The purpose of this study was to evaluate the suitability of the glucose analogue 2-deoxyglucose (2-DG) for measurement of glucose transport activity in rat skeletal muscles in vitro when transport rates are high. The goal was to determine whether glucose phosphorylation rather than transport becomes limiting under experimental conditions normally employed in muscle incubation experiments. The rate of 2-DG uptake assayed in the presence of 8 mM 2-DG and a maximally effective concentration of insulin remained linear for > or = 60 min in the split soleus and 120 min in the epitrochlearis. Hexokinase activity assayed in skeletal muscle homogenates was not inhibited appreciably by 2-deoxyglucose 6-phosphate (2-DG-6-P) concentrations in the range of those achieved intracellularly during the linear phase of 2-DG uptake (i.e., 2-DG-6-P below approximately 30 mM). During this linear phase of 2-DG uptake, total intracellular 2-DG concentrations did not exceed 30 mM. The combined effects of contractions plus a maximally effective concentration of insulin on glucose transport activity measured at a near-saturating concentration of 2-DG were additive in the epitrochlearis and the soleus. Our results indicate that, under the conditions employed in our isolated muscle preparations, 2-DG uptake accurately reflects glucose transport activity and that 2-DG is the most appropriate glucose analogue for measurement of glucose transport activity when transport rates are high.

In this study we investigated the possibility that an increase in cytoplasmic Ca2+ concentration that is too low to cause muscle contraction can induce an increase in glucose transport activity in skeletal muscle. The compound N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), which induces Ca2+ release from the sarcoplasmic reticulum (SR), caused a dose-dependent increase in tension in rat epitrochlearis muscles at concentrations more than approximately 200 microM. Although 100 microM W-7 did not increase muscle tension, it accelerated loss of preloaded 45Ca2+. Glucose transport activity, measured with the nonmetabolizable glucose analogue 3-O-methylglucose, increased sixfold in muscles treated for 100 min with 50 microM W-7 (P less than 0.001) and eightfold in response to 100 microM W-7 (P less than 0.001). The increase in glucose transport activity was completely blocked with 25 microM cytochalasin B. There was no decrease in ATP or creatine phosphate concentrations ([approximately P]) in muscles incubated with 50 microM W-7. Dantrolene (25 microM), which blocks Ca2+ release from the SR, blocked the effects of W-7 both on 45Ca2+ release and on glucose transport activity. 9-Aminoacridine, another inhibitor of Ca2+ release from the SR, also blocked the stimulation of hexose transport by W-7. Caffeine, a compound structurally unrelated to W-7 that also releases Ca2+ from the SR, also increased glucose transport activity. Incubation of muscles with 3 mM caffeine for 30 min, which did not cause contraction or lower [approximately P], induced a threefold increase in 3-O-methylglucose transport (P less than 0.001). These results provide evidence suggesting that an increase in cytoplasmic Ca2+ too low to cause contraction or [approximately P] depletion can bring about an increase in glucose transport activity in skeletal muscle.

Both the anabolic hormone insulin and contractile activity stimulate the uptake of glucose into mammalian skeletal muscle. In this study, we examined the role of phosphatidylinositol 3-kinase (PI 3-kinase), a putative mediator of insulin actions, in the stimulation of hexose uptake in response to hormone and contraction. Phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-triphosphate accumulate in skeletal muscle exposed to insulin but not hypoxia, which mimics stimulation of the contractile-dependent pathway of hexose transport activation. The fungal metabolite wortmannin, an inhibitor of PI 3-kinase, completely blocks the appearance of 3'-phospholipids in response to insulin. Moreover, wortmannin entirely prevented the increase in hexose uptake in muscle exposed to insulin but was without effect on muscle stimulated by repetitive contraction or hypoxia. These results support the view that PI 3-kinase is involved in the signaling pathways mediating insulin-responsive glucose transport in skeletal muscle but is not required for stimulation by hypoxia or contraction. Furthermore, these data indicate that there exist at least two signaling pathways leading to activation of glucose transport in skeletal muscle with differential sensitivities to wortmannin.

Exercise, along with dietary intervention, represents first-line therapy for diabetes mellitus. Aerobic exercise is recommended for its beneficial effects on glucose control as well as its abilities to retard the progression of other comorbidities common in patients with diabetes, such as cardiovascular disease. The capability of aerobic exercise to improve glycemic control in diabetes is well documented, although adherence to exercise regimens is problematic. More recently, the glucose-lowering effects of resistance training have also been documented; this form of exercise has additional benefits, such as the capability to counteract sarcopenia, which is common in older people with type 2 diabetes. Exercise in people with diabetes, however, also can present significant challenges to glycemic control. Excessive glucose lowering can occur under certain conditions, enhancing the threat of hypoglycemia; in other situations, hyperglycemia can be accentuated. An understanding of the interactions between specific antidiabetic medications and various forms and intensities of exercise is essential to optimizing glycemic control while minimizing the potential for acute derangements in plasma glucose levels. Exogenous forms of insulin and agents that stimulate insulin secretion in a glucose-independent manner (such as sulfonylureas and glinides) increase the propensity for hypoglycemia during low- to moderate-intensity aerobic exercise. In contrast, exercise protocols characterized by high intensity are more likely to result in episodes of hyperglycemia. Strategies to minimize inappropriate swings in glycemic control are reviewed.

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