Obesity/metabolic syndrome are common risk factors for overactive bladder. This 
study aimed to investigate the functional and molecular changes of detrusor 
smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the 
role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction. Male 
C57BL/6 mice were fed with high-fat diet for 10 weeks. In vitro functional 
responses and cystometry, as well as PKC and Ca(v)1.2 expression in bladder were 
evaluated. Obese mice exhibited higher body weight, epididymal fat mass, fasting 
glucose and insulin resistance. Carbachol (0.001-100 µM), α,β-methylene ATP 
(1-10 µM), KCl (1-300 mM), extracellular Ca(2+) (0.01-100 mM) and 
phorbol-12,13-dibutyrate (PDBu; 0.001-3 µM) all produced greater DSM 
contractions in obese mice, which were fully reversed by the Ca(v)1.2 blocker 
amlodipine. Cystometry evidenced augmented frequency, non-void contractions and 
post-void pressure in obese mice that were also prevented by amlodipine. 
Metformin treatment improved the insulin sensitivity, and normalized the in 
vitro bladder hypercontractility and cystometric dysfunction in obese mice. The 
PKC inhibitor GF109203X (1 µM) also reduced the carbachol induced contractions. 
PKC protein expression was markedly higher in bladder tissues from obese mice, 
which was normalized by metformin treatment. The Ca(v)1.2 channel protein 
expression was not modified in any experimental group. Our findings show that 
Ca(v)1.2 blockade and improvement of insulin sensitization restores the enhanced 
PKC protein expression in bladder tissues and normalizes the overactive 
detrusor. It is likely that insulin resistance importantly contributes for the 
pathophysiology of this urological disorder in obese mice.