November 13, 2008
The Center for Disease Control recently announced a dramatic increase in the number of Americans being diagnosed with diabetes. Even as this occurs, there are other problems: the current research calls into question the goals of care for treating diabetes.
The number of people diagnosed with Type-2 diabetes has doubled over the last ten years. The rate rose from 4.8 per 1,000 people from 1995 to 1997 to 9.1 per 1,000 people from 2005 to 2007. The highest increases came, without surprise, in those areas of the country, where obesity is most common, namely: Alabama, Florida, Georgia, Kentucky, Louisiana, South Carolina, Tennessee, Texas and West Virginia
Minnesota has the fewest new cases of diabetes; five per 1,000 people while West Virginia has more than double the cases, 12.7 per 1,000 in. Puerto Rico wins, or rather loses, with the most new cases at 12.8 per 1,000 people. Grab a recent newspaper and find one of those maps depicting Red versus Blue states. The red areas pretty much correspond to the areas with the greatest incidence of diabetes. I’m not going to try and explain this phenomenon though.
Almost all of these new cases, 90-95%, are type- 2 diabetes or what was once called adult- onset diabetes. 
As bad as this sounds, there is even worse news. There are questions about the generally accepted standards of care. Avandia, one of the most common medications used to treat this sort of diabetes is dangerous and consumer groups are bugging the FDA to pull it completely off the market, yet there are even bigger problems. The treatment goals we have encouraged people to strive for in managing diabetes may be causing harm.
Last February 7, the researchers running the ACCORD study (for Action to Control Cardiovascular Risk in Diabetes) closed down the study 17 months ahead of schedule. Early evaluation of the data suggested that the treatment was hurting people.
The ACCORD study is the third major intervention trial that attempted to lower blood sugars in people with diabetes in order to reduce risk of heart attacks and stroke. For decades, the whole theory in treating diabetes has been simple; keep the patients’ blood sugar levels as close to normal as possible.
In all, 23,000 people with diabetes have taken part in these clinical trials.
The first two studies, one called ADVANCE that followed patients in 20 countries, and the second, the Veterans Affairs Diabetes Trial (VADT) were set up to measure the expected benefit resulting from maintaining low blood sugars. Neither study showed any benefit from therapy. The explanation for these unexpected failures was that the patients didn’t keep their blood sugars low enough. While they only failed to show benefit, ACCORD was worse, more people died in the treatment arm of the study than in the control arm.
Since the 1940s, doctors have thought that high blood sugar from diabetes is responsible for the problems caused and the focus of treatment has been keeping blood sugars in the normal range.
In these three studies researchers monitored blood sugar levels using a test called hemoglobin A1c that measures the percentage of hemoglobin molecules in the blood bound to a glucose molecule. The higher a person’s blood sugar gets, the more glucose binds to hemoglobin and the higher the A1c is. Hemoglobin A1c measurement allows researchers to calculate a person’s average blood sugar levels for the preceding three months. In healthy people A1c is below 6%. Untreated diabetics usually have levels above 9.5%. The ADVANCE, and VADT trials lowered hemoglobin A1c below 6.5%. The ACCORD trial went all out and kept hemoglobin A1c levels below 6%.
So why did this backfire and cause more deaths? There are a number of possible explanations. One is that the ACCORD therapy was too intense, it lowered blood sugars too far. When the concentration of sugar in the blood falls below 79 mg/dL, a condition called hypoglycemia or low blood sugar, the body triggers a stress response to raise the sugar level back up, releasing epinephrine, glucagons, cortisol and growth hormone. Instead of controlling blood sugar by lowering it with insulin, the participants in the ACCORD trial were often controlling sugar levels by raising it with cortisol. Triggering these sudden and repeated stress reactions may be what triggered the increase in heart attacks. 
Another suggested explanation is that the study wasn’t long enough and that if it went longer the data would have been better. When you see three studies fail in a row, this argument doesn’t ring true. After all who are you going to convince to stay in the study if their risk of dying is increasing. You can’t ethically tell them to, “Stick with it.”
Eminent colleagues have suggested to me that the problem was the diet these participants followed. They used the American Diabetic Association (ADA) diet that does not restrict carbohydrate intake to the same degree as the Berenstein Diet, a favored approach by many of my colleagues for treating diabetes. The higher carbohydrate loads in the ADA diet necessitated higher insulin and greater chance to trigger hypoglycemia.
Researchers had reason to think these studies should produce benefit. In 1993, the Diabetes Control and Complications Trial (DCCT), reported that keeping blood sugar down prevented complications in type-1 diabetics and a follow up of the same people ten years later showed they had lower risk of heart attacks. But that study looked only at type-1 diabetes where people no longer make insulin and need to take it. In type-2 diabetes people still make plenty of insulin, their cells just don’t respond to it. To control their blood sugar these people need to make or take excess insulin. Perhaps high insulin is the problem and not the sugar. Remember type-2 diabetes was rare until the 1980s.
Here’s another idea to consider. Writing in a June 2007 edition of New Scientist, Andy Coghlan describes how diabetes causes ‘lasting havoc’ in the body. He writes,
“One of the nasty tricks that diabetes has up its sleeve is the ability to carry on harming people long after they have got the level of glucose in their blood under control. ……..
“The idea builds on the discovery that when cells are exposed to the high levels of glucose typical of diabetes, proteins within the cells' mitochondria suffer damaging changes. The proteins become permanently attached to sugar-like molecules called glycans, and this not only prevents them doing their job properly but also makes them produce harmful molecules called reactive oxygen species.
“The reactive oxygen species circulate throughout the body, attacking and damaging tissues, particularly in the limbs and eyes. Because the changes to the cellular proteins are not reversible, they continue to pump out these molecules even when glucose levels have returned to normal.” 
It could be that the increase in heart disease is due to exposure to excess reactive oxygen species that continue to be generated even though the glucose levels have returned to normal.
Antonio Ceriello suggested as early as 2003 that this damage from oxidation could be neutralized using anti-oxidant supplements.  He went on to demonstrate in 2007 that in type-1 diabetes vitamin C injections could be used to lower blood pressure.  Though vitamin C can neutralizes the oxidants produced, it doesn’t stop more from being made. Ceriello thinks diabetics may need to inject both insulin and vitamin C to keep their blood vessels healthy.  To be effective diabetics need extra anti-oxidants for life.  If this is the case, the problem with these treatment trials that yielded negative benefit seems obvious.
For a diabetic to keep hemoglobin A1c as low as required in the ACCORD trial isn’t easy. The participants probably had to drastically decrease the amount of carbohydrates they ate. No doubt they avoided all sugar but probably decrease fruit as well. Decreasing fruit consumption would have decreased antioxidant action in the blood significantly. If a healthy person avoids fruit, they will increase risk of chronic diseases including heart disease and cancer; this effect would be even more striking in diabetes.
Though Ceriello used vitamin C injections with good effect in his study, oral vitamin C for some reason may increase risk.
Janet Raloff writing in Science News back in early 2005, reviewed research that vitamin C appears to increase heart attack risk in female diabetics. In a study that compared 1,923 postmenopausal women with diabetes against 35,000 healthy recruits, researchers found that women with diabetes who consumed 300 or more milligrams of vitamin C a day were twice as likely to die of stroke or heart disease than women who didn’t. 
If you aren’t feeling confused by this, you aren’t paying attention.
Vitamin C injections seem like they might be helpful but oral doses appears dangerous. Giving older type 2 diabetics oral vitamin C, either .5 gram or 1 gram, increases glutathione levels in the body but this doesn’t decrease lipid peroxidation, that is the chemical name for when fat in the blood goes rancid.  Lipid peroxidation is a major contributor to cardiovascular disease. Maybe one needs higher doses of vitamin C to have a positive effect. Perhaps we can find arguments to counter the information in Raloff’s article but I confess to being very hesitant to suggest that diabetics take extra vitamin C.
So where does all this leave us? Confused to say the least. It still seems logical to keep blood sugar close to the normal range. After all this still decreases symptoms of the disease and the long-term complications even if it does not ‘fix’ the heart disease problem. Routine use of antioxidants makes sense but for unexplained reasons, vitamin C may not be appropriate unless the patient commits to high dose IV therapy. Even if exercise and weight loss often bring sugar control back into the normal range, the need for protection against oxidative damage may persist for life.
In most cases diabetes is a disease of excess and deficiency: too many calories, not enough exercise, too much TV and not enough sunlight, perhaps too much Rush Limbaugh and not enough, I don’t know, what would the opposite of Rush be?
Developing insulin resistance is a logical response to the excessive calories, albeit inappropriate. Maintaining a reasonable level of fitness and avoiding excessive weight gain remain the best strategies on a national level. Why the red and blue divide for diabetes incidence exists, well that is just as confusing as the rest of this.
Rate of Diabetes Cases Doubles in 10 Years: CDC
The obesity epidemic is fueling the type 2 disease epidemic, officials say
Posted October 30, 2008 By Steven Reinberg
Science 17 October 2008:Vol. 322. no. 5900, pp. 365 - 367
DIABETES: Paradoxical Effects of Tightly Controlled Blood Sugar
How to stop diabetes wreaking lasting havoc. 29 June 2007. New Scientist Andy Coghlan
Diabetes Care. 2003 May;26(5):1589-96.
New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. Ceriello A.
Diabetes Care. 2007 Jul;30(7):1694-8. Epub 2007 Apr 24. Telmisartan shows an equivalent effect of vitamin C in further improving endothelial dysfunction after glycemia normalization in type 1 diabetes.
Ceriello A, Piconi L, Esposito K, Giugliano D.
Diabetes Care. 2007 Mar;30(3):649-54. Simultaneous control of hyperglycemia and oxidative stress normalizes endothelial function in type 1 diabetes.
Ceriello A, Kumar S, Piconi L, Esposito K, Giugliano D.
issue 2610 of New Scientist magazine, 29 June 2007, page 11
Vitamin C and diabetes: Risky mix? Janet Raloff
Science News January 1st, 2005; Vol.167 #1 (p. 12)
Arch Gerontol Geriatr. 2007 Dec 10. Effects of vitamin C supplementation on antioxidants and lipid peroxidation markers in elderly subjects with type 2 diabetes.
Tessier DM, Khalil A, Trottier L, Fülöp T.