ADA Research Highlights, 1998

by John Walsh, P.A., C.D.E. & Ruth Roberts, M.A.
© 1998 Diabetes Services, Inc.

See also Inhaled Insulin

Researchers and clinicians gathered in June on Lake Michigan by the thousands for the 58th Annual ADA Convention. Information flowed like waves through the huge confines of McCormick Place Convention Center which bridges a six lane freeway. The information below is the authors' gleanings of a few of the research highlights from this meeting.

AGE Is Reversible

Everyone with diabetes copes with substances known as AGE (advanced glycosylation endproducts). These are the damaged remains of enzymes, DNA and collagen that accumulate in the body and contribute to the accelerated aging found in diabetes—making the acronym AGE particularly appropriate. AGEs contribute to collagen damage in joints, skin and artery walls, causing a doubling of arthritis complaints in people with diabetes as well as acceleration of atherosclerosis, heart disease and cataracts.

AGEs begin to form when glucose attaches to the amino acids lysine and arginine within protein structures (AKA, glycosylation). Then zinc can form a crosslink between two nearby glycosylated proteins. When someone has a HbA1c test, the results reveal a lot more than just the average blood sugar level over the last 6 weeks. This test measures glycosylation of proteins in hemoglobin, and in turn tells how likely it is that AGEs are being formed in the body. The higher the HBA1c, the greater the rate of AGE formation.

Until now, AGEs were thought to be permanent damage, but in research sure to get the attention of anyone with atherosclerosis, wrinkles, cataracts, or arthritis, an international team of French, Dutch and American scientists have been able to break the "permanent" crosslinks that hold AGEs together. When diabetic rats were given a compound called ALT-711, they showed a 25 to 33 percent increase in blood flow after only 3 weeks of treatment, along with a 20 percent increase in cardiac output. The compound also reversed the excess stiffness of the animal's carotid arteries. ALT-711 or other compounds like it may open a new frontier in the treatment of some diseases of aging like atherosclerosis, arthritis, wrinkles, and cataracts.

High Blood Sugar Makes You Feel Low

Does poor blood sugar control cause depression? According to the results of a study by Brazilian researchers, the answer appears to be yes. These researchers split a group of 76 people with diabetes and split them into 2 groups, those whose HbA1c levels was 9% or less and those above 9%. They then gave everyone a standardized test for depression. In people whose HbA1c was lower, only 21% tested as depressed, compared to 42%, or nearly half, of those whose HbA1c was over 9%.

Results from a study at Washington University in St. Louis corroborates these results. Researchers there started their study with people with diabetes who were already depressed. They used cognitive behavior therapy to try to reverse the depression. Those whose depression improved had an average HbA1c of 8.3%, while those who remained depressed had an average HbA1c of 11.3%.

Retinopathy Risks Come Into Focus

In news to see better by, researchers have identified a substance called vascular endothelial growth factor (VEGF) as being one of the primary bad guys in proliferative diabetic retinopathy. It is also a suspect in macular edema (swelling of the retina).

VEGF causes abnormal growth of new blood vessels into spiderweb-like formations that extend into the clear vitreous gel within the center of the eye. When this occurs, any quick movement or increase in blood pressure can trigger bleeding and sudden loss of vision. VEGF has also been shown to cause leakage of proteins from retinal capillaries similar to that seen in macular edema.

Growth hormone was also fingered in the lineup of eye-damaging suspects. Produced by the pituitary, growth hormone was originally implicated in retinopathy 45 years ago when surgeons noticed that removal of the pituitary stopped the progression of diabetic eye disease, and again 20 years later when physicians noted that dwarfs with long term diabetes did not develop eye disease. Growth hormone's role in diabetic retinopathy appears to be less important than that of VEGF, but higher levels of either apparently contributes to eye damage.

One hopeful treatment for preserving eyesight is lipoic acid which researchers have shown to lower Vascular Endothelial Growth Factors (VEGF) levels. Lipoic acid lowers VEGF regardless of blood sugar control, but good blood sugar control keeps VEGF and growth hormone at normal levels. Lipoic acid, itself a potent antioxidant found in the body, recycles vitamin E and vitamin C back to their protective form after they have picked up toxic free radicals.

At high doses of 1800 units a day, Joslin scientists have found that vitamin E has also been shown to improve blood flow in the retina. The improved blood flow is thought to be due to a reduction in high levels of protein kinase C and diacylglycerol, which usually accompany high blood sugars and reduce blood flow. In this study, actual improvements in kidney function were also seen with vitamin E. (If you try vitamin E, we suggest you use "mixed tocopherols" rather than straight alpha tocopherol to prevent the muscle aches occasionally seen when straight alpha tocopherol is taken at these doses.) Similar results have also been reported in other studies using 1200 units a day.

Researchers at the University of Wisconsin and elsewhere have found that antioxidants can lower the high levels of glutamate found in the retina when blood sugars are high. Glutamate is an "excitotoxin" that activates nerves but can kill them at high levels. In the retinas of diabetic rats, glutamate levels rose to 1.6 times normal levels. But when rats were given an antioxidant complex, glutamate levels did not rise despite the high blood sugars.

Proliferative diabetic retinopathy (PDR) has similarities to cancer in its uncontrolled formation of new blood vessels. A new class of cancer drugs, called angiogenesis inhibitors, work by blocking the formation of new blood vessels. Researchers suspect that these inhibitors might be used to treat PDR and reduce the need for laser therapy. But strong cautions were expressed by some investigators regarding the use of vascular inhibitors in people with diabetes. The formation of new blood vessels helps to prevent amputations and heart damage, and any inhibitory effect could increase circulatory risks. Nevertheless, it may be possible to localize the effect of angiogenesis inhibitors so they act primarily on the eye if these can be delivered with eyedrops.

In exercise news, the risk of retinopathy was found to drop by 6% for every 500 kcal increase in energy expenditure per week. For instance, a 2 mile walk each day would lower the risk of retinopathy by 12%, a moderate 10 mph bike ride for 40 minutes a day would reduce risk by 30%, and running 30 minutes a day would reduce risk by 38%.

Excess Iron Linked To Type 2 Diabetes

Finnish doctors looked at whether excess iron in the body may cause Type 2 diabetes. Hemochromatosis, a disease where iron accumulates in cells due to a genetic defect, is known to cause diabetes in about half of those who receive not treatment for the condition. Using a test called ferritin, researchers measured iron stores in 42 men who developed diabetes during a four year followup and compared them to 82 controls. Men with high iron stores were found to be 2.5 times as likely to develop diabetes.

The cause for this increased risk is not known. It may be related to a higher intake of animal products which are rich in iron, or to iron-induced oxidation, to which beta cells are very susceptible. Besides liver and red meats, other sources of iron include some vitamin tablets and certain boxed cereals.

Type 1 Diagnosed In Teens Causes Self-Care Problems

The teenage years are often a difficult period for everyone. Now researchers in a 4 year study in Wisconsin have tabulated some of the extra problems brought about when diabetes is diagnosed during the teen years. Comparing 267 kids who were diagnosed at less than 9 years of age to 271 others who were diagnosed with Type 1 diabetes between the ages of 10 and 30, researchers found that the frequency of blood sugar self-monitoring fell steadily in teens who were diagnosed between the ages of 15 and 18. In this group, testing frequency fell over the 4 years of study to less than twice a day, while in the group who were diagnosed earlier, testing continued at more than 3.5 times a day through their teenage years.

Kids who tested the least—those diagnosed between 15 and 18 years of age—had the poorest HbA1c scores, often falling between 11.5% and 22.8%. It is not know if monitoring frequency will improve as this late teen group matures into their twenties, but a trend toward less and less monitoring over the duration of this study is especially disturbing. The diagnosis of diabetes in the teen years appears to require greater support and followup if complications are to be avoided.

Dietary Links To Kidney Disease (Is it the protein?)

Austrian researchers, in a small, but well-designed study, found that people with Type 1 diabetes who consumed more salt, more saturated fat, and more simple sugars were more likely to suffer progression of their kidney damage. For five years, the researchers analyzed 16 dietary factors that might contribute to kidney disease in 37 people with Type 1 diabetes and early kidney changes.

Of particular interest, the intake of two fatty acids, myristic acid and arachidonic acid, was higher in those whose kidney disease worsened. Myristic acid is a saturated fat found in tropical oils and margarine. Arachidonic acid is a polyunsaturated fat found at high levels in cattle and pigs, but not in peanuts as many believe. Arachidonic acid intake in the U.S. diet has doubled over the last 150 years due to an increased consumption of meat, eggs, milk and cheese. People with diabetes have higher levels of arachidonic acid in their blood.

Normally safely sequestered within cell membranes, arachidonic acid can released into the blood from cell membranes, especially when prostaglandin 1 levels are low. After release, arachidonic acid triggers inflammation and clotting. The prostaglandin 1 family is derived from linoleic (and linolenic) acid. When researchers isolated the effect of linoleic acid, it was found to protect against kidney damage. In the kidneys, arachidonic acid is known to trigger retention of sodium and higher blood pressure. The increased damage associated with extra salt intake could be linked to the damage associated with arachidonic acid. 

In contrast to other studies, protein intake was not significantly linked to kidney disease in this study. Other studies have shown that a lower protein intake helps protect the kidneys. But over the last several years, other European researchers have noted that protein intake from beans, chicken and fish did not seem to be as damaging to the kidneys as protein from other animals. This raised a central question about whether kidney disease was worsened simply by protein intake, or was it linked to something else that traveled with the protein found in beef and pork, such as salt and these fatty acids.

While the Austrian study clearly suggests that kidney disease may be worsened by salt and certain fatty acids in beef and pork, we suggest waiting for additional studies that confirm these findings before overhauling your diet. Nevertheless, reducing the intake of meat and animal products appears to be a safe bet for preventing or treating kidney disease.

ACE Inhibitors Offer Protection

Scientists in Greece and the U.S. have found that blood pressure medications called ACE inhibitors, widely used in diabetes, appear to protect against autonomic neuropathy. Because autonomic neuropathy is strongly linked to heart attacks, arrhythmias, and sudden death, this finding is quite interesting. This study measured heart rate changes so it is not known if ACE inhibitors will protect against autonomic neuropathy measured in other ways. It is also not known how this protection occurs.

Brazilian researchers found that people with Type 2 diabetes, who had elevated blood pressure during sleep, a sign of autonomic neuropathy, were much more likely to develop kidney disease. Interestingly, their daytime blood pressure was not different from the others who did not have elevated nighttime blood pressures. It is possible that ACE inhibitors, which are noted for their ability to protect against kidney disease, might be doing this through correction of autonomic neuropathy and lower overnight blood pressures.

If you have Type 2, will you get kidney disease? In a study of 1,374 people with Type 2, Belgian scientists found that the risk of developing microalbuminuria was strongly related to how well the blood sugars are controlled, smoking, excess weight and abdominal girth, being male, and having high triglycerides or a low HDL.

Short Takes

Dutch researchers wanted to find out why their diabetes patients weren't listening. They surveyed people in two general practice clinics and found that only 2.3% of those without diabetes used hearing aids, but that 19.7% of their diabetes patients were using such devices.

In a large meta-analysis of 25 research trials on aspirin that involved 29,000 people, researchers found 35% fewer nonfatal heart attacks, 27% fewer nonfatal strokes, and 15% fewer deaths from heart disease in people who took low dose aspirin each day. An aspirin a day does help keep your doctor away!

Kaiser researchers found that women who took hormone replacement therapy had significantly lower HbA1c levels compared to those not taking hormones following menopause. HbA1c levels were 0.5% to 0.7% lower in women on hormone replacement in each of the four race groups studied. Reasons for this difference are not clear, but estrogen may improve insulin sensitivity.

Blacks in Atlanta were discovered to have high rates of kidney disease, even when their diabetes had been present for less than a year. Among blacks whose diabetes had been diagnosed within the last year and who also did not have high blood pressure, 21% already had microalbuminuria and 2% had existing kidney disease. When those with high blood pressure were included, 27% had microalbuminuria and 4.6% had kidney disease. Among those with diabetes longer than one year, 52% had microalbuminuria and 14.1% had existing kidney disease.

In news that underscores the number of people who may not really know how to use insulin, 30% of insulin users in the U.S. and 40% worldwide are now on premixed 70/30 insulin. Despite the marked jump in insulin pump sales and overwhelming use of Humalog insulin, there also appears to be a growing number of people using less effective, fixed ratio insulins like 70/30. Combined from Regular and NPH, 70/30 does not cover meals well and cannot be tailored to missed meals or a flexible lifestyle. Unfortunately, it is likely to continue to sell because it's easy to use by those who do not know the value of precise blood sugar control. Privately, even some insulin sales representatives have expressed concern about how widely premixed insulin is being used.

German researchers studied the effect of intensive control of blood pressure. 45 of 91 patients were placed in an intensive control group where enough blood pressure medications were used to keep the blood pressure below 140/90 over a ten year period. The remainder in the control group had their blood pressure treated but without a stringent target pressure. After 10 years, only 24% of the intensive group required dialysis compared to 39% of the control group, and only 18% of the people who kept their blood pressure low had died, compared to 48% of the control group. Now, don't break a leg finding those blood pressure pills!

Insulin resistance was fingered in one study as the major risk factor for heart disease. But researchers are now finding that insulin resistance appears to come from two sources. About half appears to originate from amongst a number of candidates like abdominal obesity, lack of exercise, genes, loss of first-phase insulin release, etc. But, in uncontrolled diabetes, a full 50% of the insulin resistance appears to be caused by the high blood sugars themselves. This adds to the long list of reasons for improved blood sugar control in Type 2, and possibly Type 1, diabetes.