Type 2 diabetes in the overweight is often described as having heterogeneous pathophysiology, but also often is attributed to a duality of insulin resistance (insensitivity) and failure of compensatory insulin secretion. However, the term 'insulin resistance' is not an understanding of some pathological process, but merely a description of the finding that plasma insulin levels are high, and unable to bring high glucose levels down. Indeed a little thought will show that 'failure of compensatory insulin secretion' is a mirror of the same problem, as ultimately if insulin is not able to work properly it is bound to be the case that the body eventually reaches its limits in trying to overcome the problem by greater insulin delivery.
Insulin resistance as a pathological process has defied our understanding. Epidemiological associations of confusing variety have been described, but have contributed little understanding. Insulin receptors, receptor activation, and post-receptor pathways are wonderfully better described than 30 years ago, as are glucose transport systems, but all contributing so little insight that not one new medical product tackling the issue has arisen from these understandings. But is our thinking wrong? Perhaps our intuition that somehow the petrol (insulin) is not firing our engine (metabolism) correctly is wrong, and the real truth is that the mechanisms are so rusted that friction is preventing the car going faster. This then is not 'insulin resistance', a defect of insulin signalling and action, but something more fundamental, a problem with the functioning of cellular metabolism.
Thinking more fundamentally, type 2 diabetes is strongly associated with being overweight, often obese. Note 'associated', not 'caused by'. Studies of reduction of caloric intake show diabetes ameliorates long before there is significant body weight change, or indeed before there are major changes in muscle or liver fat. Measured insulin sensitivity also changes with a different, faster, time course compared with obesity and tissue fat. Further we are all familiar a class of drugs, the PPAR-γ agonists, that improve insulin sensitivity but worsen obesity. Exogenous insulin does the same.
Other pointers to the underlying problem come from our clinical experience with glucose-lowering medications, which are all extraordinarily ineffective – HbA1c falls of around 0.6 % (7 mmol/mol) in 18 months from a starting level of 8.0 % (64 mmol/mol) per single therapy. Why does physiology resist these drugs? A lesson from sulfonylurea use adds a further pointer – these agents are very effective at 1-2 weeks but only as good as metformin and rosiglitazone by 8 months. This really does look as though endogenous insulin, going straight to the liver, reverses its own efficacy with time.
Our knowledge of liver metabolism and its regulation has also improved in the decades – indeed continuously since the 1960s. This leads to the question as to what happens to the liver when faced with the non-physiological challenge of excess calorie load. To some extent the liver copes by turning it to fat, either for export or local storage (hence fatty liver), but even that throughput of metabolic substrates will stress hepatocyte metabolism via for example consumption of co-factors. In recent years our understanding is that pushed to extremes, and in order to protect its internal homeostasis, the liver stops taking up glucose, and indeed begins to export it, ridding itself of excess calories. Muscle also needs to limit glucose uptake once glycogen stores are full - merely burning off calories is not an option.
So type 2 diabetes is a consequence of metabolic calorie resistance, not insulin resistance.