Redefining diabetes: Lines blurring in diagnosis

Mark E. Meijer, MD, a family physician in South Hill, Va., has noticed that, when it comes to his patients, the lines between type 1 and type 2 diabetes are increasingly blurry.

"The majority by far are easy to distinguish, but there are more and more patients who are ambiguous," said Dr. Meijer, the author of the book, Ten Steps to Control Diabetes.

For instance, one woman had been a type 1 diabetic her whole life, but she was also obese and had cholesterol levels as high as many of his patients with type 2. Another example: a man in his 30s who looked like a typical type 2 diabetic. But when Dr. Meijer had him fast as part of his assessment, he went rapidly into diabetic ketoacidosis -- a problem far more typical of those with type 1.

These are anecdotes, but they support the notion that doctors increasingly are faced with more complex diabetic patients, including those who don't fit neatly in the type 1 or type 2 box. Actually, they appear to have characteristics of both.

"We'd like to believe that type 1 diabetes and type 2 diabetes are very distinct, and that it's very clear when we see a patient which type of diabetes they have," said Nathaniel Clark, MD, national vice president for clinical affairs for the American Diabetes Assn. "In fact, that's not true."

Patients are showing up overweight and with evidence of insulin resistance, signals that seem to point toward a diagnosis of type 2. On testing, however, they appear to be positive for the antibodies that suggest type 1. Or they might present with diabetic ketoacidosis, a clear sign of the onset of type 1, only to come up negative on tests for antibodies. After a short period of time on insulin, many are able to maintain their health on the oral agents usually reserved for those with type 2.

"These people, once they get over the acute episode, they then go on to look like an absolutely bona fide type 2 diabetic patient," said Mary Ann Banerji, MD, who published several related papers and is the director of the Diabetes Center at the State University of New York Health Science Center in Brooklyn. "There's an overlap in how they clinically present."

No more boundaries?

According to a study in the October 2003 issue of Diabetes Care, one in four African-American and one in 10 Caucasian children diagnosed with type 1 diabetes appeared to have characteristics of both types. Several studies also have documented cases of this merger in adults, and researchers are struggling to determine why the borders between type 1 and type 2 appear to be getting ever fuzzier.

Theories abound. Some feel that the disease has never really fit into specific classifications, and the combining of these categories in some patients is a result of a better scientific understanding of the disease's pathology.

"I think it's always been there, but we're seeing it more often," said Fred Miser, MD, associate professor of family medicine at Ohio State University College of Medicine and Public Health in Columbus.

This science also has given physicians the ability to test for type 1 antibodies, something that has become more available over the past decade and is being used more than ever.

"Before we were defining solely on the basis of the phenotype," said Richelle Koopman, MD, assistant professor of family medicine at the Medical University of South Carolina College of Medicine in Charleston. "Now we're looking for more because we have the ability to find more."

Many experts believe, though, that scientific knowledge and new tools explain only part of the increasing complexity of this disease.

The most widely accepted theory is that this trend is driven by the obesity epidemic. The average weight of those with type 1 diabetes has increased along with that of the general population. As a result, these patients are developing type 2 symptoms.

"Getting type 1 diabetes doesn't protect you from becoming obese," said Phil Zeitler, MD, PhD, a pediatric endocrinologist at the Children's Hospital, Denver, and an associate professor at the University of Colorado Health Sciences Center School of Medicine. "I don't think these are two types of diabetes crashing into each other. They're two relatively common problems that sometimes occur in the same patient."

The more contentious possibility is the "accelerator hypothes" is that calls into question whether an autoimmune response is really at the core of type 1. This theory suggests that the underlying mechanism for both types of diabetes is insulin resistance.

"The stress of obesity and the stress of our sedentary lifestyle and everything that's going on is causing insulin resistance, and this insulin resistance may be accelerating the damage to the cells that make insulin," said Dr. Dorothy Becker, chief of the division of pediatric endocrinology at Children's Hospital of Pittsburgh who is researching this theory.

An increase in type 1 has paralleled the increase in type 2, and proponents for this theory suggest that the only difference between the two might be the rate at which the beta cells die. This concept suggests that the obesity epidemic is driving both types.

"The pillars supporting the notion of autoimmunity as the cause of childhood diabetes were erected in the 1960s and early 1970s. However, despite an enormous amount of research since, no cause for type 1 diabetes has been found. No mechanism been explained, and no effective treatment or prevention is forthcoming," said Dr. Terence Wilkin, the theory's originator and professor of endocrinology and metabolism at Peninsula Medical School in Plymouth, England. "It seemed not unreasonable to ask the question: Is the paradigm right, because it's not paying dividends?"

This theory is perhaps the least accepted, although still taken seriously.

Most recently, an editorial in the February Diabetic Medicine called for "interested skepticism."

"Nobody can say this is proven, although there are some people who like this idea," said Dr. Denis Daneman, author of the piece and chief of the division of endocrinology and professor of pediatrics at the Hospital for Sick Children at the University of Toronto.

This line of research also is attracting financial backing. Dr. Wilkin gets funding from his country's National Health Service and several major pharmaceutical companies to pursue his theory. On this side of the pond, Dr. Becker is the North American primary investigator for the National Institutes of Health-funded trial to reduce insulin-dependent diabetes in the genetically at risk. This study will attempt to determine whether the food that at-risk newborns consume will affect their chance of developing the type 1 version of the disease.

Early results suggest this could be a promising track. A study in the same issue of Diabetic Medicine found that in the past 20 years children with type 1 diabetes had become heavier at diagnosis. Those who were heavier tended to develop the disease younger.

"Over the years in which type 1 diabetes has been on the increase, obesity has been on the increase," said Dr. Wilkin, one of the study's authors. "That's what we attribute to type 2, so it's not irrational as a possible candidate for type 1 as well."

But debate exists over when Dr. Wilkin's accelerator hypothesis might kick in. Most experts find it plausible that the obesity epidemic will make both forms of diabetes worse, but many question how obesity could play a role in initiating the first immune system assault against the beta cells in type 1 diabetes.

"There's other things going on besides just simple obesity," said Jerry Palmer, MD, an endocrinologist and professor of medicine at the University of Washington in Seattle who has authored several studies on these patients. "It's not that I'm not a fan of the accelerator hypothesis, but I don't think it's an adequate explanation for everything that's going on."

This issue is expected to be addressed in a new paper by researchers from the Search for Diabetes in Youth, a multicenter study funded by the Centers for Disease Control and Prevention and NIH, aimed at better understanding the disease in this age group. "In our data, overall BMI was associated with a younger age of onset of type 1 only among patients with low residual insulin secretion at diagnosis," said Dana Dabelea, MD, PhD, diabetes epidemiologist and assistant professor at the University of Colorado Health Sciences Center. She is one of Search's lead investigators. "This needs to be confirmed, but we think this acceleration process happens late in the natural history of the diabetes process."

What's in a name?

But by far the noisiest debate is what to call the problem. Some of the monikers now circulating include double diabetes, type 1.5, type 3 and hybrid diabetes. "I don't think there is good agreement among doctors as to what this should be called," Dr. Clark said. "We may be in a time when diabetes should be redefined, because we're realizing that there's more complexity than was recognized previously."

And while researchers are looking for why, many physicians are trying to determine the optimal therapy for these complex patients.

"If they have both, what do you do?" asked James Gill, MD, MPH, associate professor in family medicine and health policy at Jefferson University in Philadelphia. "Typically for type 1, it would be inappropriate to prescribe an oral medication, but if you're not sure what they have, it's really unclear about what's appropriate."

What is clear is that the implications of having characteristics of both types can be dire.

For example, a study published in the October Journal of Autoimmunity found that children with characteristics of both type 1 and type 2 experienced a more aggressive disease process, as did those who seemed to have only type 2 but had autoimmune markers that indicated a risk for type 1. Similar results also have been found for adults.

"What we really need to do is to understand what this means in the long run," said Lisa Gilliam, MD, PhD, lead author on that paper and an endocrinologist at the University of Washington in Seattle. "Being able to put somebody into a category is one thing, but being able to understand what's going to happen to them in five or 10 years is the important question."