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Background: Diabetes bladder dysfunction (DBD) is a major urologic complication associated with type 2 diabetes (DM2). In a mouse model that develops DM2 using a hepatic-specific insulin receptor substrate 1 and 2 (Irs1/Irs2) deletions (double knockout: DKO), we have shown specific molecular alterations associated with DBD. Previously, we have shown that DBD occurs progressively with hyperactivity in the early stage and hypoactivity in late stage of DBD. Here we demonstrate that correction of hyperglycemia/hyperinsulinemia with a third hepatic-specific deletion of Foxo1 gene (i.e.: IRS1/IRS2/Foxo1 triple knockout: TKO) restores the bladder dysfunction in DKO type 2 diabetic animals.
Materials & Methods: Insulin and glucose levels were measured and glucose tolerance tests (GTT) were carried out in DKO, TKO and control animals at 4, 8, 12, and 20 weeks of age. Bladder functional alterations were evaluated by in vivo cystometry and voiding stain on paper (VSOP) for 12 and 20 week old mice. Bladders were harvested for ex vivo muscle strip contraction analyses.
Results: The DKO mice developed significant insulin resistance and glucose tolerance starting from 5 weeks of age, and persisted at the age of 8, 12, and 20 weeks. TKO animals with hepatic-specific deletion of Irs1/Irs2/Foxo1 genes did not develop hyperglycemia or hyperinsulinemia. In the diabetic DKO animals, the post void residual (PVR) urine volume in in-vivo cystometry was elevated and the voiding efficiency was lowered at 12 weeks and 20 weeks in comparison to the controls. The bladder compliance and capacity of 12 week but not 20 week DKO mice was lower than age-matched controls. An abnormal voiding pattern was observed in the DKO mice as determined by VSOP analysis with lower micturition volumes, and higher frequency of small volume voids. In TKO animal, the voiding parameters were restored to normal levels equivalent to age-matched controls.
Conclusions: Our findings demonstrate that secondary complication of diabetes, DBD, is corrected in diabetic animals with hepatic-specific genetic modification in the TKO mice, with deletions of IRS1/IRS2 & Foxo1 genes. Our findings suggest that the DKO and TKO reversible diabetic mouse model system is a rational model to evaluate the pathophysiology and molecular alterations associated with diabetic cystopathy.
Funding source:
NIH/NIDDK grant (Animal Models of Diabetic Complications Pilot & Feasibility Project, 09MCG72) and the American Urological Association/Pfizer Pharmaceutical Company competitive grants to AFO.