Why some cases of retinopathy worsen when diabetic control improvesBMJ 1997; 315 doi: https://doi.org/10.1136/bmj.315.7116.1105 (Published 01 November 1997) Cite this as: BMJ 1997;315:1105
Worsening retinopathy is not a reason to withhold intensive insulin treatment
- a Department of Medicine, Heinrich Heine University, D-40001 Düsseldorf, Germany
- b St Thomas's Hospital, London SE1 7EH
In the 1970s Engerman et al showed that strict control of diabetes could prevent the development of retinopathy in diabetic dogs.1 When close monitoring of glycaemia and methods of giving frequent insulin injections became possible in routine practice clinicians had great expectations that similarly strict control in humans could prevent the development of diabetic retinopathy and arrest or even reverse early lesions. These expectations were dashed, however, when it became clear that tightening control in patients with existing retinopathy could make the lesions worse.2 This normoglycaemic re-entry phenomenon has puzzled clinicians,3 and, although there is still much to learn about its mechanism, it is becoming clearer how to manage it.
Early findings that patients with varying degrees of retinopathy suffered a paradoxical worsening of their lesions as their diabetic control improved2 3 4 5 6 have been confirmed in a recent large study of non-insulin dependent diabetics started on insulin.7 But even before then the Diabetes Control and Complications Trial had shown beyond doubt that this early deterioriation of retinopathy at the time of normoglycaemic re-entry was a true finding.8 In this study 1441 patients with insulin dependent diabetes were randomly allocated either to continue with their conventional treatment (control group) or to change to intensive treatment aimed at maintaining near normal glycated haemoglobin concentrations. During the first year of the study retinopathy deteriorated by three or more levels in only 2% of controls but 5% of intensively treated patients. Moreover, the deterioration was most marked in those with more advanced retinopathy.9 10
While no doubt exists about the reality of the normoglycaemic re-entry phenomenon, very little is known about its pathogenesis. Since most cases, especially severe ones, occur after rapid lowering of longstanding severe hyperglycaemia, the rate of fall of blood glucose concentration and the accompanying reduction in blood flow have been thought to be the trigger.3 4 6 This suggestion was supported by the finding of Grunwald et al, who showed a 20% reduction of blood flow when blood glucose concentrations fell from about 15 mmol/l to 8 mmol/l.11 12 The nature of the lesions—an increased number of cotton wool spots, haemorrhages, and development of proliferative lesions—suggest increasing ischaemia. However, changes in blood flow are transient, and the beneficial effect of a slow reduction of blood glucose and glycated haemoglobin concentrations has yet to be shown.
Another possible mechanism implicates growth factors,13 particularly IGF-13 13 For normal secretion of IGF-1 by the liver an adaequate insulin level in the portal system is required. In poorly controlled insulin dependent diabetes, therefore, plasma IGF-1 concentrations are low. In a patient with Mauriac's syndrome (growth and sexual retardation due to inadaequate insulin therapy) intensive control of diabetes caused development of proliferative retinopathy, and this was accompanied by a large acute rise in IGF-1 concentrations.14 Even in the absence of Mauriac's syndrome a rapid rise of IGF-1 from low to normal values has been found to accompany worsening of retinopathy when insulin therapy is intensified and diabetic control improved.15
Experimental evidence supports a possible role for IGF-1 in the normoglycaemic re-entry phenomenon. Intravitreal injection of IGF-1 induces vasodilatation, microaneurysm formation, and neovascularisation.16 Infusion of recombinant IGF-1 can cause retinal abnormalities.17 Furthermore, clinical conditions associated with increasing concentrations of IGF-1, such as pregnancy and puberty, accelerate diabetic retinopathy. In contrast, pituitary ablation was associated with improvement of proliferative retinopathy and reduction of IGF-1 values.18 Recent work by Smith et al suggests that reduction of IGF-1 values by a somatostatin analogue reduces neovascularisation by about a third in ischaemic mice.19
Given that rapid and sustained improvement of chronic extreme hyperglycaemia may trigger a deterioration of retinopathy, sometimes transient, sometimes not, what should the clinician do? Discouraging patients with incipient or existing microvascular complications from improving their glycaemic control is certainly not justified. The Diabetes Control and Complications Trial has shown beyond doubt that the long term beneficial effect of intensive therapy is closely related to the concentration of glycated haemoglobin, each percentage reduction being of benefit.20
There is no report of intensified insulin treatment initiating diabetic retinopathy in patients who did not have lesions before. Therefore early identification of the small minority of patients at risk of normoglycaemic re-entry phenomenon is important. Patients with preproliferative or proliferative retinopathy should not be sent away to improve their control before laser treatment is offered but should be treated simultaneously with laser and intensified insulin therapy. Patients with retinopathy should be followed carefully, and monitoring of IGF-1 concentrations might be helpful. In the meantime, more definite information should also come from the long promised report of the Diabetes Control and Complications Trial on the early worsening of diabetic retinopathy.9