Statistics from Altmetric.com
Clinical trials have demonstrated a significant correlation between poor glucose control and a high incidence of diabetic complications.1 Consequently, an intensive insulin treatment regimen is recommended to counteract the deleterious effects of chronic exposure to high levels of glucose. However, insulin is known to positively regulate the production of insulin-like growth factor type 1 (IGF-1) and evidence presented in this issue of theBJO (p 725) demonstrates a clear association between high levels of IGF-1 and the advancement of diabetic retinal disease.
IGF-1 may affect the progression of diabetic retinopathy directly by its mitogenic action2 3 on retinal endothelial cell growth, or indirectly via an increased cell survival because of the antiapoptotic properties of IGF-1.4 The influence of IGF-1 on the induction of other growth factors—for example, vascular endothelial growth factor,5 IGF-1 mediated regulation of glucose metabolism,6 the altered responsiveness of cells to growth factors exposed to high concentrations of glucose,7-9 and the mitogenicity of insulin for REC2 may also be of significance. The concentrations of IGF-1 that are reported in the study presented here are well within the range that are known to promote endothelial cell growth in vitro2 and in vivo.3 However, some studies indicate no real association between IGF-1 levels and the progression of retinal disease10 and a simple correlation between the level of IGF-1 and diabetic retinopathy remains elusive. Other factors compound the difficulties in drawing definitive conclusions from such studies. For example, the bioavailability and the bioactivity of IGF-1 is regulated via IGF binding proteins (IGF-BP). These proteins have been shown to be increased in patients and animal models of diabetes11 12 and may be of significance for the correlation of retinal disease.13 Furthermore, the patients in the study by Chanteleau had been restricting food intake which is known to dramatically increase the production of hepatic IGF-BP 1 and 2 (for review see Straus14). The restoration of normal food intake of the patients may be associated with a decrease in the available IGF-1-BP and the bioavailability of IGF-1 will consequently be increased. Thus, there remains a number of key questions regarding the implementation of an intensive insulin regimen and the factors that affect the balance between the deleterious actions of IGF-1 with the beneficial consequences of this treatment.
The recommendation for continuation of intensive insulin therapy, despite worsening of diabetic retinopathy represents a significant cause for concern regarding the development of diabetic retinopathy. In general, continued longitudinal analyses of patients on intensive insulin treatment indicated a subsequent improvement of retinal disease and it is believed that the deterioration of diabetic retinopathy represents only a transient worsening. Although there is no controlled study for a gradual normalisation of blood glucose being of benefit in reducing the progression of diabetic retinopathy, clinical experience does advise this approach and it would be of great relevance to specifically address this issue given the implications that this has for the management of diabetic retinopathy. A tempered approach to the normalisation of blood glucose by insulin may be preferable and the outcome of patients may be significantly improved if a less aggressive approach to normalisation of blood glucose with insulin was embraced.
If a gradual normalisation of blood glucose is preferable for the reduction of the exacerbation of the complications of diabetes, what then is the stimulus for this adaptive response? Glucose concentration is clearly not the whole story and we need to consider how cells, in particular, how retinal cells, may adapt to the conditions in which they find themselves. The entry of glucose into a cell occurs via a facilitative transport system15 which may itself be regulated in response to changes in the glucose concentration,16-18 growth factors, including IGF-1 and insulin,19 with mechanisms to increase glucose transporter expression in hypoglycaemia and hyperglycaemia,20 and ischaemia,21 all of which are conditions relating to that present in the retina of patients with diabetes. Consequently, patients chronically exposed to high levels of glucose may adapt to conditions by the regulatory processes relating to this and the rapid normalisation of blood glucose concentration may not allow for the restoration of a “non-adapted response”.
While the mitogenic and antiapoptotic properties of IGF-1 are significant, it is the metabolic properties of IGF-1 that have been exploited in the development of recombinant IGF-1 therapy for the normalisation of blood glucose levels in patients with severe insulin resistance. Although this approach has been relatively successful with respect to the reduction of HBA1c(%) levels22 23 and clearly illustrates the metabolic potential of IGF-1, studies have shown that there are deleterious side effects resulting from the proliferative properties of IGF-1—namely, an increase in the incidence of proliferative diabetic retinopathy.23 24 It is unlikely that we could approach this therapy with the same rationale as we approach the intensive insulin treatment. For those patients within the latter group, the rise in the level of IGF-1 occurs as a result of insulin treatment and is often seen to level off after a period of time. However, the continual administration of levels of IGF-1 which are known to be mitogenic represents a clear conflict and the therapeutic use of IGF-1 has to be considered in the light of the potential complications with diabetic retinopathy for patients receiving recombinant IGF-1.
In the light of the accumulating evidence regarding the role of IGF-1 in diabetic retinopathy it is clear that the normalisation of blood glucose, by intensive insulin treatment or the administration of recombinant IGF-1, should be carried out with due consideration to the impact that this will have on other regulatory responses. Thus, if we are to effectively harness the therapeutic potential of these approaches, we must first elucidate the factors that affect the balance between glucose concentration, insulin, IGF-1, and the ability of the retina to respond to the physiological demands that are placed upon it.