Glucose Transport and Phosphorylation in Skeletal Muscle in Obesity: Insight from a Muscle-Specific Positron Emission Tomography Model

Abstract

A controversial area in understanding the contribution of obesity to skeletal muscle insulin resistance is the distribution of control of glucose metabolism across proximal steps of glucose delivery, trans-membrane transport, and intracellular trapping via phosphorylation. Dynamic positron emission tomography (PET) imaging of skeletal muscle [(18)F]2-deoxy-2-D-glucose ((18)F-FDG) uptake provides an in vivo method for assessment of these steps in humans. In the current study we have examined the application of a four-compartment skeletal muscle-specific model for assessment of (18)F-FDG metabolism that takes interstitial (18)F-FDG kinetics into account and compared this to the classic three-compartment model in lean and obese volunteers. We assessed the effects of insulin infusions at three rates (0, 40, and 120 mU/m(2).min). In comparison with the classic model, the skeletal muscle-specific model reveals more clearly definable effects of insulin on transmembrane glucose transport and an impairment of this response in obesity. Compared with the classic model for assessment of (18)F-FDG metabolism, both the skeletal muscle-specific and the classic model indicate that, with respect to distribution of control, glucose phosphorylation has an important effect at low to moderate levels of insulin stimulation in both lean and obese subjects.

Impact of Intravenous Insulin on 18F-FDG PET in Diabetic Cancer Patients

“…The aims of this study were to evaluate the effectiveness of a standardized insulin protocol in reducing glycemia, review 18 F-FDG biodistribution with such a protocol, and assess its clinical impact. Methods: Sixty-three patients with glycemia greater than 10 mmol/L received insulin doses intravenously according to a standardized protocol.…”

“…One hundred six consecutive euglycemic patients (,6.2 mmol/L) served as controls. 18 F-FDG biodistribution was evaluated by 2 experienced PET readers on a 5-point visual scale based on muscular uptake. The 63 patients who received insulin were divided into insulin subgroup A, with adequate biodistribution (score 0, 1, or 2) and insulin subgroup B, with altered biodistribution (score 3 or 4).…”

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

“…In a follow-up publication (66), using similar methodology, the same group reported a normal rate constant for glucose transport in obese individuals but a decreased rate constant for glucose phosphorylation. In subsequent publications (67,68), the investigators used a muscle-specific compartmental model and demonstrated a reduction in the insulin-stimulated glucose transport parameter in obese nondiabetic subjects vs. obese T2DM subjects. Since a lean T2DM group was not studied (67,68), it is difficult to discern whether T2DM or obesity was responsible for the reported defects in glucose transport and glucose phosphorylation.…”

“…In subsequent publications (67,68), the investigators used a muscle-specific compartmental model and demonstrated a reduction in the insulin-stimulated glucose transport parameter in obese nondiabetic subjects vs. obese T2DM subjects. Since a lean T2DM group was not studied (67,68), it is difficult to discern whether T2DM or obesity was responsible for the reported defects in glucose transport and glucose phosphorylation. Moreover, there was a marked difference in the severity of insulin resistance in the obese nondiabetic groups in these two studies (67,68).…”

“…Since a lean T2DM group was not studied (67,68), it is difficult to discern whether T2DM or obesity was responsible for the reported defects in glucose transport and glucose phosphorylation. Moreover, there was a marked difference in the severity of insulin resistance in the obese nondiabetic groups in these two studies (67,68). This is of importance because most investigators have reported a similar magnitude of insulin resistance in obese nondiabetic and lean T2DM subjects (19,31).…”