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Smooth Muscle Insulin Receptor Deletion Causes Voiding Dysfunction: A Mechanism for Diabetic Bladder Dysfunction

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posted on 25.07.2022, 13:35 authored by Huan Chen, Ali Wu, Mark L. Zeidel, Weiqun Yu

Diabetic bladder dysfunction (DBD) is the most common complication in diabetes mellitus (DM). Myogenic abnormalities are common in DBD, however, the underlying mechanisms leading to these remains unclear. To understand the importance of smooth muscle insulin receptor (IR)-mediated signaling in the pathogenesis of DBD, we conditionally deleted it to achieve either heterozygous (SMIR+/-) or homozygous (SMIR-/-) deletion in smooth muscle cells. Despite impaired glucose and insulin tolerance seen with SMIR-/- mice, both SMIR+/- and SMIR-/- mice exhibited normal blood glucose and plasma insulin levels. Interestingly, these mice had abnormal voiding phenotypes, that included urinary frequency and small voids, and bladder smooth muscle (BSM) had significantly diminished contraction force. Morphology revealed a dilated bladder with thinner BSM layer, and BSM bundles were disorganized with penetrating interstitial tissue. Deletion of IR elevated FoxO and decreased mTOR protein expression, which further decreased the expression of Chrm3, P2x1, Sm22, and Cav1.2, crucial functional proteins for BSM contraction. Furthermore, we determined the expression of adiponectin in BSM, and deletion of IR in BSM inhibited adiponectin-mediated signaling. In summary, disruption of IR-mediated signaling in BSM caused abnormalities in proliferation and differentiation, leading to diminished BSM contractility and a voiding dysfunction phenotype that recapitulates human DBD. 

Funding

The authors acknowledge funding received from the U.S. National Institute on Aging/ National Institutes of Health grant R21AG064633 (W.Y), National Institute on Diabetes and Digestive and Kidney Diseases/National Institutes of Health grant R01DK126674 (W.Y), and financial support provided by the NIDDK Diabetic Complications Consortium (DiaComp, [http://www.diacomp.org)] www.diacomp.org), grant DK076169 (W.Y).

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