The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice.
OBJECTIVE
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
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.
Nycomed: a Takeda company, Nycomed GmbH, Institute of Pharmacology and Preclinical Drug Safety, Department RDP/LP, Haidkrugsweg 1, 22885, Barsbüttel, Germany. Stefanie.Vollert@takeda.com.
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S
Vollert
Nycomed, Konstanz, Germany.
N
N
Kaessner
Nycomed: a Takeda company, Nycomed GmbH, Institute of Pharmacology and Preclinical Drug Safety, Department RDP/LP, Haidkrugsweg 1, 22885, Barsbüttel, Germany.
A
A
Heuser
Nycomed, Konstanz, Germany.
G
G
Hanauer
Nycomed, Konstanz, Germany.
A
A
Dieckmann
Actelion Pharmaceuticals, Allschwil, Switzerland.
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D
Knaack
Nycomed, Konstanz, Germany.
H P
HP
Kley
Nycomed, Konstanz, Germany.
R
R
Beume
Nycomed, Konstanz, Germany.
C
C
Weiss-Haljiti
D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D051379:Mice; D008817:Mice, Mutant Strains; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D000631:Aminopyridines; D001549:Benzamides; D001786:Blood Glucose; D003521:Cyclopropanes; D007004:Hypoglycemic Agents; D007328:Insulin; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D052216:Glucagon-Like Peptide 1; C517734:roflumilast N-oxide