I am a research scientist in the diabetes research unit at Novo Nordisk. More specifically I work in protein and peptide chemistry. We are the people who design and synthesise new drugs – of course with the help and input of a lot of other people from other departments.

I have been at Novo Nordisk for about two years now. This is my first "real" job; before I have been working at different universities in Germany, the UK and the United States, such as Ludwig Maximilians University in Munich, Oxford University and the University of California in Berkeley, as a Ph.D. student and as a postdoc.

Oral administration of insulin represents a formidable scientific and medical challenge. For oral insulin therapy to be a viable option, the insulin molecule must not only survive the aggressive environment of the gastrointestinal tract, but additionally must be effectively absorbed in intact form into the circulation with very little variation. I will present the molecular engineering of the first long-acting insulin analogues for safe and efficacious oral therapy.

Molecules were designed to have increased solubility and stability towards proteolytic degradation and additionally exhibit ultra-long pharmacokinetic profiles to minimize variability in plasma exposure following absorption. When formulated in sodium caprate tablets and dosed orally to dogs, these insulin analogues were rapidly absorbed with a bioavailability of 3-4% and displayed glucose lowering activity. An elimination plasma half-life, approximatel 20h in dogs and approximately 70h in man, was achieved by adding a strong albumin binding moiety to reduce clearance, lowering the insulin receptor affinity 500-fold. Furthermore, at peak absorption albumin binding ensured high liver exposure with minimal and slow distribution to peripheral tissues.

Thus, the peaked absorption profile mediated an initial liver-centric insulin action that was able to blunt hypoglycaemia even in response to overdosing. These tailor-made long-acting insulin analogues have enabled the first successful once daily chronic administration of basal oral insulin in man, providing effective glucose control with no additional hypoglycaemia incidents compared to injectable insulin glargine.