High Point Clinical Trials Center is a recognized Center of Excellence for Metabolic research offering industry leading Patient recruitment via innovative outreach initiatives, an active database of 6000+ Patients with Diabetes and extensive experience executing complex clinical pharmacology studies.
We have invested significantly in medical, scientific and technical resources to meet the ever-evolving needs of our Sponsors. Clayton Dehn, our Vice President of Clinical Pharmacology Services, has a vast background in metabolic disorders and in-depth knowledge in the planning and conduct of glucose clamp studies. Below, he lays out the rationale behind glucose clamps, the different methodologies and how these studies relate to diabetes medications.
A brief introduction to glucose clamps:
If you have worked in the Metabolic disorders space or for a biopharmaceutical company focusing on the development of treatments for Diabetes, obesity or Fatty liver, there is a high probability that you’ve encountered the term “glucose clamps”. What is a clamp and what is its purpose? What do these studies represent? What types of clamps are commonly used and what is the objective of each one? What do the results indicate and how are they used? What are the complexities and risks associated with these studies and how is participant safety assured?
What are glucose clamps?
At their core, glucose clamps are infusion-based tests that in some way interrupt the insulin-glucose feedback loop. These procedures offer no therapeutic value. Although they could arguably offer some diagnostic insight, that utility is restricted by the esoteric complexity of the tests limiting their practical implementation into clinical practice. Glucose clamps are, however, incredibly valuable research methodologies that are exquisitely reproducible within an individual when testing occurs under similar and tightly-controlled conditions. This means that baseline testing compared to post-interventional testing offers strong confidence that any differences observed can be associated with the intervention and that changes from baseline can be detected in smaller study populations.
What are the different types of glucose clamps and how do they work?
There are many types of clamp procedures, and they can tell us different things.
Quantification of Insulin Sensitivity:
The classic glucose clamp is the hyperinsulinemic-euglycemic clamp, which is the gold-standard measure of insulin sensitivity. In this test, insulin is infused to artificially increase the circulating concentration to physiologically relevant levels, usually replicating peak post-prandial insulinization. The normal physiological response to this hyperinuslinization is the suppression of both endogenous insulin and glucose production as well as peripheral glucose uptake. The net effect should be a decline in blood glucose, but this is prevented with intense glucose monitoring and adjustment of a variable counter-infusion of glucose. The glucose infusion rates required to maintain the target blood glucose represents the subject’s sensitivity to insulin, whereby those requiring a higher glucose infusion are more sensitive to insulin than those who require less.
It is important to note that although the hyperinsulinemic-euglycemic clamp can be performed in insulin-resistant populations to demonstrate a therapeutic response to an insulin-sensitizing agent, it does require additional consideration. Insulin resistance also affects the liver and endogenous glucose production is dysregulated in this population. The exogenous insulin infusion may be inadequate to achieve full suppression of endogenous glucose production. Enriching the glucose infusion with a stable isotope of glucose may be necessary to quantify any residually unsuppressed hepatic glucose production that may be contributing to the glycemic control during the clamp procedure.
Quantification of beta cell response:
Many antidiabetic medications under investigation and on the market are insulin secretagogues. The therapeutic approach of overwhelming insulin resistance by stimulating endogenous insulin release has evolved in sophistication from agents associated with a high risk of hypoglycemia such as sulfonylureas to those that avoid hypoglycemia by depending upon hyperglycemia to co-stimulate insulin release. These features and ability to stimulate the beta cells to increase insulin release are easily characterized with a type of glucose clamp called a hyperglycemic glucose clamp. In this type of clamp, glucose is infused to achieve an elevated target blood glucose. Insulin, glucose infusion rates, and glycemia can be evaluated as estimates of post-therapeutic response. As an alternative to hyperglycemic glucose clamps, graded glucose infusions, which are clamp-like procedures in which glucose is infused at progressively increasing but fixed rates for set periods of time, can be used to characterize beta cell response.
Time-action profile clamps are used to describe the activity of insulin products. In these clamps, the investigational insulin product is administered as it is intended to be used therapeutically, a subcutaneous injection for example. Dextrose is infused to counter the glucose-lowering effects of the insulin product. From the changing rate of glucose infusion required to maintain the glycemic target the onset, peak, duration, and offset of the insulin product can be determined.
Do glucose clamping and diabetes medications work together?
Glucose clamps are an important test for developing some antidiabetic medications, not every diabetes medication needs to be tested with glucose clamps. For example, glucose clamp testing glucose-independent insulin secretagogues, such as the sulfonylureas, would not be very informative as these agents do not act in pathways that can be elucidated by the glucose clamp.
New medications to treat diabetes must go beyond improving glycemic control. Innovation in antidiabetic drug development is stifled by how crowded the market is with effective approved medications, and by the cost associated with the relatively recent (2008) requirement for thorough cardiovascular risk assessment. For drug developers looking to address the unmet need for antidiabetic medications with acceptable safety profiles that improve insulin sensitivity, glucose clamps are all but prerequisite.