Is Type 2 diabetes an autoimmune disease?

May be subcategory that needs separate treatment

Two researchers are presenting challenging new ways of looking at Type 2 diabetes, one suggesting that the disease in the elderly is sometimes caused by an autoimmune response and the other that it should be added to the growing list of inflammatory diseases.

One scientist suggest that there may even be a subcategory of Type 2 diabetes that he calls Latent Autoimmune Diabetes in Adults (LADA), and the other found markers of inflammation that appear to be predictive of the development of diabetes.

Massimo Pietropaolo, MD, assistant professor of pediatrics and medicine at the University of Pittsburgh and a researcher in the department of immunogenetics at Children’s Hospital of Pittsburgh, estimates that 10% to 33% of elderly Type 2 diabetics may actually have an autoimmune form of the disease requiring different treatment.

"The fact that islet cell autoimmunity is associated with poor diabetes control among elderly patients raises the possibility that these individuals may require aggressive intervention to reduce the risk of the complications related with hyperglycemia . . . and may be useful in predicting the likelihood of insulin requirement," Pietropaolo wrote in a paper presented at the American Diabetes Association Scientific Sessions in June.

"It is more than likely a different disease, that results from a combination of abnormalities in both insulin secretion and insulin action," says Pietropaolo. "And when you think that 16 million people have diabetes in this country, that percentage means a very large number of people may have LADA."

In a study of 196 elderly Type 2 diabetic patients and 94 nondiabetic controls, Pietropaolo found a "significant" increase in fibrinogen and C-reactive protein levels in addition to high levels of GAD-65 (islet autoantigen glutamic acid decarboxylase) and/or IA-2 (protein tyrosine phosphatase-like protein molecules found in islet cells) antibodies, triggering an acute phase response associated with islet cell autoimmunity "that may in part explain the defect in insulin secretion seen in Type 2 diabetes."

Those who had higher levels of the autoantibodies had higher fasting glucose levels, higher glucose levels after a two-hour glucose tolerance test, had lower serum albumin levels and had a proportionately higher use of oral antidiabetic agents over the seven years of the study.

Pietropaolo says there are several hypotheses about the cause of LADA, ranging from genetic predisposition to aging to overnutrition. "This isn’t really a new idea," says Pietropaolo. "It’s simply that we have more reliable assays to identify them, particularly autoantibodies against GAD-65 [glutamic acid decarboxylase] and we can now find factors not present in Type 2 or Type 1 diabetes."

Pietropaolo adds, "We’re still in the stage of understanding. There are no guidelines as yet because there simply aren’t enough numbers. We’re in the process of increasing the sample size, and we’re currently running 11,000 samples to substantiate our hypothesis."

Specifically, Pietropaolo found that some Type 2 diabetics manifest symptoms typical of Type 1 diabetes, for example, a younger age at diagnosis, lower body mass index and a relentless loss of beta cell mass.

The diagnosis of LADA involves collecting blood samples and testing them for recombinant human glutamic acid decarboxylase and recombinant IA-2, says Pietropaolo.

He recommends the use of medications to block autoimmunity and anti-inflammatory responses early to prevent complications. He also notes that low serum albumin and high levels of fibrinogen and C-reactive protein may all be markers of inflammation and underlying cardiovascular disease.

That makes Pietropaolo think it is "conceivable" that inflammation may be part of the autoimmune reaction that leads to the malfunction of pancreatic beta cells.

The perceptions of diabetes may continue to expand, as Brazilian scientists add some data to the theory of diabetes as an inflammatory disorder in a paper presented to the ADA.

Looking at more than 12,000 subjects participating in the Atherosclerosis Risk In Communities Study, Maria Ines Schmidt, MD, a researcher at the Federal University of Rio Grande do Sul in Porto Alegre, Brazil, and her colleagues found markers she says are predictive of Type 2 diabetes. They found specific markers of inflammation, particularly high white cell counts and fibrinogen levels and low levels of albumin.

Adjusting for risk factors such as family history or obesity, those in the 25th percentile of white cell counts were twice as likely to develop diabetes within seven years. Those with the lowest levels of albumin and the highest levels of fibrinogen were also at a higher risk for diabetes.

Schmidt also found above average levels of orosomucoid and sialic acid were predictive of developing diabetes within three years. She says the inflammation is the common element bridging cardiovascular disease and diabetes.

"Although these findings have no immediate clinical application, a lot more research on this issue needs to be done in order to find new clues as to how to prevent and manage diabetes," Schmidt said.

[For more information, contact Massimo Pietropaolo at (412) 692-6491.]