Increased activity of the glucose cycle in the liver: early characteristic of type 2 diabetes.

The aims were to assess in the mild, lean, type 2 diabetics the activity of the hepatic futile cycle (glucose cycling) in the basal state and during an infusion of glucose and the overall contribution of futile cycling and the relative contributions of the liver and the periphery to excessive hyperglycemia during a glucose challenge. To determine hepatic futile cycling, we studied seven healthy controls (C) and eight mild, lean, type 2 diabetics with decreased oral glucose tolerance test and blood glucose of 123 +/- 4 mg/dl. Experiments included an equilibration period, followed by a 2-hr infusion of glucose at 2 mg/kg of body weight per min. In each subject, two such experiments were performed randomly with infusions of [2-3H]glucose or [3-3H]glucose to calculate, respectively, total glucose output or total glucose phosphorylation and glucose production or irreversible glucose loss. Futile cycling equals the difference between glucose turnover measured by the two tracers. In controls basal glucose production was 2.0 +/- 0.09 mg/kg per min, and it decreased by 75% during glucose infusion; futile cycling could not be detected. Plasma glucose increased by 30% and plasma C-peptide by 88%. In the diabetics total glucose output (2.41 +/- 0.17 mg/kg per min) was larger than glucose production (2.12 +/- 0.16 mg/kg per min), indicating a glucose cycle. During the glucose infusion, glucose production in the diabetics as well as in the controls decreased by 75% (to 0.6 mg/kg per min) despite higher than normal plasma glucose and C-peptide; futile cycling amounted to 0.6 mg/kg per min, which is half of the total glucose output; increase of glucose uptake was essentially only due to phosphorylation of glucose because irreversible uptake increased only marginally; and most glucose taken up by the liver during the glucose challenge reenters the blood stream without being oxidized or polymerized. These findings, when compared to our previous work in which controls were infused with glucose at 4 mg/kg per min, indicate that excessive hyperglycemia in the diabetics during glucose infusion is due to a decrease in irreversible glucose uptake (impaired phosphorylation and futile cycling) and to a decrease in suppression of glucose production. The relative contributions of the liver and periphery to hyperglycemia seem to be almost equivalent. The mechanism behind the increased glucose cycle activity is not clear; it may be due to a relative decrease of glycogen synthase or increase in glucose-6-phosphatase or both.