How long should a long acting insulin analogue be?

After the discovery of insulin in the last century, rapidly efforts were undertaken to prolong the duration of action of injected insulin, in a naïve attempt to achieve physiological insulin profiles by just one injection of insulin a day [1]. However, the insulin profile achieved by beta-cells is quite different from a continuous supply of insulin. Indeed, when reflecting on the gold standard in insulin therapy, the beta-cell itself, one can distinguish between on the one hand the small amounts of insulin being produced almost continuously aimed at keeping anabolism going and on the other hand the peaks of insulin released at moments where meals are entering the system. The main target organ for both the basal and the bolus insulin secretion of the beta-cell is the liver, with a substantial first pass effect. The major asset of the insulin secretion of the beta-cell is that it is glucose-sensitive and thus, in periods without meals, no peaks of insulin release will occur, but more importantly, when metabolism needs to switch to catabolism, also the basal secretion will diminish and shut down, allowing gluconeogenesis and glycogenolysis in liver to occur.