Effects of fasting on plasma glucose and prolonged tracer measurement of hepatic glucose output in NIDDM

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Abstract
We studied the measurement of hepatic glucose output (HGO) with prolonged [3-3H]glucose infusion in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM).Over the course of 10.5 h, plasma glucose concentration fell with fasting by one-third, from 234 ± 21 to 152 ± 12 mg/dl, and HGO fell from 2.35 ± 0.18 to 1.36 ± 0.07 mg · kg−1 · min−1 ( P < .001). In the basal state, HGO and glucose were significantly correlated ( r = 0.68, P = .03), and in individual patients, HGO and glucose were closely correlated as both fell with fasting (mean r = 0.79, P < .01). Plasma [3-3H]glucose radioactivity approached a steady state only 5-6 h after initiation of the primed continuous infusion, and a 20% overestimate of HGO was demonstrated by not allowing sufficient time for tracer labeling of the glucose pool. Assumption of steadystate instead of non-steady-state kinetics in using Steele's equations to calculate glucose turnover resulted in a 9-24% overestimate of HGO. Stimulation of glycogenolysis by glucagon injection demonstrated no incorporation of [3-3H]glucose in hepatic glycogen during the prolonged tracer infusion. In a separate study, plasma glucose was maintained at fasting levels (207 ± 17 mg/dl) for 8 h with the glucose-clamp technique. Total glucose turnover rates remained constant during this prolonged tracer infusion. However, HGO fell to 30% of the basal value simply by maintaining fasting hyperglycemia in the presence of basal insulin levels. Inconclusion, elevated HGO is a major determinant of fasting hyperglycemia in NIDDM, and the close relationship of plasma glucose and HGO is maintained as both fall during a day-long fast. Insufficient time for tracer equilibration, and assumption of steady-state kinetics may result in significant overestimates of HGO. HGO is suppressed by 70% when the fall in glucose level is prevented by performing a glucose clamp at the fasting glucose level. This effect should be considered in studies with the isoglycemic clamp technique to study effects of interventions on HGO of NIDDM.