Smarter Modeling to Enable a Smarter Insulin.

Abstract

> I dream things that never were, and I say “Why not?” > > —George Bernard Shaw Pancreatic β-cells secrete insulin to maintain physiological health. While the glucose level is the principle driver of insulin secretion, β-cells also respond to other regulatory inputs including circulating metabolites (most notably amino acids), regulatory hormones, gut peptides, and neurotransmitters. Insulin secretion increases when glucose levels are high, thereby increasing total body glucose utilization and suppressing endogenous glucose production. Of critical importance, insulin secretion is suppressed when glucose levels are low, which protects against life-threatening hypoglycemia. There have been remarkable advances to enhance efficacy and safety of insulin therapy since the discovery of insulin 100 years ago. Insulin pharmacokinetics has been optimized through both formulation and modification of the peptide itself. Sophisticated mechanical devices can provide continuous insulin delivery and continuous glucose monitoring. Pancreatic islets can be transplanted, and bihormonal pumps more closely mimic normal physiology. Despite technological advances, most insulin-dependent patients do not achieve physiological glucose control. The risk of severe hypoglycemia is particularly troublesome because it limits the ability to safely achieve optimal glycemic control, which in turn makes it harder to protect against the long-term risk of microvascular complications (1,2). To underscore this point, half of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort experienced severe hypoglycemia (∼40 episodes per 100 patient-years) (3). Furthermore, self-reported severe hypoglycemia is associated with 3.4-fold increased risk of death during a 5-year follow-up period (4). The pursuit of a glucose-responsive insulin (GRI) therapy is an ambitious technical objective. In type 2 diabetes, incretin therapy enhances insulin secretion when glucose levels are high but does not cause hypoglycemia because it does not promote insulin secretion when glucose levels are low. Similarly, GRI technology aims to mimic the ability of β-cells …