Elevated expression of urotensin II and its receptor in skeletal muscle of diabetic mouse

Urotensin II (UII) is a somatostatin-like peptide recently identified to be involved in metabolic regulation and to play a significant role in diabetes and its complications. In the present study, we investigated the expression of UII and its receptor UT in the soleus muscle of male diabetic KK/upj-AY/J mice (2DM group) and the effects of UII on glucose uptake by the skeletal muscle to explore the role of skeletal muscle-derived UII in the pathogenesis of insulin resistance and diabetes. Radioimmunoassay, RT-PCR, immunohistochemistry and radio-ligand binding assay were used in this study. Compared with C57BL/6J mice (control group), 2DM mice showed increased UII content, by 34.0% in plasma, 15.4% in skeletal muscle tissue and 30.6% in medium containing UII from muscle (all P < 0.05 or P < 0.01). UII protein and UT mRNA expression were significantly enhanced in the skeletal muscle of 2DM mice. On [125I]UII binding to muscle sarcolemma, UT binding exhibited a saturable single-component characteristic in a specific and time-dependent manner. Scatchard plot analysis showed higher maximal number of specific binding sites (Bmax) in skeletal muscle, by 42.9% (P < 0.01), and a lower dissociation constant (Kd), by 26.4% (P < 0.01), in the 2DM group than in controls. On in vitro tissue pre-incubation with UII (10− 9, 10− 8 and 10− 7 mol/L), the insulin-stimulated [3H]-2-DG uptake by split soleus muscle was lower, by 9.5%, 33.4% and 39.7% (all P < 0.01), respectively, than without UII incubation. UII/UT upregulated in skeletal muscle of 2DM mice suggests that UII derived from skeletal muscle might induce the pathogenesis of skeletal muscle insulin resistance as an autocrine factor.