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The Plasma C5 Glucose/²H₂O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis during Hyperinsulinemic Euglycemic Clamps in either Non-Diabetic or Diabetic Humans

¹Division of Endocrinology, Diabetes, Metabolism & Nutrition, Mayo Clinic College of Medicine, Rochester, MN
²Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, OH

Objective: Measurement of plasma C2 glucose enrichment is cumbersome. Therefore the plasma C5 glucose/²H₂O rather than the plasma C5/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 & Methods: 10 non-diabetic and 10 diabetic subjects ingested ²H₂O the evening before study. The following morning insulin was infused at a rate of 0.6 mU/kg/min and glucose was clamped at 5.3 mmol/l for five hours. Plasma C5 glucose, C2 glucose and ²H₂O enrichments were measured hourly from two hours onward.

Results: Plasma C2 glucose and plasma ²H₂O 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 ²H₂O enrichment remained unchanged. Since the C5 glucose concentration and hence the C5glucose/²H₂O ratio is influenced by both gluconeogenesis and glucose clearance whereas the C5/C2 glucose ratio only is influenced by gluconeogenesis, the C5glucose/²H₂O 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 non-diabetic and diabetic subjects.

Conclusions: The plasma C5 glucose/²H₂O ratio does not provide an accurate assessment of gluconeogenesis in non-diabetic or diabetic subjects during a traditional (i.e. 2-3 hour) hyperinsulinemic euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated.

Key Words: glucose production • glycogenolysis • insulin action • deuterated water method

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