ESPE Yearbook of Paediatric Endocrinology

Nature 2024;634(8035):944-951. PMID: 39415004

Brief summary: This study reports the design and properties of NNC2215, an insulin conjugate with a bioactivity reversibly responsive to ambient glucose, due to a switch between an active and less-active conformation status. The insulin receptor affinity for NNC2215 increased 3.2-fold following glucose increases from 3 to 20 mM. In animal models, NNC2215 was able to protect against hypoglycemia while partially covering glucose excursions.

Developing glucose-sensitive insulins that can automatically adjust their activity in response to fluctuations in blood glucose levels has long been a key goal to improve diabetes management (1).

NNC2215 was created by modifying human insulin at specific regions and consists of an insulin backbone (DesB30 Human insulin -degludec), a glucose-binding macrocycle (ring shaped molecule) in the B29 region anda glucoside (glucose-derived molecule) in the B1 region. At high glucose concentrations, glucose binds to the macrocycle leading to an open conformation, whereas at low glucose concentrations, the glucoside occupies the macrocycle, putting NNC2215 into a closed conformation, with a low affinity for the insulin receptor, thus preventing hypoglycemia.

Safety and effectiveness of NNC2215 were tested through various in vitro experiments using genetically modified hamster kidney cells and in vivo using animal models (mice and pigs).

In insulin receptor-binding studies, NNC2215 demonstrated a 12.5-fold increase in insulin receptor binding affinity when glucose was raised from 0 to 20 mM and a 3.2-fold increase for changes from 3 to 20 mM. In animal studies, NNC2215 demonstrated glucose-responsive behavior by adjusting insulin release according to blood glucose levels in rats. In pig models, it also showed a protective effect against hypoglycemia. NNC2215 could compensate for up to 30% of additional human insulin when lower doses of NNC2215 were administered.

NNC2215 shows potential to enhance diabetes treatment by reducing the risk of hypoglycemia and partially addressing the need for rapid-acting mealtime insulin. This may enable more aggressive insulin titration than is currently possible. However, it remains to be determined whether NNC2215 can accurately respond to fluctuations in glucose levels within a tighter more physiological glycemic range. Clinical trials are also needed to establish the safety and efficacy of NNC2215 in humans.

Reference: 1. Liu Y, Wang S, Wang Z, Yu J, Wang J, Buse JB, Gu Z. Recent Progress in Glucose-Responsive Insulin. Diabetes.2024;73(9):1377-1388.