A glucose-responsive insulin therapy protects animals against hypoglycemia

JCI Insight. 2018 Jan 11;3(1):e97476. doi: 10.1172/jci.insight.97476.

Abstract

Hypoglycemia is commonly associated with insulin therapy, limiting both its safety and efficacy. The concept of modifying insulin to render its glucose-responsive release from an injection depot (of an insulin complexed exogenously with a recombinant lectin) was proposed approximately 4 decades ago but has been challenging to achieve. Data presented here demonstrate that mannosylated insulin analogs can undergo an additional route of clearance as result of their interaction with endogenous mannose receptor (MR), and this can occur in a glucose-dependent fashion, with increased binding to MR at low glucose. Yet, these analogs retain capacity for binding to the insulin receptor (IR). When the blood glucose level is elevated, as in individuals with diabetes mellitus, MR binding diminishes due to glucose competition, leading to reduced MR-mediated clearance and increased partitioning for IR binding and consequent glucose lowering. These studies demonstrate that a glucose-dependent locus of insulin clearance and, hence, insulin action can be achieved by targeting MR and IR concurrently.

Keywords: Diabetes; Endocrinology; Glucose metabolism; Insulin; Metabolism.

MeSH terms

  • Animals
  • Antigens, CD
  • Blood Glucose
  • Cell Line
  • Diabetes Mellitus, Type 2
  • Disease Models, Animal
  • Glucose / metabolism*
  • Hypoglycemia / drug therapy*
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology*
  • Lectins, C-Type / drug effects
  • Liver / pathology
  • Macrophages
  • Male
  • Mannose Receptor
  • Mannose-Binding Lectins / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Receptor, Insulin / drug effects
  • Receptors, Cell Surface / drug effects

Substances

  • Antigens, CD
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Lectins, C-Type
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • INSR protein, human
  • Receptor, Insulin
  • Glucose