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The Center for Metabolic Research’s top priorities are patient safety and study
integrity. Our certified staff have more than 20 years experience in performing
hyperglycemic clamps, hyperinsulinemic euglycemic clamps, OGTTs, FSIVGTTs,
and other infusion studies.

A number of procedures are employed on the CMR to study substrate metabolism
and hormone secretion. They are briefly described below, together with sample references.

Hyperinsulinemic/euglycemic clamp

Long considered the ‘gold standard’ for the evaluation of insulin action on whole body
glucose utilization. Insulin and glucose are infused at controlled rates for 3-5 hours while
glucose levels are kept constant. Primary endpoint is the Glucose Disposal Rate (GDR), a
measure of insulin-stimulated glucose utilization, primarily in muscle.  Multiple insulin
levels can be tested in the same procedure.

Metabolic and hormonal changes induced by pioglitazone in polycystic ovary syndrome:
a randomized, placebo-controlled clinical trial.

Aroda VR, Ciaraldi TP, Burke P, Mudaliar S, Clopton P, Phillips S, Chang RJ, Henry RR.
J Clin Endocrinol Metab. 2009 Feb;94(2):469-76.
PMID 18984667

Tracer-derived glucose turnover

Subjects are infused first for 4 hours with tracer amounts of 3H-glucose or 2H-glucose
to label the endogenous glucose pool. This infusion is continued together with insulin as
part of a hyperinsuinemic/euglycemic clamp or the hyperglycemic clamp. Measurement of
the glucose specific activity in plasma permits calculation of the rate of endogenous glucose production (EGP), both in the fasting state and during suppression by insulin. Results are comparable for the two isotopes.

Intravenous glargine and regular insulin have similar effects on endogenous glucose
output and peripheral activation/deactivation kinetic profiles.

Mudaliar S, Mohideen P, Deutsch R, Ciaraldi TP, Armstrong D, Kim B, Sha X, Henry RR.
Diabetes Care. 2002 Sep;25(9):1597-602
PMID 12086949

Hyperglycemic clamp/arginine stimulation test

The 2-step hyperglycemic clamp provides a means to measure endogenous insulin
secretion.  After collection of baseline (fasting) blood samples, a primed continuous
infusion of 20% Dextrose is begun to achieve and maintain square wave hyperglycemia
with plasma glucose = 280 mg/dL. Plasma glucose concentration is monitored using a
bedside glucose instrument, and the glucose infusion rate is adjusted to maintain plasma
glucose = 280 mg/dL. Samples are collected for glucose, insulin and C-peptide determinations
at multiple time points. After 180 minutes the infusion of glucose is increased to achieve and maintain plasma glucose = 450 mg/dL and sample collection continued. A modification of
this procedure is to inject a bolus of arginine after glucose levels are stable at 450 mg/dL.
Samples are collected frequently over the next 10 minutes. The arginine stimulation
permits assessment of the maximal rate of insulin secretion

Effects of weight loss and reduced hyperglycemia on the kinetics of insulin secretion in obese non-insulin dependent diabetes mellitus.
Gumbiner B, Polonsky KS, Beltz WF, Griver K, Wallace P, Brechtel G, Henry RR.
J Clin Endocrinol Metab. 1990 Jun;70(6):1594-602
PMID 2189885

Frequently sampled intravenous glucose tolerance test (FSIVGTT)

This procedure provides information about both insulin secretion and insulin action.
After collection of baseline samples, subjects are given an iv bolus of glucose and
samples collected frequently over 20 minutes. At that point they are given a bolus of insulin
and sample collection continued for up to a total of 3 hours. Glucose and insulin levels are measured and used to calculate several indices: Si – insulin sensitivity index, an aggregate measure of hepatic and peripheral insulin sensitivity to stimulate glucose disposal; Sg,
– glucose effectiveness, the ability of glucose to promote its own disposal, and DI –
disposition index, which represents a measure of ß-cell function.

Determinants of glucose tolerance in impaired glucose tolerance at baseline in the
Actos Now for Prevention of Diabetes (ACT NOW) study.

DeFronzo RA, Banerji MA, Bray GA, Buchanan TA, Clement S, Henry RR, Kitabchi AE,
Mudaliar S, Musi N, Ratner R, Reaven P, Schwenke DC, Stentz FD, Tripathy D; ACT NOW
Study Group.
Diabetologia. 2010 Mar;53(3):435-45.
PMID 20012012

Indirect Calorimetry

This procedure involves collection of expired gases and real time measurement of VO2
and VCO2.   Urine is collected by analysis of creatinine, urea and uric acid. From this data
it is possible to calculate rates of carbohydrate, fat and protein oxidation, as well as energy expenditure. This can be performed as a stand-alone procedure or together with any of the
other procedures described above.

Substrate oxidation errors during combined indirect calorimetry-hyperinsulinemic
glucose clamp studies.

Thorburn AW, Gumbiner B, Flynn T, Henry RR.
Metabolism. 1991 Apr;40(4):391-8
PMID 2011080