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 ( 18 F]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.

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

“…Williams et al showed that glucose transport increased in response to insulin in lean and obese patients but not significantly in type 2 diabetic subjects. A dose-responsive pattern of glucose phosphorylation stimulation was observed in all groups but was lower in obese and type 2 diabetic patients (22). Weight loss (23), exercise training (24,25), rosiglitazone (26), and troglitazone (27) have all been shown to improve skeletal muscular 18 F-FDG uptake.…”

Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance

“…Rather, the model indicates a lower cellular uptake and/or decreased phosphorylation rate of glucose, as indicated by the lower phosphorylation fraction in the fasted condition. As stated above, it should be noted that glucose transport into BAT reflects movement of [ 18 F]FDG to both intracellular and interstitial space [33] and that two-tissue compartment modelling does not completely discriminate between (GLUTmediated) glucose transport into brown adipocytes and/or subsequent phosphorylation by hexokinase. We are therefore not able to distinguish between brown adipocyte [ 18 F]FDG uptake or [ 18 F]FDG phosphorylation as the main determinant of decreased BAT [ 18 F]FDG uptake upon fasting.…”

The physiological regulation of glucose flux into musclein vivo

“…Insulin resistance can be associated with deficits in muscle blood flow (Clerk et al, 2007;Duplain et al, 2001;Inyard et al, 2009;Laakso et al, 1992), membrane glucose transport (Han et al, 1995;Liu et al, 1996;Zierath et al, 1997) and intracellular capacity to phosphorylate glucose (Bonadonna et al, 1996;Braithwaite et al, 1995;Pendergrass et al, 1998;Williams et al, 2001). We delineated the steps that cause the functional impairment in muscle glucose uptake by applying the countertransport method to rats fed a high-fat diet.…”