Revealing the dangers of glycemic variability through a three-tiered approach
There is little debate about the dangers of high glucose concentrations. It is commonly believed to be the cause of damage in the bodies of children with type 1 diabetes. Children’s Mercy is investigating another aspect of glycemic control that may be just as dangerous.
|Mark Clements, MD, Phd, CP
Mark Clements, MD, PhD, CPI, Pediatric Endocrinology, and Assistant Professor Pediatrics at University of Missouri-Kansas City School of Medicine, believes glycemic variability may be just as dangerous as sustained high glucose values. He is leading a three-tiered research project at Children’s Mercy to determine the potential dangers of glycemic variability and the best approaches for treating it.
"I believe glycemic variability is a significant problem that relates not only to acute complications, like the risk for low blood sugar, but also to the risk for chronic complications like the eye, kidney and peripheral nerve disease that patients with diabetes can get," said Dr. Clements. "There is an abundance of literature on the impact of glucose fluctuations on cells in a dish. There is also evidence from observational studies that fluctuating blood sugars in humans is associated with an increase in stress markers that indicate free radical damage to cells."
Three Approaches to Understanding Glycemic Variability
Tier 1. Build and execute an animal model to confirm the link between glucose variability and complications
Tier 2. Evaluate children to measure the influence of glycemic variability and genetic differences in the response to glycemic variability on vascular health
Tier 3. Leverage “Big Data” to study the influence of glycemic variability on the rate of progression to complications
Tier 1. Confirming Variability in the Animal Model
The Tier 1 animal model at Children’s Mercy is bringing together several technologies not used in concert before.
They include use of a continuous glucose monitor to keep track of animals’ blood glucose in a very refined way. An insulin dosing paradigm is followed to control the average blood sugar. We developed new tools to deliver insulin and glucose intermittently and create rapid oscillations of blood glucose. And the testing is all being done in free-roaming animals so they can be followed over a period of months instead of weeks.
Early results show that glycemic variability in an animal model over the course of a month is associated with more oxidative stress or free radical buildup in both the animals’ blood and hearts. The next step is to extend the testing over longer and longer periods to monitor the animals for chronic complications.
Tier 2. Examining the Link to Chronic Conditions
Tier 2 of the research at Children’s Mercy involves examining pediatric patients with type 1 diabetes.
A number of earlier biomarker studies in adults have shown an association between glycemic variability and chronic conditions. The Children’s Mercy study is among the first to examine a possible association in children. Dr. Clements is also examining if genetic differences among patients places them at higher risk for developing oxygen-free radicals. The patient evaluation studies are in preliminary stages.
Tier 3. Studying Health Outcomes Data to Understand Glycemic Variability
The third tier of the study is drawing on the unequaled warehouse of electronic health records at Children’s Mercy. Reaching back to 1987, researchers are identifying all patients with type 1 diabetes who have received care at Children’s Mercy and are creating a health outcomes database that includes information about care provided and patients’ blood glucose control. With the data, researchers are able to follow patients over time and look for any ties between variability in blood glucose concentrations and the development of early complications of diabetes such as nephropathy and hypertension.
Researchers are following two methods to clinically define glycemic variability.
The first measures the hemoglobin A1C biomarker to measure average blood sugar over the previous three months. The biomarker is routinely monitored during clinical care, and measuring the variability in hemoglobin A1C over time offers researchers a long-term look at glucose variability.
The second method of clinically defining glycemic variability involves downloading and warehousing the tracking data from patients’ glucose meters and insulin pumps. Children’s Mercy began gathering de-identified data five years ago, and the information allows researchers to measure day-to-day glycemic variability.
"We have some very exciting early findings that indicate chronic glycemic variability is associated with increased progression to early kidney disease in children," Dr. Clements said. "While our findings are still preliminary, if we can settle the question of whether glycemic variability is associated with an increased risk of chronic complications, we can better equip our patients with the most efficacious and cost-effective tools to care for their diabetes. Some patients may have low glycemic variability and won’t need any special interventions. But those patients with high glycemic variability may really benefit from newer therapies."