Mechanisms to Elevate Endogenous GLP-1 Beyond Injectable GLP-1 Analogs and Metabolic Surgery

Diabetes. 2018 Feb;67(2):309-320. doi: 10.2337/db17-0607. Epub 2017 Dec 4.

Abstract

Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (∼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)-deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (∼5-30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (∼300-400 pmol/L), drastically reducing glucose in Gipr null and Leprdb/db mice in a GLP-1 receptor-dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Drug Resistance
  • Drug Synergism
  • Drug Therapy, Combination
  • Drugs, Investigational / administration & dosage
  • Drugs, Investigational / therapeutic use*
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / therapeutic use
  • Hyperglycemia / prevention & control
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Models, Biological*
  • Proof of Concept Study
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / metabolism
  • Sitagliptin Phosphate / therapeutic use

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Drugs, Investigational
  • Ffar1 protein, mouse
  • Gpbar1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • Glucagon-Like Peptide 1
  • gastric inhibitory polypeptide receptor
  • Sitagliptin Phosphate