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Lixisenatide improves beta cell function without altering beta cell mass in New Zealand Obese mice (#221)

Benjamin J Lamont 1 , Matthew F Waters 1 , Sof Andrikopoulos 1
  1. The University of Melbourne, Heidelberg, VIC, Australia

Early use of aggressive anti-hyperglycaemic drug therapy in type 2 diabetes can improve pancreatic beta cell function and thus reduce the progressive decline in blood glucose control. GLP-1R agonists have been shown to directly improve beta cell function and can also protect beta cells against apoptosis. In contrast, exogenous insulin is thought to preserve insulin secretory function by reducing exposure to elevated blood glucose.
In this study we directly compared the effects of lixisenatide (lixi) and insulin glargine (glargine) on beta cell mass and function in a mouse model of type 2 diabetes. We also determined whether the combination of these two agents could have an additive benefit for maintaining insulin secretory function. Prior to the onset of hyperglycaemia, New Zealand Obese (NZO) mice (n=8-10) were injected twice daily with lixi (10 nmol/kg), glargine (5 IU/kg) or a combination of both (10 nmol/kg and 2.5 IU/kg) for 8 weeks. Blood glucose and body weight was measured weekly. At the end of the treatment period, 24-h after the final injections, an IVGTT was performed to assess beta cell function, and pancreas was collected for histological analysis.
Lixi and glargine similarly reduced blood glucose levels (6.8 and 6.5 vs. 9.4mM 2-h after injections), and the effect of the combination was slightly greater (4.7 mM). Lixi therapy reduced body weight gain, while glargine led to increased body weight. The combination was weight neutral. Lixi improved glucose stimulated insulin levels (AUCinsulin: 83.5 ± 18.3 vs. 26.0 ± 4.2 ng/ml x min), and the addition of glargine did not further increase this response (AUCinsulin: 75.3 ± 16.6 ng/ml x min). Glargine alone had only a mild effect on insulin secretion (AUCinsulin: 42.1 ± 9.1 ng/ml x min). Beta cell mass was not altered by any of the drug therapies. This study in mice suggests that the use of lixi prior to the onset of overt hyperglycaemia may have a greater potential than insulin therapy to improve beta cell function. We also found that an improvement in insulin secretion with GLP-1R agonist therapy can occur without an increase in beta cell mass.

  1. Sanofi-Aventis Australia Pty Ltd provided funding for this study. This company was not involved in the design, collection, analysis or interpretation of the study, but they were given the opportunity to review this abstract prior to submission. The decision to submit for publication was made by the authors independently.