The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

  • Diabetologia. 2012 Oct;55(10):2779-2788. doi: 10.1007/s00125-012-2632-z.
S Vollert  1 ,  N Kaessner  2 ,  A Heuser  3 ,  G Hanauer  2 ,  A Dieckmann  2 ,  D Knaack  4 ,  H P Kley  2 ,  R Beume  2 ,  C Weiss-Haljiti  2
Affiliations
  • 1. Nycomed: a Takeda company, Nycomed GmbH, Institute of Pharmacology and Preclinical Drug Safety, Department RDP/LP, Haidkrugsweg 1, 22885, Barsbüttel, Germany. [email protected].
  • 2. Nycomed, Konstanz, Germany.
  • 3. Nycomed: a Takeda company, Nycomed GmbH, Institute of Pharmacology and Preclinical Drug Safety, Department RDP/LP, Haidkrugsweg 1, 22885, Barsbüttel, Germany.
  • 4. Actelion Pharmaceuticals, Allschwil, Switzerland.
PMID: 22790061 DOI: 10.1007/s00125-012-2632-z
Abstract

Aims/hypothesis: The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 Inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects.

Methods: Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA(1c), blood glucose, serum Insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on Insulin release was investigated in primary mouse islets.

Results: Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5- and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA(1c) by 50% and doubled fasted serum Insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolin-induced Insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling.

Conclusions/interpretation: Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and Insulin activities.

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