EFFECT OF GLUCOSE ON INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-4 PROTEOLYSIS

The role of hyperglycemia in diabetic changes of the insulin-like grow th factors (IGFs) and their binding proteins (IGFBPs) has not been cle arly established. We therefore determined whether glucose modulates IG FBP synthesis and stability in vitro. Porcine vascular smooth muscle c ells (pSMC) cultured in low glucose (pSMC-L) had 2.1-fold more IGFBP-4 in the conditioned medium compared with pSMC cultured in high glucose (pSMC-H) (P < 0.01). In contrast, IGFBP-2 levels remained constant. A lthough pSMC-H and pSMC-L cultures expressed similar levels of IGFBP-4 messenger RNA, in vitro protease assays demonstrated an increase in I GFBP-4 proteolysis in pSMC-H conditioned medium compared with pSMC-L c onditioned medium (P < 0.01). The protease had properties similar to a previously characterized IGFBP-4 protease. The addition of 20 mM mann itol to pSMC-L cultures did not decrease IGFBP-4 levels, suggesting th at the difference in IGFBP-4 proteolysis was not osmotically induced. The change was not due to selection bias, because cultures that were i nitially isolated from aortic explants in high and low glucose still e xhibited the glucose-dependent difference in IGFBP-4 proteolytic activ ity. The results suggest that high glucose acts on pSMC to induce a ch ange in IGFBP-4 proteolytic activity, which results in increased IGF-I availability to its receptors thereby enhancing the SMC proliferative response.