Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance

Abstract

It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport and phosphorylation has also been proposed. The current study examined whether the respective contributions of transport and phosphorylation to insulin resistance are modulated across a dose range of insulin stimulation. Rate constants for transport and phosphorylation in skeletal muscle were estimated using dynamic positron emission tomography (PET) imaging of 2-deoxy-2[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) during insulin infusions at three rates (0, 40, and 120 mU/m² per min) in lean glucose-tolerant, obese glucose-tolerant, and obese type 2 diabetic subjects. Parallel studies of arteriovenous fractional extraction across the leg of [¹⁸F]FDG and [2-³H] glucose were performed to measure the “lumped constant” (LC) (i.e., the analog effect) for [¹⁸F]FDG to determine whether this value is affected by insulin dose or insulin resistance. The value of the LC was similar across insulin doses and groups. Leg glucose uptake (LGU) also provided a measure of skeletal muscle glucose metabolism independent of PET. [¹⁸F]FDG uptake determined by PET imaging strongly correlated with LGU across groups and across insulin doses (r = 0.81, P < 0.001). Likewise, LGU correlated with PET parameters of glucose transport (r = 0.67, P < 0.001) and glucose phosphorylation (r = 0.86, P < 0.001). Glucose transport increased in response to insulin in the lean and obese groups (P < 0.05), but did not increase significantly in the type 2 diabetic group. A dose-responsive pattern of stimulation of glucose phosphorylation was observed in all groups of subjects (P < 0.05); however, glucose phosphorylation was lower in both the obese and type 2 diabetic groups compared with the lean group at the moderate insulin dose (P < 0.05). These findings indicate an important interaction between transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.