Growth Factor Protein May Treat Diabetes Treatment aids control of blood sugar without exacerbating complications
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nvestigators at four collaborating hospitals in Sweden and the U.K. suggest that a regulatory protein called insulin-like growth factor 1 (IGF-1) may find a role in management of diabetes. Their relatively long-term study in young people with juvenile-onset insulin-dependent diabetes indicates that daily injections of IGF-1 in addition to insulin improve control of blood sugar and do not exacerbate complications of diabetes [Lancet, 350,1199(1997)]. If further studies of long-term risks and benefits are positive, the treatment may become an important facet of maintenance in such patients. But like so many research projects, this one raises tantalizing questions, and further work is needed to help answer them. The study was performed by pediatric endocrinologists David B. Dunger and Carlo L. Acerini at John Radcliffe Hospital, Oxford, England; Martin O. Savage at St. Bartholomew's Hospital, London; Anna Kernell at University Hospital, Linkoping, Sweden; and Otto Westphal at University Hospital, Goteborg, Sweden. The study was coordinated by research assistant Caroline M. Patton at Oxford. IGF-1 was supplied by Pharmacia & Upjohn, which introduced the recombinant human protein in Sweden in 1994 for treatment of Laron-type dwarfism. In the U.S., there are about 675,000 insulin-dependent diabetics, according to the American Diabetes Association, Alexandria, Va. Most contract the condition as children when their pancreas abruptly stops producing insulin. This condition is different from the more common insulinindependent diabetes that develops gradually in middle-aged, overweight people. On a daily basis, insulin-dependent diabetics run the risk of a "sugar shock" called diabetic ketoacidosis from excess blood sugar, or of insulin shock owing to low blood sugar. But over their lifetimes, they may suffer other complications, including blindness, kidney failure, accelerated coronary heart disease, periodontal disease, diseases of peripheral nerves and
peripheral blood vessels, and amputations of toes, feet, or legs. On a positive note, the seven-year Diabetes Control & Complications Trial showed that aggressive, tight control of blood sugar by several finger-stick blood tests and multiple injections of insulin daily delays the start and slows the progression of eye, kidney, and nerve disease [New Engl J. Med., 329, 977 (1993)]. The downside is that insulin-dependent diabetes usually begins before or at adolescence, a period of profound hormonal, metabolic, and emotional change. These changes can combine with depression from having been diag-
nosed with diabetes to cripple vigilant self-care. The focus on IGF-1, also called somatomedin-1, stems from the widespread upset in intricate metabolic systems that comes from lack of pancreatic insulin. Insulin-dependent diabetics can only inject the hormone under the skin, and from there it spreads throughout the body. In nondiabetics, the pancreas secretes insulin strategically into the portal vein, which carries blood from the stomach and intestines to the liver. Insulin not only triggers uptake of glucose by liver and muscle cells, but also, among many other functions, stimulates liver production of IGF-1. Normal IGF-1 concentrations serve to keep production of growth hormone (GH) under control. Insufficient insulin reaching the liver leads to low concentrations of IGF-1 and high concentrations of GH. And high GH is thought to stimulate abnormal proliferation of tiny new blood vessels in the retina, which leads to blindness, as well as tissue changes that lead to the other diabetic complications. GH also antagonizes the functions of
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Structure of somatomedin-1 (insulin-like growth factor 1) is shown in a space-filling model (center) and in a stylized trace of the protein's backbone (upper right).
insulin. Excesses of GH may trigger what is called the dawn phenomenon, in which the diabetic person's blood sugar rises in the very early morning hours. But in another twist of metabolic complexity, GH also stimulates local pro-
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duction of IGF-1 in the retina and perhaps in kidney and nerve tissue as well. This local overproduction of IGF-1 contributes to tissue changes that lead to diabetic complications. So the question for research is: Can supplemental injections
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of IGF-1 stabilize the normal balance of GH production in the GH/IGF-1 axis without accelerating development of complications? The British-Swedish team randomly assigned 26 male and 27 female insulindependent diabetics from 11 to 21 years old to three groups to get either 20 ug of IGF-1 per kg of body weight daily, 40 jug, or a placebo. The investigators photographed patients' retinas and measured their urinary filtration rates at the beginning and end of the 24-week study to see any advance of eye or kidney disease. At 24 weeks, this is the largest and longest IGF-1 study in diabetic patients to date. They also measured concentrations of glycated hemoglobin every four weeks as a check of overall control of blood sugar. Excess glucose in the blood reacts with amino groups on the side chains of lysine molecules to form Schiff bases, which go on to rearrange and cross-link the protein chains. This glycation of hemoglobin and tissue proteins also contributes to development of complications. Red blood cells live about 120 days from production to destruction, so levels of glycated hemoglobin indicate average sugar control and the potential for development of complications. The overall result was a significant drop in glycated hemoglobin in the treated groups, and the drop was greater in the 40 ug-per-kg group. Also, there was no deterioration of retinal tissue or kidney function. But the drop in glycated hemoglobin was greatest at 12 weeks and returned to roughly the original values at 24 weeks. This raises the question of whether lapses in routines of blood testing and injections among such young people caused an initial benefit to taper off. Or perhaps the bioavailability or effectiveness of injected IGF-1 changes. The patients were selected among those who were already managing on multiple blood tests and multiple insulin injections per day. The investigators suggest that new trials in people with higher initial levels of glycated hemoglobin may show greater benefits of IGF-1 treatment. In addition, they say the overall treatment regimen could be made simpler and easier to follow. And they call for intensified monitoring of progress of diabetic complications. Specific future research at Oxford includes investigating in humans the mechanism by which low doses of IGF-1 heighten sensitivity to injected insulin. Stephen Stinson
