Plasma C5 Glucose–to– 2 H 2 O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic
or Diabetic Humans
Rita Basu 1 ,
Visvanathan Chandramouli 2 ,
Betty Dicke 1 ,
Bernard R. Landau 2 † and
Robert A. Rizza 1
1 Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota
2 Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, Ohio
Corresponding author: Robert A. Rizza, rizza.robert{at}mayo.edu
Abstract
OBJECTIVE— Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose–to– 2 H 2 O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during
hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown.
RESEARCH DESIGN AND METHODS— Ten nondiabetic and 10 diabetic subjects ingested 2 H 2 O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU · kg −1 · min −1 and glucose was clamped at ∼5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and 2 H 2 O enrichments were measured hourly from 2 h onward.
RESULTS— Plasma C2 glucose and plasma 2 H 2 O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis.
In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma 2 H 2 O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose–to– 2 H 2 O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced
by gluconeogenesis, the C5 glucose–to– 2 H 2 O ratio overestimated ( P < 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis
exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.
CONCLUSIONS— Plasma C5 glucose–to– 2 H 2 O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional
(i.e., 2–3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 April 2008.
†
† Deceased.
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Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

10.2337/db08-0195