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San Franciscan Diabetologist Writes About a New Drug
The causes of diabetic complications are not yet completely understood, but there are some strong suspicions about certain changes in tissues and organs. It seems almost undeniable (especially after the recent DCCT) that hyperglycemia plays a major role in triggering the mechanisms that ultimately lead to diabetic complications. Two of the suspected mechanisms are osmotic effects from the hyperglycemia itself and glycosylation (glucose sticking to other molecules) of various important proteins-like hemoglobin, and the tissues of the eye, kidney, nerve, and blood vessels. Also suspected is the accelerated action of some enzyme systems when they are fed by extra glucose.
Glycosylation, which progresses at a rate relative to the level of sugar in the blood, leads to the development of advanced glycosylation end products (AGEs) which may also contribute to many of the consequences of normal aging. The development of AGEs depends on both the level of blood sugar and the length of time to which tissues are exposed to the blood sugar. It used to be taught in medical school that the physiologic age (the apparent age as far as organ function) of a diabetic person was equal to the real age in years plus the duration of diabetes. For example, a 30-year-old who has had diabetes for 20 years might be expected to respond to medical procedures, drugs, surgeries, etc. as if he or she were 50 years old. But this idea was promulgated before intensive diabetes control became possible. A diabetic person with an average blood sugar of 160 mg/dl for 30 years might experience aging similar to that of a non-diabetic person with a blood sugar of 80 mg/dl for 60 years.
AGEs have been implicated in the development of atherosclerosis and other normal aging processes in people without diabetes, but their effect is even more significant in diabetic people with poorly controlled blood sugars. Experimental research on animals over the last ten years using aminoguanidine (now called pimagedine) has revealed some fascinating information on the effect of blocking AGE formation. This agent inhibits (slows down or prevents) the development of diabetic retinopathy in rats.
In humans with diabetes, the increase in circulating AGE has been found to parallel the severity of diabetic kidney disease. It has also been shown that AGEs accumulate more quickly than normal in the blood and arteries of patients with diabetes.
Diabetic rats treated with pimagedine showed a reversal of inadequate blood flow to the nerves and gradual improvement of the nerves' ability to transmit signals. This suggests that pimagedine may have potential for treating diabetic neuropathy.
In many tissues, once AGEs begin forming they become self-perpetuating and irreversible. Some glycosylated proteins undergo complex chemical interactions with other proteins, even in the absence of continued high blood sugar. Theoretically, as the AGEs become self-perpetuating and well-established in certain tissues, even if the diabetes were cured and blood sugar returned to normal, the AGEs might continue to increase, thereby leading to diabetic complications.
AGE peptides have been given intravenously to rats and rabbits without diabetes. The AGEs were found to induce kidney enlargement typical of diabetic kidney disease, in the absence of hyperglycemia.
Pimagedine is thought to act by blocking the process whereby the AGEs become self-perpetuating. If this is the case, and pimagedine proves to be clinically useful, then it could be the best thing to happen to diabetes care since the advent of insulin.
In diabetic rats, pimagedine has been found to retard proteinuria, the spilling of protein into the urine, which is an indication of diabetic kidney disease. Pimagedine also inhibits many of the microscopically visible, typical diabetic changes in the kidney. Also, in rats, pimagedine was found to prevent hyperglycemia-induced cross-linking of artery wall protein which could be responsible for some diabetes-related macrovascular disease (hardening of the arteries). It is known that in people with diabetes, the rate of increase in protein cross-linking is greatly accelerated.
Pimagedine has been found to inhibit oxidation of some very important lipoproteins, especially LDL, which is thought to be a major player in the development of coronary artery disease. Lipoproteins are cholesterol and triglyceride-carrying proteins that can become glycosylated. The glycosylation interferes with their normal metabolism and makes them more likely to cause atherosclerosis (hardening of the arteries.) By inhibiting glycosylation, pimagedine might diminish the incidence of a major killer-84% of people with diabetes die of cardiovascular disease.
In keeping with these findings, pimagedine reduced the development of atherosclerosis in rabbits on high cholesterol diets without any effect on cholesterol levels. This further supports the idea that AGEs might be involved in the development of macrovascular disease, even in "normal aging."
AGEs have also been found to interfere with the normal dilation of blood vessels when intravenously injected into young, healthy rats for ten days. These changes were similar to those seen in rats after having had diabetes for two months. If, however, the AGEs were given intravenously along with pimagedine, the pimagedine was found to significantly inhibit the development of the defective responses to normal blood vessel dilation.
Paul J. Beisswenger, MD, a well-respected researcher in this field, found that AGEs chemically linked to collagen and correlated significantly with the earliest stages of diabetic retinopathy and increases in urinary albumin in 50 human subjects with type I diabetes. Beisswenger hypothesizes that elevated levels of AGE might be used as an early indicator of diabetic eye and kidney disease.
These are but a few of the experiments over the last ten years that have strongly implied that AGEs play an important role in the development of diabetic complications in animals and humans.
Last year the first large trials using pimagedine in humans with diabetes began. These will last several years and will measure the progression of diabetic complications. In the last year alone there have been 85 publications in scientific literature regarding pimagedine. This exciting compound may change the prognosis for diabetes complications.
Recruitment is still open for people with diabetes who already have a specific degree of diabetic kidney disease. If you would like to learn more about pimagedine studies and volunteer, you may call (800) 449-1937.
0 comments - Sep 1, 1995
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