Circulating IGF-I and its protective role in the pathogenesis of diabetic angiopathy

To document the frequency, importance of, and risk factors for "early worsening" of diabetic retinopathy in the Diabetes Control and Complications Trial (DCCT). The DCCT was a multicenter, randomized clinical trial comparing intensive vs conventional treatment in insulin-dependent diabetic patients who had no to moderate nonproliferative retinopathy. Retinopathy severity was assessed in 7-field stereoscopic fundus photographs taken at baseline and every 6 months. For this study, worsening was defined as progression of 3 steps or more on the Early Treatment Diabetic Retinopathy Study final scale, as the development of soft exudates and/or intraretinal microvascular abnormalities, as the development of clinically important retinopathy, or as any of the above, and was considered "early" if it occurred between baseline and 12-month follow-up visits. Early worsening was observed at the 6- and/or 12-month visit in 13.1% of 711 patients assigned to intensive treatment and in 7.6% of 728 patients assigned to conventional treatment (odds ratio, 2.06; P < .001); recovery had occurred at the 18-month visit in 51% and 55% of these groups, respectively (P = .39). The risk of 3-step or greater progression from the retinopathy level present 18 months after entry into the trial was greater in patients who previously had had early worsening than in those who had not. However, the large long-term risk reduction with intensive treatment was such that outcomes in intensively treated patients who had early worsening were similar to or more favorable than outcomes in conventionally treated patients who had not. The most important risk factors for early worsening were higher hemoglobin A1c level at screening and reduction of this level during the first 6 months after randomization. We found no evidence to suggest that more gradual reduction of glycemia might be associated with less risk of early worsening. Early worsening led to high-risk proliferative retinopathy in 2 patients and to clinically significant macular edema in 3; all responded well to treatment. In the DCCT, the long-term benefits of intensive insulin treatment greatly outweighed the risks of early worsening. Although no case of early worsening was associated with serious visual loss, our results are consistent with previous reports of sight-threatening worsening when intensive treatment is initiated in patients with long-standing poor glycemic control, particularly if retinopathy is at or past the moderate nonproliferative stage. Ophthalmologic monitoring before initiation of intensive treatment and at 3-month intervals for 6 to 12 months thereafter seems appropriate for such patients. In patients whose retinopathy is already approaching the high-risk stage, it may be prudent to delay the initiation of intensive treatment until photocoagulation can be completed, particularly if hemoglobin A1c is high.

The insulin-like growth factor binding proteins (IGFBPs) are a family of six proteins that bind to insulin-like growth factor-I and -II with very high affinity. Because their affinity constants are between two- and 50-fold greater than the IGF-I receptor, they control the distribution of the IGFs among soluble IGFBPs in interstitial fluids, IGFBPs bound to cell surfaces or extracellular matrix (ECM) and cell surface receptors. Although there are six forms of insulin-like growth factor binding proteins, most interstitial fluids contain only three or four forms, and usually only one or two predominate. The proteins differ significantly in their biochemical characteristics, and this accounts for many of the differences that have been observed in their biological actions. Several different types of protease cleave these binding proteins. Proteolytic cleavage generally inactivates the binding proteins or reduces their ability to bind to IGF-I or -II substantially. Several cell types have been shown to secrete these proteases; therefore, the factors that regulate protease activity can control binding protein actions indirectly. Other post-translational modifications, such as glycosylation and phosphorylation, have been shown to alter IGF binding protein activity. While binding protein actions have been studied extensively in vitro, many of the in vivo activities of these proteins remain to be defined.