Lixisenatide Resensitizes the Insulin-Secretory Response to Intravenous Glucose Challenge in People With Type 2 Diabetes--A Study in Both People With Type 2 Diabetes and Healthy Subjects

Diabetes Obes Metab. 2014 Sep;16(9):793-800. doi: 10.1111/dom.12278. Epub 2014 Mar 25.

Abstract

Aims: Glucagon-like peptide-1 (GLP-1) receptor agonists improve blood glucose control by enhancing glucose-sensitive insulin release, delaying gastric emptying and reducing postprandial glucagon secretion. The studies reported here investigated the insulin response to an intravenous (iv) glucose challenge after injection of lixisenatide (LIXI) 20 µg or placebo.

Methods: Two single-centre, double-blind, randomized, placebo-controlled, single-dose, crossover studies were performed in healthy subjects (HS) and people with type 2 diabetes mellitus (T2DM). Participants received subcutaneous LIXI or placebo 2 h before an iv glucose challenge. Study endpoints included first- and second-phase insulin response, insulin concentration (INS), glucagon response and glucose disposal rate (K(glucose)). LIXI exposure was measured over 12 h.

Results: LIXI 20 µg reached maximum concentration after 2 h and resensitized first-phase insulin secretion by 2.8-fold in T2DM to rates comparable with those in HS on placebo, and raised second-phase insulin secretion by 1.6-fold in T2DM. INS rose correspondingly and glucose disposal was accelerated by 1.8-fold in T2DM. First-phase insulin secretion and glucose disposal were also augmented by LIXI in HS, whereas second-phase insulin secretion reduced blood glucose concentrations to below fasting levels and then ceased, accompanied by a rapid, short-lasting rise in glucagon. Otherwise, suppression of glucagon release subsequent to augmentation of insulin release was unaffected in T2DM and in HS.

Conclusions: LIXI resensitized the insulin response to an iv glucose challenge in people with T2DM, thereby accelerating glucose disposal to nearly physiological intensity, and did not impair counter-regulation to low glucose levels by glucagon.

Keywords: healthy subjects; insulin response; lixisenatide; pharmacodynamics; pharmacokinetics; type 2 diabetes mellitus.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Fasting
  • Female
  • Gastric Emptying / drug effects
  • Glucagon / drug effects
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1 / agonists*
  • Glucose Tolerance Test
  • Healthy Volunteers
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Injections, Intravenous
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Male
  • Peptides / therapeutic use*
  • Postprandial Period
  • Treatment Outcome

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • lixisenatide
  • Glucagon-Like Peptide 1
  • Glucagon