what were reading November/December, 2006
We know it's impossible to stay current with all the news in diabetes. The immense flow of information can be contradictory, confusing, and just plain overwhelming. Who has time to read it all?
Well, we do.
It's not just our livelihood. For those of us with diabetes, it's our life, so we look for articles that are smart, useful, and surprising.
We pore over every possible diabetes publication and, in this column, we identify our most important discoveries from recent patient magazines and newsletters. (When possible, we will give you the direct link to the article.) We hope this saves you time, and were pleased to point out to you pieces you might otherwise miss! We also follow the professional scientific journals such as Diabetes Care, JAMA, and the New England Journal of Medicine, and we will report on one diabetes research article each issue.
Our favorite patient articles for this issue:
"The Benefits of Tight Control: No End in Sight", Wayne Clark, Diabetes Self-Management, May/June 2006.
(The site is www.diabetesselfmanagement.com, but the article itself is not available online.) This article presciently reviews what we know about tight control - how many people with diabetes in the U.S. are getting there, and what it means for complications. Clark recounts the details of the Diabetes Control and Complications Trial (DCCT), which proved the hypothesis that tight glucose management reduces the risk of complications. The study also famously proved that there is no glycemic threshold, or point below which a lower HbA1c does not yield additional benefit. The follow-up study to the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, found that even years after the DCCT, when the A1c's of the two patient groups converged, patients from the intensive management cohort still had fewer complications. A similar study, the United Kingdom Prospective Diabetes Study (UKPDS) published in 1998, found that intensive control in type 2 diabetes reduced microvascular complications by 25%.
Despite these impressive studies - which collectively followed more than 6,500 patients - data show that less than one-third of patients today are reaching glucose targets. In the article, Clark reviews some barriers to tight control, including lack of insurance coverage, the progressive nature of type 2 diabetes, and the way in which medical care is delivered. On this last point, MaineHealth in Portland, Maine, has implemented a Chronic Care Model that tackles diabetes using electronic registries, automated reminders and notices, and multidisciplinary treatment teams. As part of this program, nurse specialists called Chronic Illness Care Managers are incorporated into primary care practices to provide patients with more intensive education and motivational support. The model has been successful; the percentage of people with A1c values under 7% jumped from 41% to 49%, while the percentage of people with an A1c higher than 8% decreased from 31% to 24%.
The bottom line: Despite the poor outcomes for many diabetic patients, the Chronic Care Model used in Maine shows that enlightened, rigorous treatment can benefit many people with the disease. The challenge is how to spread these efforts to other parts of the country.
Special Report: How to Save Your Heart, Hope Warshaw, Diabetic Living, Summer 2006.
(You can read this online at www.diabeticlivingonline.com.) We love articles with information that you can apply to your own life. In this article, you receive guidance on how to lower your risk of cardiovascular disease, the number one cause of death in people with diabetes. As Dr. Francine Kaufman of Children's Hospital of Los Angeles says, "When you have diabetes, your risk of a heart attack is as high as it is for a person without diabetes who's had a heart attack." Near normal glucose levels can reduce the risk of heart attack and stroke. In addition to what might be termed obvious tips - 1) slim down; 2) eat smart; 3) get moving; and 4) take your medication - other more actionable advice from Warshaw includes testing blood lipids once a year, possibly taking a daily low-dose aspirin (75 to 162 mg), choosing unsaturated over saturated or trans fats, and knowing the signs of heart attack or stroke. From a patient perspective, we found her ABC Goals most compelling: A1c (under 6.5% or 7%, depending on which organization you ask), blood pressure (under 130/80 mmHg), and blood cholesterol (LDL under 100 mg/dL, HDL above 40 mg/dL for men and 50 mg/ dL for women, triglycerides under 150 mg/L). If you know your goals and your test results, you can be sure that your glucose and lipids are at healthy levels.
The bottom line: People with diabetes often worry more about microvascular complications, but heart disease is a real threat. With specific tips on how to live a healthier lifestyle, this article would benefit anyone, but its especially important for people with diabetes who are at higher risk for cardiovascular disease.
Learning the ABCs of Beta Cells, Robert S. Dinsmoor, JDRF Countdown, Spring 2006. (www.jdrf.org.)
Beta cell regeneration, dedifferentiation, redifferentiation, isolation, and encapsulation: this article reviews some of the leading curative research, profiling scientists who are furiously trying to replace beta cells as a therapy for type 1 diabetes. Dinsmoor writes about projects across the world. For instance, a group in Denmark is using fluorescent protein tags in mouse models to better understand gene expression in beta cell differentiation, while researchers at Mt. Sinai are looking at how to make endoderm from embryonic stem cells. (Endoderm is the embryonic tissue layer that generates beta cells.) Researchers are now focused on learning what causes beta cells to develop. While we know that endoderm, a type of embryonic tissue, becomes the pancreas and the beta cell, we do not understand how this happens. Understanding the signaling that transforms generalized tissue into beta cells may help researchers create new beta cells for people with diabetes.
The bottom line: Although curative research seems at times to be agonizingly slow, progress is being made. Researchers now understand considerably more about the genetics of beta cell differentiation. That said, even when researchers understand how beta cells are created, more work needs to be done before we can engineer cells to replace beta cells. As Dinsmoor writes, "Real beta cells must be able to synthesize insulin, store it, and secrete it in a glucose-responsive manner." Thats a tall order.
Diabetes Research Update
In April 2006, Dr. Louis Monnier and colleagues published an article in JAMA that challenged the conventional wisdom about diabetes management and complications. The article suggests that complications can occur not only because of high blood glucose but also because of fluctuations in glucose.
Microvascular complications (like eye, kidney, and nerve problems) and macrovascular complications (like atherosclerosis and cardiovascular disease) have been linked to oxidative stress, a damaging cellular process. In the study, investigators compared the effects of chronic sustained hyperglycemia and acute glucose fluctuations on the activation of oxidative stress. Twenty-one sub- jects with type 2 diabetes were enrolled in the study along with 21 controls, or people without diabetes. All subjects wore a continuous glucose monitor, the Minimed CGMS system, to measure their glucose levels over three consecutive days. As a gauge of oxidative stress, researchers measured the subjects urine excretion of 8-iso-prostaglandin (8-iso-PGF2a), a marker of free radical production.
The study compared the data collected on the mean urinary excretion rate of 8-iso-PGF2a to the standard measurements of glycemic control. The strongest positive correlation was found between the mean urinary excretion of 8-iso-PGF2 and MAGE, or Mean Amplitude of Glucose Excursion. MAGE is an average of the differences between consecutive peaks and valleys in a glucose trend (e.g., a measure of how much glucose levels are fluctuating).
Levels of free radical production were twice as high in subjects with diabetes than in the control group, and glucose fluctuation was strongly correlated with high free radical production. Superoxide production also correlated strongly with postprandial instability. The authors concluded that glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia (1681).
The same issue of JAMA published an editorial about the findings. Drs. Michael Brownlee and Irl B. Hirsch, who are well known for their expertise in glycemic variability, wrote: "If confirmed in larger studies, [these findings] have enormous clinical implications." Previous work has suggested that excursions are damaging, even in patients with low glucose levels overall. Dr. Brownlee saw the impact of MAGE in his currently unpublished research on the activity of the endothelial cell enzyme, prostacyclin synthase, which inhibits atherosclerosis. When patients experienced induced hyperglycemic excursions with special hyperglycemic clamps, they saw a dramatic free-radical induced decrease in prostacyclin synthase. Both authors view the work of Monnier as further confir- mation that patients with type 2 diabetes should be more strongly encouraged to test frequently.
The bottom line: Dr. Monniers work challenges the standards of treatment, adopted since the DCCT, that have made A1c scores the gold standard of care. The focus on A1c may be too narrow, downplaying the possible damage caused by glucose excursions. We believe that devices like continuous glucose monitors and drugs like Byetta and Symlin can diminish glycemic instability and can minimize excursions. They could play a much larger role in diabetes care if and when this latest research gains more adherents. If nothing else, this research reinforces the imperative of intensive management.
(Monnier D. et al. Activation of Oxidative Stress by Acute Glucose Fluctuations Compared With Sustained Chronic Hyperglycemia in Patients With Type 2 Diabetes. JAMA April 2006. 295 (14): 1681-1687. Saudek, Christopher, et al. Assessing Glycemia in Diabetes Using Self-monitor- ing Blood Glucose and Hemoglobin A1C. JAMA. 12 Apr 2006. 295(14):1688-1697.)