system has a considerable degree of plasticity, and may be scaled upwards or downwards based on the energy balance in the body.
The problems arise, however, when caloric surplus is maintained over time. This provokes a higher degree of insulin resistance in metabolically stressed organs, among them adipose tissue. When the body reaches its maximum storage capacity, the upper limit of insulin resistance is also reached, and further beta cell compensation with increased insulin production is futile. Further hyperinsulinemia in such a case may be detrimental, for example for heart muscle tissue, because it will become subject to metabolic overload (12, 13). In light of this scenario, it has recently been proposed that «beta cell failure» in itself may also represent an adaptive physiological defence mechanism, where the beta cells do not necessarily collapse due to overwork, but reduce their insulin production actively to protect vital organs, and themselves, from overexposure to insulin (20). This is still only an hypothesis, but what is clear is that the beta cells are in a precarious position: They are set to monitor blood glucose and respond to increases in blood glucose by secreting insulin. When this no longer works because the effect of insulin has diminished, the resulting hyperglycaemia may also harm them. By reducing their uptake of glucose, and thereby their insulin production, acute beta cell death may be prevented. This may contribute to maintaining some level of insulin production, and may therefore delay an even more rapid progression to serious diabetes. If the beta cells in the body are subjected to chronic hyperglycaemia under experimental conditions, insulin production is reduced, but the beta cells do not die, because the condition is reversible upon release of the hyperglycaemic pressure (21). Whether the hypotheses around adaptive beta cell failure have any validity remains to be seen, but they are interesting because they are in radical conflict with the current paradigm on the role of the beta cells in the pathogenesis of type 2 diabetes.