Insulin at 100 years – is rebalancing its action key to fighting obesity-related disease?

One hundred years ago, insulin was purified and administered to people with diabetes to lower blood glucose, suppress ketogenesis and save lives. A century later, insulin resistance (IR) lies at the heart of the obesity-related disease pandemic. Multiple observations attest that IR syndrome is an amalgamation of gain and loss of insulin action, suggesting that IR is a misnomer. This misapprehension is reinforced by shortcomings in common model systems and is particularly pronounced for the tissue growth disorders associated with IR. It is necessary to move away from conceptualisation of IR as a pure state of impaired insulin action and to appreciate that, in the long term, insulin can harm as well as cure. The mixed state of gain and loss of insulin action, and its relationship to perturbed insulin-like growth factor (IGF) action, should be interrogated more fully in models recapitulating human disease. Only then may the potential of rebalancing insulin action, rather than simply increasing global insulin signalling, finally be appreciated.