Glucose Clamping in Humans: Establishing Early Proof-of-Concept in the Development of Diabetes Interventions

This webinar will discuss glucose clamping as a method for quantifying insulin resistance and secretion, outlining methods used, including algorithm controlled clamping, and all its inherent benefits.

The glucose clamp technique has long been utilized to maintain blood glucose levels by the intravenous infusion of glucose at a variable rate in response to frequent blood glucose measurements. The glucose clamp is a highly reproducible and reliable method of assessing pancreatic ß-cell sensitivity to glucose and tissue sensitivity to insulin. The clamp also benefits from limiting the incidence of hypoglycemic episodes due to the high frequency of blood glucose samples taken during the procedure. Since its introduction, the use of the glucose clamp technique has been widespread and is considered the gold standard technique for assessing ß-cell function and in vivo insulin sensitivity.

What is a Glucose Clamp?

The glucose clamp technique is a method for quantifying insulin secretion and resistance. It is used to measure either how well an individual metabolizes glucose or how sensitive an individual is to insulin. Two types of clamps are quite commonly used. The hyperglycemic clamp, which requires maintaining a steady state hyperglycemia by infusion of 20 % dextrose solution, is a method to quantify beta-cells response to glucose (i.e., insulin release). The hyperinsulinemic-euglycemic clamp, is a method to quantify peripheral and hepatic tissue sensitivity to insulin.

Glucose clamping is beneficial as the blood glucose concentration is maintained stable at the desired level by use of an intravenous infusion of glucose (usually a 20% solution). By keeping the glucose concentration constant the normal glucose-insulin feedback mechanism is overridden and the plasma glucose concentration is placed under the control of the investigator. The glucose infusion rate (GIR) at any given time is equal to the net disappearance of glucose from the blood, in effect the ‘drug action’. The clamp technique provides the direct pharmacodynamic (PD) effect of the ‘drug’ to be assessed using the GIR-time profile. The blood glucose concentration is maintained at the desired level by frequently taken blood samples. During clamps, which can run up to 48 hours in duration, samples are usually taken every 5-15 minutes.

The hallmark of the glucose clamp is that it’s remarkably reproducible, giving greater confidence that observed treatment effects can be attributed to the therapeutic intervention. What’s more, this sophisticated technique can detect treatment effects even in studies with relatively few subjects compared to typical early phase studies, allowing accelerated development through early signals of efficacy.

Common Types of Glucose Clamps:

• Hyperinsulinemic-euglycemic Clamp, where hyperinsulinemia is achieved by intravenous infusion (or subcutaneous administration) of insulin in order to stimulate peripheral glucose uptake and suppress hepatic glucose production while maintaining target euglycemia with a variable infusion of 20 % dextrose
• Hyperglycemic Clamp, where glucose concentrations are raised and maintained at an elevated concentration
• Hypoglycemic Clamp, where glucose concentrations are reduced in a controlled environment

Computer Algorithm Controlled Glucose Clamping

At ICON plasma glucose levels, during either the hyperglycemic or hyperinsulinemic –euglycemic clamps, are maintained stable with the use of a computer derived algorithm which employs the equations published by DeFronzo, Tobin, and Andres. The priming dose of both IV insulin, during the hyperinsulinemic clamp, or 20% glucose, during the hyperglycemic clamp, have been modified in order to eliminate the overshoot observed during the first 10-15 minutes; i.e., a true square wave of insulin of glucose is created. The glucose or insulin is infused with syringe loaded, screw driven pumps which increase the accuracy of the infusion rates delivered. Plasma glucose is measures with a FDA hospital and ICU approved glucometer, Stat Strip. We have verified the superiority of this instrument compared to the YSI or the Beckman II glucose analyzer and have published the results in a peer reviewed journal. Stat Strip glucometer uses only six µL of blood and provides plasma glucose concentration in 6 seconds with elimination of hematocrit effect and electrochemical interferences. Additional advantage is that the phlebotomist can measure plasma glucose and there is no need for a technician to run the glucose analyzer.

Glucose Clamping at ICON plc

The clinical research glucose clamp laboratory at ICON in San Antonio is directed by Dariush Elahi, who has been investigating glucose homeostasis using the clamp methodology for over 35 years. The methodology was learned from his mentor, Reubin Andres, who invented the technique at NIH.

He was a fellow with Dr. Andres and subsequently became a member of the laboratory at NIH for over 10 years. He has been a faculty member at several universities including Harvard Medical School, Johns Hopkins medical school, and the University of Pennsylvania’s Perlman school of medicine. He has conducted more than 2000 clamps during the past 35 years.

Speakers

Dariush Elahi, PhD, Director of Metabolic Research, Early Phase Services, ICON plc

Dariush Elahi, PhD, Director of Metabolic Research, Early Phase Services, ICON plc – Dr. Elahi Leads ICON’s early phase glucose clamping programs globally, and provides expert, scientific consultation to sponsors who are developing therapeutic agents to treat endocrine/ metabolic disease. Clinical physiologist with over 30 years of research experience, predominantly focused on translational investigations in humans in the area of regulation of glucose homeostasis in states of glucose tolerance and intolerance; including the study of volunteers with “normal “glucose tolerance, obesity, type II diabetes mellitus, and aged volunteers with academic appointments as a professor at The Johns Hopkins University School of Medicine. Expert with respect to the methodologies used to conduct these types of investigations, including the clamp technique (Hyperinsulinemic / Euglycemic, Time-Action Profile, Hyperglycemic, Hypoglycemic, Pancreatic), the MinMod technique, as well as measurements of hormones (IRA and ELISA); and kinetics analyses of fuel substrates using both stable and radioactive tracers and the employment of these techniques during clamp studies. Dr. Elahi has authored 147 scientific publications and is nationally and internationally recognised for his work on the role of insulin. He also served as Research Physiologist and Senior Staff Fellow at the National Institutes of Health (NIH) and National Institutes on Aging.

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Dennis Ruff, MD, Vice President, Medical Director, Early Phase Services, ICON plc

Dr. Dennis Ruff, Vice President and Medical Director, received his Doctor of Medicine in 1982 from Albany Medical College Union University, Albany, NY. After receiving his board certification in internal medicine he opened his practice in internal medicine in 1985. He joined Healthcare Discoveries (formerly South Texas Clinical Trials, now ICON Development Solutions) in 1988 as an Investigator, and in 1994 he became Medical Director and President. He has been involved in early phase clinical research since 2000. Dr. Ruff has served as a Clinical Professor in the Dept. of Medicine at UTHSC San Antonio, TX, from 1989 to 2004. Dr. Ruff has acted as Principal Investigator or Sub-Investigator for over 450 studies. A seasoned investigator and an expert manager, Dr. Ruff ensures swift and safe clinical operations. Dr. Ruff has over 24 years of experience in research

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