Novel strategy for oral peptide delivery in incretin-based diabetes treatment

Gut. 2020 May;69(5):911-919. doi: 10.1136/gutjnl-2019-319146. Epub 2019 Aug 10.


Objective: To fulfil an unmet therapeutic need for treating type 2 diabetes by developing an innovative oral drug delivery nanosystem increasing the production of glucagon-like peptide-1 (GLP-1) and the absorption of peptides into the circulation.

Design: We developed a nanocarrier for the oral delivery of peptides using lipid-based nanocapsules. We encapsulated the GLP-1 analogue exenatide within nanocapsules and investigated in vitro in human L-cells (NCl-H716) and murine L-cells (GLUTag cells) the ability of the nanosystem to trigger GLP-1 secretion. The therapeutic relevance of the nanosystem in vivo was tested in high-fat diet (HFD)-induced diabetic mice following acute (one administration) or chronic treatment (5 weeks) in obese and diabetic mice.

Results: We demonstrated that this innovative nanosystem triggers GLP-1 secretion in both human and murine cells as well as in vivo in mice. This strategy increases the endogenous secretion of GLP-1 and the oral bioavailability of the GLP-1 analogue exenatide (4% bioavailability with our nanosystem).The nanosystem synergizes its own biological effect with the encapsulated GLP-1 analogue leading to a marked improvement of glucose tolerance and insulin resistance (acute and chronic). The chronic treatment decreased diet-induced obesity, fat mass, hepatic steatosis, together with lower infiltration and recruitment of immune cell populations and inflammation.

Conclusion: We developed a novel nanosystem compatible with human use that synergizes its own biological effect with the effects of increasing the bioavailability of a GLP-1 analogue. The effects of the formulation were comparable to the results observed for the marketed subcutaneous formulation. This nanocarrier-based strategy represents a novel promising approach for oral peptide delivery in incretin-based diabetes treatment.

Keywords: GLP-1; bioavailability; diabetes; nanocarriers; steatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analysis of Variance
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Administration Schedule
  • Drug Carriers / administration & dosage
  • Exenatide / administration & dosage*
  • Glucagon-Like Peptide 1 / drug effects*
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Incretins / administration & dosage*
  • Insulin Secretion / drug effects
  • Male
  • Mice
  • Nanocapsules / administration & dosage*
  • Random Allocation
  • Treatment Outcome


  • Drug Carriers
  • Hypoglycemic Agents
  • Incretins
  • Nanocapsules
  • Glucagon-Like Peptide 1
  • Exenatide