April 12, 2007

In this Issue...

Understanding the Pathology Before Pre-Diabetes
By Julie McDowell


Six million Americans have diabetes and don’t know it, while another 54 million Americans have pre-diabetes, according to recent data from the American Diabetes Association (ADA). These statistics underscore the need for better detection of this disease—especially in the early stages when diet, exercise, and other interventions might prevent the onset of type 2 diabetes. But the pathogenic mechanisms that characterize the pre-diabetes stage are complex. A recent study presented at this weeks’s American Association of Clinical Endocrinologists Sixteenth Annual Meeting and Clinical Congress in Seattle, Wash., uncovered some new findings on the pathogenic signs of pre-diabetes. This issue of Strategies examines this research and what it means for the clinical evaluation of patients at risk for developing diabetes.

Patients with impaired fasting plasma glucose (IFG) and/or impaired glucose tolerance (IGT) are considered to have pre-diabetes, according to the ADA. One of the principal determinants of fasting plasma glucose in type 2 diabetes patients is hepatic glucose production, which occurs in the liver. In patients with IFG, it’s expected than a rise in hepatic glucose production will be accompanied by a rise in fasting glucose. However, researchers at the University of Texas Health Sciences Center (UTHSC) at San Antonio have demonstrated that, in the non-diabetic range among patients at high risk for developing pre-diabetes, the rise in FPG concentration is associated with a mild decrease in HGP. In addition, the glucose clearance rate, which is the glucose disposal rate divided by the FPG, decreased during the fasting state and was closely associated with the increase in plasma glucose concentration. The researchers concluded that this impaired glucose uptake was instead performed by the skeletal muscle, rather than the liver. “These results indicate that, during the fasting state, a decrease in insulin-independent tissue glucose clearance is responsible for the increase in FPG concentration,” said Rucha Jani, MD, one of the researchers, who presented these findings at this week’s AACE meeting. “The resulting increase in FPG stimulates basal insulin secretion, and the rise in fasting plasma insulin concentration in turn inhibits HGP, ameliorating the rise in FPG.”

Moving forward, Jani and her research team, which is lead by Ralph A. DeFronzo, MD, Chief of the Diabetes Division at UTHSC, hope that this observation—that the increase in fasting plasma glucose concentration within the non-diabetic range is related to the decrease in glucose clearance—helps inform research on the progression of pre-diabetes to type 2 diabetes. This is the “missing link” between these two disease states that needs to be pinpointed, according to Jani. “Identifying this link is important because it allows us to identify potential future targets, and to develop effective therapies to hopefully prevent the progression to type 2 diabetes,” she added.

Insulin Sensitivity

Jani’s findings are important in understanding insulin resistance and how it is manifest in decreased glucose clearance, said Richard Hellman, MD, Clinical Professor, University of Missouri School of Medicine in Kansas City, and current AACE President.

“The important message from these findings is that by the time a clinician sees either a rise in fasting plasma glucose or early changes in glucose tolerance, a lot has occurred beforehand,” he explained.

Research conducted about a decade ago established that insulin resistance can significantly increase before there is clinical evidence of changes in compensatory hyperinsulinism and glucose levels. These findings emphasize that there are some insulin resistant patients who have more of a hepatic problem, while others have more of a skeletal muscle problem. “The people with the skeletal muscle problem will show more of a problem in the glucose tolerance test after the glucose is given because in this type of test, the uptake is largely determined by the activity of the skeletal muscle,” said Hellman.

For the clinical laboratory community, it’s important to understand that research—including this recent study—has shown that in the fasting state, the glucose level is determined by the degree of hepatic sensitivity of the insulin. “In other words, the more sensitive you are to insulin, the more you shut off hepatic production of glucose, and the less sensitive you are, the more unable you are to shut it off,” added Hellman.

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