ELSEVIER

EDITORIAL

Susceptibility to Diabetic Complications

The unpredictability of diabetic complications has al- ways intrigued me. For example, I never could under- stand why some diabetic individuals were ravaged by the eye, kidney, and nervous system diseases that ac- company diabetes mellitus and others seem to avoid them. At least on the surface, I never could appreciate any measurable difference between these two groups of diabetic individuals. I have always found it easy to understand why diabetic patients developed micro- vascular complications. I couldn’t understand why some didn’t. Even more interesting than whether or not an individual develops complications is what tis- sues are affected. When diabetic complications de- velop, it is usual to have retinopathy, nephropathy, and neuropathy. However, I’m sure all of you have seen diabetic individuals with severe damage to one tissue and none to others. How does that happen?

We know now, based on the results of the Diabetes Control and Complications Trial, that if diabetic pa- tients keep their blood glucose levels in the range of individuals without diabetes, complications will not occur. However, this is easier said than done. We still do not have the treatment tools to do it except in a small percentage of people. It is clear-keep the blood glucose normal and patients won’t get diabetic compli- cations. What is not clear is why some diabetic individ- uals with longstanding hyperglycemia never get sig- nificant diabetic complications. Hyperglycemia is necessary but not sufficient for the development of diabetic complications. Some genetic susceptibility fic- for(s) is also necessary.

This brings me to the point of this Editorial-the genetic susceptibility factor(s). My own group’s re- search efforts have been devoted in part to searching for a susceptibility factor. We noted several years ago that if a diabetic patient has an erythrocyte aldose re- ductase activity that is two standard deviations above that of nondiabetic individuals, that diabetic patient is almost five times more likely to have one or more serious diabetic microvascular complications as com- pared to diabetic individuals whose aldose reductase activity is not elevated. In this issue of the Journal of Diabetes and Its CompIications, Ashok Patel, et al., re-

Journal of Diabetes and Its Complications 1996; lo:62 0 Elsevier Science Inc., 1996 655 Avenue of the Americas, New York, NY 10010

port interesting findings that bear on this issue. They studied the gene that codes for the enzyme, aldose reductase in diabetic patients. This gene has been lo- calized to chromosome 7q35. They noted that there were polymorphisms of the gene for aldose reductase. This information, when coupled with their previously described T-cell antigen receptor constant P-chain lo- cus (previously also localized to chromosome 7q35), allowed them to “dissect susceptibility genotypes.” They concluded that chromosome 7q35 harbors a gene(s) which may be involved in the pathogenesis of diabetic complications.

I am quite excited about these data. This work may represent the discovery of a potential “genetic suscep- tibility factor” that could predispose individuals to de- velop diabetic microvascular disease in the presence of hyperglycemia. There is, of course, no reason to believe that there is only one or two of these and not more. Dr. Patel’s work suggests that they may even be tissue specific. This would explain why some diabetic patients are blind from proliferative retinopathy and have not a microgram of albumin in their urine.

The challenge for the future in diabetes, as I see it, includes a search for other potential “susceptibility fac- tors.” It would be great if we could determine at the diagnosis of diabetes where on the “susceptibility curve” for diabetic complications a particular individual falls. We could then double our efforts on the susceptible individuals and relax a little on those who are not. We also need better treatment modalities. Treatments need to be developed that make it easier to achieve normoglycemia. There is movement in that direction. New insulin analogs for people with insulin-dependent diabetes and a whole series of new compounds, all with different mechanisms of action, to help with the oral therapy of noninsulin-dependent diabetes. Fi- nally, drugs that perhaps protect even susceptible tis- sues from the damaging effects of hyperglycemia.

Clearly, everybody’s life would be made easier if we could identify which of our diabetic patients were most susceptible to diabetic complications. Dr. Patel’s work is a step in the right direction.

Philip Raskin, M.D.

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