Research Tips From Past ADA Conferences

Research Tips From Past ADA Conferences

by Ruth Roberts, M.A. & John Walsh, P.A., C.D.E.

From talks, research posters, and oral presentations, plus lots of hype, promo, and uplifting ideas at past ADA Annual Conferences:

"We act as though comfort and luxury were the chief requirements of life, when all that we need to make us happy is something to be enthusiastic about."

Charles Kingsley


Nerves

What nerve! Nerve cells send messages as electrical charges along fine "wires" called axons. Insulation is needed around the outer walls of axons to conduct these electrical messages. This insulation comes from the myelin sheath, that is composed largely of fat. Disappearance of this protective myelin sheath as a result of high blood sugars likely contributes to nerve damage. British researchers (41) have now shown that the myelin sheath becomes damaged before neuropathy symptoms start, adding weight to its role in neuropathy. Japanese researchers (43) revealed that a research drug called aminoguanidine prevents most of this myelin loss, and improves blood flow, which is important for nerves that depend on nutrition supplied by tiny blood vessels.

Oh well! But in a disturbing report, Danish researchers (638) found no protective benefit from aminoguanidine on rat kidneys. Instead, after eight months of aminoguanidine treatment, 3 of 9 rats had developed kidney cancer. Of 130 published reports, this is the first time cancer has been linked to this promising drug. Aminoguanidine works by blocking the formation of advanced glycosylation of proteins, and is often discussed in the same breath as anti-aging. Human clinical trials of aminoguanidine are planned to begin shortly. It is not known how this study will change things. (Essential fatty acids, particularly linolenic fatty acid, have been shown to prevent myelin loss with no risk of cancer.)

More Nerve: In another report, Japanese researchers found that N-acetyl cysteine was also able to block the loss of myelin by 70%. (642) Cysteine is an important natural antioxidant that probably works by protecting complex fats within the sheath from oxidation, and by lowering levels of inflammatory cytokines, like tumor necrosis factor. Nerves (and brain cells) contain complex (and essential) fatty acids, many related to fish oils that are more likely to suffer oxidative damage due to their complex structures. Other antioxidants besides cysteine have also been shown to protect nerves from damage in stressful environments, including that of high blood sugars. Protective tools like these may also provide some benefit in other neuropathies, such as those found in alcoholism and post-polio syndrome.

"No diet will remove all the fat from your body because the brain is entirely fat. Without a brain you might look good, but all you could do is run for public office."

Covert Bailey


Cardiac karate: In a major study of 566 people with NIDDM and 114 others with IDDM over a four year period, Japanese researchers (248) measured how quickly blood vessels get blocked. Compared to people with no heart risk, the presence of diabetes caused a 7 to 8 fold increase in the rate of thickening of blood vessel walls. But researchers discovered that damage could be stopped or reversed in those who kept their blood sugars lower (HbA1c = 7.07%) compared to another group which had the highest blood sugars and the greatest increase in closure (HbA1c = 8.67%). Note that the difference in these HbA1c values is not that great!

Short of air? If you run high blood sugars, you are. Austrian researchers (abstract 610) measured lung capacity and air flow in 41 people with IDDM. Not surprisingly, people who ran high blood sugars couldn't breathe as well. Air flow was reduced by 15% on average. If you have normal blood sugars, though, you can breathe easy. No air flow reduction was found in these folks. Whew!

Why would high blood sugars affect breathing? Breathing depends on a combination of chest wall muscle movement, nerve control, and flexible lung membranes. High blood sugars can interfere with any of these mechanisms. This physical problem in breathing oxygen would be particularly stressful to cells already metabolically deprived of oxygen due to high blood sugars.

Full breathing capacity is important to everyone, but especially to athletes, to those exposed to smog, and to those who have heart disease. The oxygen deficit created by these lung problems may add to proliferative retinopathy, where oxygen deprivation is believed to trigger the growth of new blood vessels.

"Never go to a doctor whose office plants are dying."

Erma Bombeck


OK, mom, OK! A study out of Toronto is going to be tough for young women to take. The Canadians followed 90 women with IDDM over a four year period, starting at an average age of 14, to determine the frequency of eating disorders. During this time, teens who admitted taking less insulin to lose weight rose from 14% to 33% in the group, while self-induced vomiting rose from 8% to 17%. Diabetic eye damage was present in 89% of those who were diagnosed as suffering from severe eating disorders, compared to only 24% of those without this problem!

Thin may be in, but is it healthy? A 12 year European study (86) of 1200 people with IDDM found weight had no effect on mortality, EXCEPT that thin people were far MORE likely to die. Compared to the men who were thin (the highest risk group), men who were normal weight, mildly, moderately and severely obese were only 51%, 41%, 48% and 60% as likely to die. Compared to thin women, rates in the same weight categories were 74%, 49%, 57% and 55%. None of the usual risk factors like high blood pressure, high blood sugar, high cholesterol, or smoking seemed to explain this excess mortality in the thin. (Remember, this is only people with IDDM and will not hold for those with NIDDM.)

The thin factor is a hard one to figure. Obviously, anorexia entails major health risks and might be part of this statistic: higher blood sugars from skipping insulin, malnutrition, psychological stress, etc.. The excessive blood vessel damage, picked up as retinopathy in anorexic women, testifies to the double-whammy of high blood sugars and poor nutrition. although it is not known if there was any anorexia among the thin in the European study, this is likely to be one factor contributing to the excess mortality.

Research in people who don't have diabetes has shown anything from no extra risk to a 20% increase in the mortality rate for the thin. In some studies, the combination of a thin body style together with smoking has doubled mortality. But before rushing out and chowing down, the question remains: does the thin person with diabetes who eats healthy and keeps their blood sugars normal have any excess mortality risk? And, although it was a concern to many, that 10 pound average weight gain found in the intensive control group of the DCCT may be a blessing in disguise, foretelling a decreased risk of dying.

"I'm so neurotic that I worry I'll lose weight when I'm on a diet."

Grace Hodgson


Uh-Oh, where are those antioxidants: Our genetic blueprint, DNA, takes it on the chin with diabetes. Buffalo researchers (as in NY, 104) studied the genes of 12 men who had had IDDM for more than 10 years and who also had moderate kidney disease. DNA damage was found to be 4 times as high in these men (126 pg/mg vs. 31 pg/mg) compared to controls. This type of DNA damage comes from oxidation, which is increased by both diabetes and kidney disease. In another study (429), Swedish researchers discovered that birth defects in diabetic rats were actually caused by oxidizing free radicals. Using two different antioxidants, they were able to lower the risk of birth defects by 20% with a vitamin E substitute called Trolox, and by 70% with N-acetyl-cysteine.

In both STOP the Rollercoaster and Pumping Insulin, we explain how damaging oxidation is likely a factor in the development of diabetes complications. This Swedish study brings out an excellent point discussed there: protection from oxidation depends on the entire antioxidant system. Less protection resulted when the vitamin E substitute was used than when cysteine was used. Reason: when an antioxidant picks up a damaging free radical, the antioxidant itself becomes a weak free radical. although both drugs used in this study are antioxidants, cysteine was more powerful. It recycles glutathione back to its active form, and then glutathione is able to recycle vitamin E from a weak free radical back to its protective form.

Glutathione and its recycling enzyme, glutathione peroxidase, are both lowered by high blood sugars. This can allow vitamins E and C to become stuck in their useless forms. Antioxidants work as a team: the best effects come from using them as a complex with all members of the team present. Of course, normal blood sugars are the best way, by far, to decrease oxidative damage and prevent kidney disease at the same time.

Birth defects and NIDDM: Los Angeles researchers (230) provided further proof of the importance of control when they studied 131 births in women with NIDDM. Birth defects occurred in 15% of women who had been on diet treatment alone (and who had slightly higher HbA1c values), compared to only 7% in women who were on pills or insulin. The HbA1c values at the time the women first came into the clinic appears to explain the risk for birth defects, not the type of treatment. This study reinforces for women with NIDDM the advice given to those with IDDM: if you want a healthy baby, control the blood sugars before conception.


The DCCT, Hypoglycemia and HbA1c: although the DCCT study as a whole showed the risk for hypoglycemia rises steadily as average blood sugars dropped, individual sites showed no relationship between the two. altogether, 29 sites participated in the DCCT, and they varied considerably in how close to normal they could get their participant's blood sugars versus their risk of hypoglycemia. Some sites achieved nearly normal average HbA1c values with little severe hypoglycemia. Does this mean that tight control can be managed without severe hypoglycemia? Is it all in knowing what you're doing? No one has certainty, but suspicions are STRONG.

As noted by Dr. Jay Skyler of Florida, although many people think the DCCT suggested insulin pumps cause slightly more hypoglycemia than multiple injections, they really don't. A pump is only a device and nothing more. If the target blood sugars are set too low, you get more hypoglycemia. Hypoglycemia can be avoided by raising the target and using the fine insulin adjustments the device is capable of.

Kids and cornstarch: So everyone could sleep better at a diabetes summer camp, some researchers (abstract 304) gave uncooked cornstarch to kids as part of their bedtime snack. The idea was the cornstarch would keep blood sugars from dropping during the night. It worked! One or two teaspoons or raw cornstarch (7 to 14 grams or 25% to 50% of the total snack) at bedtime kept the blood sugars steady for 6 hours, instead of disappearing in 3 hours like most carbohydrates. The kids learned to flavor their security blanket in different ways for better taste. Some shrewd kids even began using it as insurance during the daytime. No one has tried it in adults yet, but health personnel were seen busily checking out the flavors.

Today's forecast: a high pressure front with low blood sugars! We've all heard about low blood sugars caused by exercise, excess insulin and skipping meals, but weatherfronts? Yup! Four Hungarian researchers (612) measured low blood sugars in 40 people with IDDM (Type I) to see if their lows were related to the weather. Low blood sugars were found to be more common with changing weather patterns, particularly as warm fronts move in and after cold weather fronts arrive. We can see it now: weather personnel required to give a diabetes update in their weather reports. John noticed as a child growing up in Kansas that lows often happened with incoming spring storms.

"If your parents didn't have children, there is a good chance that you won't have any."

Clarence Day


Hey kids, use this excuse at school! Anyone who's ever been through an insulin reaction can relate to this study. Remember how hard it is to control yourself for that eternity after a reaction? When you treat a low with glucose tablets, maltose or SweetTarts, a meter will read the blood sugar as normal in just a few minutes, yet the brain continues to scream that the sugar is low. Well, research now shows that it is low in the brain!

Previous assumptions were that glucose levels in the brain, separated by the blood/brain barrier, closely followed blood glucose levels. Connecticut researchers (144), however, finally tested this theory in four subjects who were being evaluated for epilepsy. What they found was surprising. Brain glucose levels turned out to be only one third the levels found in the blood, and when the blood sugars rose or fell, the brain's glucose level lagged behind that in the blood by 20 to 40 minutes.

This lag time could easily explain why coordination doesn't return to normal until 30 minutes after the blood sugar has been corrected and why driving should be delayed for at least 30 minutes following a low. The brain and coordination apparently need that time to fully correct.

Afterthought: When constant blood sugar monitoring hits the street, won't it be great to pick up the low blood reading, correct it rapidly with glucose or SweetTarts, and never have it hit the brain!

"Fear is that little darkroom where negatives are developed."

Michael Pritchard


Lys-Pro (Humalog) and Nasals

Faster than R: The race is on. Novo-Nordisk is still busy, but Lilly has already produced their version of fast insulin, called lys-pro (Humalog). Users love it. It can be taken immediately before eating (15 to 20 minutes lead time is best), creates lower post-meal blood sugars, and disappears in 3 to 4 hours. No more midnight lows from the dinner shot! Because it works faster, less insulin is usually needed: requirements typically drop 20 to 30%, and this could have some minor health benetits in the long run.

Yo! Techies! Lilly developed this fast insulin analogue by switching the positions of the last two amino acids in the insulin molecule, proline and lysine, hence the name lys-pro. "Regular" insulin is actually a hexamer of six individual insulin molecules that voluntarily link up to each other for stability. But this linking slows Regular down so it continues to drop the blood sugar for 5 or 6 hours after a shot. As many have noticed, this is a major disadvantage because most meals only raise the blood sugar for 2 to 3 hours. By a simple modification of its structure, lys-pro (should we call it Premium?) does not form this hexamer, acts faster, and more closely counters the effect of food on the blood sugar.

Pumps and lys-pro: With three hundred people using lys-pro, someone's going to try it. although strictly verbotten, a German physician put lys-pro in his insulin pump. Apparently, it worked great! One Lilly researcher cautions that studies are still underway to determine how compatible lys-pro is with the plastic tubing used in pumps. He admitted privately to some reassurance because lys-pro is phosphate buffered (like Velosulin) and improvements have already been made in the plastics used in infusion sets that make compatibility likely.

Reality check: One disturbing problem will arise in using lys-pro in pumps. If a clog or leak occurs, there is no pool of slower acting insulin left under the skin. Blood sugars will rapidly skyrocket in 3 to 4 hours. If insulin is unavailable, ketoacidosis would become severe much faster. Pumpers, in perticular, need to remember their basic principle of antigravity: "The faster they fall, the easier they rise." Always take an injection when in doubt. On a pump, a standard injection of lys-pro is recommended for a single blood sugar of 300 or greater to ensure that ketoacidosis does not occur.

"The human body experiences a powerful gravitational pull in the direction of hope. This is why the patient's hopes are the physician's secret weapon. They are the hidden ingredients in any prescription."

Norman Cousins


Snort at this one! Nasal insulin use in humans has been tried since 1983. Like lys-pro, nasal insulin allows for a faster insulin effect. But researchers in Denmark (498) cast a black pall over its use. When they tested nasal insulin in 31 people with IDDM, six people were taken out of the study because of high blood sugars, and one after a severe low blood sugar. Average insulin doses skyrocketed, increasing 17-fold from 39 units a day on injections to 659 units on the nasal insulin.

But other researchers working with animals offer a glimmer of hope. Research underway in France (511) and Alabama (698) shows that nasal insulin delivery improves when the insulin is made more available in a gel or when its transport is stimulated by alkylglycosides. In rats, insulin doses were brought down to only 2 or 3 times current doses by each of these methods.

By the way, 659 units is two thirds of a bottle of insulin every day! At today's insulin prices, this would come to $3,000 per person per year for just the insulin. Ah-Choooo!!!

New monitoring: New monitoring technology is headed in three directions: Non-invasive, where an external device can detect the blood sugar without pricking the finger; not-quite-as invasive, where a probe is placed through the skin but requires replacement every 2 or 3 days; and internal, where a device is surgically implanted every couple of years to transmit readings to an external device, and eventually to an implanted pump.

Implanted pumps stalled? Delivering insulin into the abdominal cavity via a surgically implanted pump has major advantages: more insulin goes to the liver, less to peripheral blood vessels, more stable blood sugars and less hypoglycemia. But this technology appears stalled. The V.A. funded a preliminary study to see if the technology would work, but problems arose in insulin delivery that exposed participants to excess surgery for correction of these problems. Funding was cut off. Design changes to overcome the technical problems would require yet another round of clinical trials, and costs are prohibitive. Delays are likely to occur in the development of an artificial pancreas: an implanted pump coupled to a constant monitoring device.

"How come dumb stuff seems so smart while you're doing it?"

Dennis the Menace


Ketoacidosis

DKA and ALC: Michigan researchers (45) discovered that acetyl-L-carnitine (ALC), a transporter for free fatty acids, protects rats from ketoacidosis (DKA), a potentially deadly acidic state found when insulin levels are severely low. ALC levels are low in diabetes (as opposed to long-chain carnitines, which are high). When the rats were given ALC in their drinking water, ketone levels dropped significantly and nerve function was totally protected. ALC would be costly for preventive use in thos who experience frequent DKA, but related substances, called L-carnitine and acyl-L-carnitine, are not quite as expensive and can be found in over-the-counter weight loss products. The researchers did not know if this less expensive substance would work as well as the ALC.

Other researchers found that high doses of the prostaglandin inhibitor Indomethacin (481) corrected the abnormal blood flow found when their rats went into ketoacidosis. Indomethacin improved the rats' NADH/NAD ratio (aka, improved energy flow) and this kept blood vessels constricting and dilating correctly. This interesting information offers hope of reducing death rates due to ketoacidosis and hints at further ways to prevent complications.

Oddities

Plump talk: Obesity is on everyone's minds. 34% of Americans are already moderately obese and the rest are worried. Dr. R. L. Atkinson, an obesity specialist at the University of Virginia, had frank words about obesity, referring to it as a chronic disease that should be treated as one. No quick fixes in this complex disease created by factors that require individualized treatments. As others, he prefers starting with diet and exercise as the best treatments, but keeping in mind that their 5 year success rate is only 2 to 3%. Priority should be placed on identifying those who really need to lose weight, with progress being determined by body measurements rather than weight, and by improvements in blood sugars, triglyceride levels, and blood pressure. Drugs taken over a lifetime should be considered. He cited recent research studies that show promising results when two and three drug combinations are given in lower doses.

He was candid about the inertia blocking clincians and patients from success: previous failures, unrealistic expectations and fears, state and FDA regulations, a lack of long term commitment, personal stigma, poor nutritional programs in school, lack of recreational areas and parks, and a lack of research funding. As one example, Dr. Atkinson pointed out that no new obesity drugs have appeared in the last 22 years!

Drugs can influence weight in many ways. People who've taken Prednisone can testify how quickly their appetite and weight are negatively affected. Drugs to reduce weight can work by: reducing intestinal absorption of calories (especially fat), suppressing appetite, increasing satiety (that full feeling), reducing the set point (the weight the body resists dropping below), and increasing metabolism.

"You show me a woman who hasn't fantaSIZEd about getting in a car and leaving home, and I'll show you a woman who doesn't drive."

Susan Sussman


Is the DCCT the real world? How well does the standard treatment group, who volunteered for the DCCT, represent the real world of IDDM? Well, Wisconsin researchers (76) gave a clue in their data from a state-wide study of eye damage among people with IDDM. In the 891 people they surveyed in the state, HbA1c values averaged 10.1% in the early 1980's, eventually falling to 9.5% as monitoring improved. Wisconsin's values, measured at the same lab, are substantially above the 8.9% average among the volunteers who started the DCCT.

This suggests participants in the DCCT standard treatment group were already better controlled than the average person with IDDM. If this state-wide Wisconsin study reflects that of other states, complications are occurring at a higher rate than suggested by the "poor" control group of the DCCT. The job of reducing health damage through better control may be harder, but the payoff will be greater as well.

Windy City family trees: Chicago researchers (78) checked out blood relatives of people with NIDDM. Of these relatives, 78% had one or more risk factor for heart disease: 46% had high blood pressure, 65% a cholesterol problem and 54% were obese. In a subgroup of 16 African American relatives who were over the age of 35, half were found to actually have undiagnosed diabetes!

"Progress might have been all right once, but it has gone on too long."

Ogden Nash


Check your LG, sir? What is LG, you ask? Liver glycogen. Connecticut researchers (238) got 9 nondiabetic and 7 IDDM subjects to swallow research meals and radioactive carbon (Good bribes for this study, we bet!) in a day long study to determine liver activity in diabetes. Lo and behold: livers of people with IDDM dump about the same amount of glucose into the blood, but they were slower to pick it up. Diabetic livers converted only 43% as much glucose from a meal into glycogen (the storage form of glucose) as control livers did. Sounds like damn lazy livers to us.

In a meal, the food first passes through the portal vein into the liver (aka metabolic central), before it enters the general circulation. Normally, half the glucose in the meal gets picked up and processed into glycogen on its first pass through the liver. By grabbing glucose, the liver keeps blood sugars from spiking after meals. In contrast, with IDDM and a lazy liver, blood sugars are more likely to spike after eating. Blood sugar control was not great in the IDDM group (HbA1c = 9.5%) and it is not known if tighter control would improve the liver's activity. Lys-pro or nasal insulin will certainly help, because they work fast and prevent most of the post-meal rise.

"It's hard to fight an enemy who has outposts in your head."

Sally Kempton


VAROOM! The VA is preparing for a DCCT-type study of their NIDDM population. Early results are in: the first 153 participants averaged 60 years of age, had diabetes for 8 years, and started the study with a HbA1c of 9.8% and fasting blood sugars of 218 mg/dl. Of these men, 38% had already suffered a heart attack or stroke, and 53% were on blood pressure medication. Subjects in the intensive control group were placed into a progressive treatment program to normalize blood sugars, and got excellent results. Fasting blood sugars dropped to 115 mg/dl compared to 200 mg/dl for the control group. Their HbA1c values dropped to around 7%.

In contrast to the DCCT, no weight gain was found. Aand amazingly, the large blood sugar drop had no effect on triglyceride levels or blood pressures, which has been seen in some studies. Blood pressures were likely well-controlled in that more than half were already on blood pressure medication.

The intensive control group actually needed only a little more insulin: 76 units a day, compared to 60 units in the standard treatment group. Severe insulin reactions in the VA's intensive group occurred at only 4% the rate found in the intensive group of the DCCT. (Not surprising really, since NIDDM are resistant to insulin, and, therefore, to insulin reactions.)

"You miss 100 percent of the shots you never take."

Wayne Gretsky


Short Takes:

With diabetes, people are 2.4 times as likely to be on a blood pressure medication and 1.7 times as likely to be on a cholesterol medication (470).

One of every 100 people with diabetes is in kidney failure (471), and men have twice the risk of women.

Girls in their teens have higher blood pressure than other girls or than boys with or without diabetes. HbA1 levels were no different between boys and girls with diabetes.

ZZZZZZ: Obese people with sleep apnea are much more resistant to insulin according to Australian researchers (257), but that excess resistance can be reversed by techniques that improve air flow.

What causes blood vessels in the retina to proliferate with advanced eye disease? Joslin and other researchers identified a good candidate: Vascular Endothelial Growth Fac- tor or VEGF. VEGF levels are 8 times as high during active proliferative retinopathy, but drop 80% following laser treatment.

Joslin researchers also showed that in the first five years of diabetes, blood flow to the retina is low and may be tied to high diaclyglycerol (DAG) levels. DAG levels were 6.2 in nondiabetic controls, 34.1 in poorly controlled diabetes, and 10.0 in the intensive control group of the DCCT. Blood flow increased to normal as blood sugars and DAG levels came down.

Of Americans with diabetes, 38% are on insulin. Those who live in the Northeast are 1.7 times as likely to use insulin as those who live in the West (101).

Researchers in Pennsylvania (239) found that blood sugars between 150 and 220 mg/dl cause insulin resistance, making blood sugars even more likely to rise.

Only 59% of people with IDDM, 49% of people with NIDDM on insulin, and 24% of those with NIDDM not on insulin have taken a class in diabetes (51). Blood sugar control in those who have NIDDM but aren't on insulin depends largely on education and diet counselling. Yet this group has the lowest rate of referral to classes and dieticians. Reminds us of the old saw, "an ounce of prevention is worth a pound of cure."

Researchers compared the average heart rates of 8 people in the DCCT intensive control group to 8 other poorly controlled people with IDDM (48). Heart rates in the well- controlled average much lower: 59 versus 70 beats a minute, due to less damage to the sympathetic nerves which allows blood vessels to constrict appropriately. The lower heart rate means better blood flow to muscles and less work on the heart.

A Pittsburgh study found high blood sugars and high blood pressure were the major causes of nerve damage in the feet (69). People who do regular blood sugar testing regularly had less nerve damage.

"After a 30 year old lawyer died, he called out to St. Peter, "How can you do this to me--a heart attack at my age? I'm only 30." St. Peter replied, "When we looked at your total hours billed, we figured you were 95."

Anon.