Thyroid hormone increases basal and insulin-stimulated glucose transport in skeletal muscle. The role of GLUT4 glucose transporter expression.

In skeletal muscle, the main site of insulin-mediated glucose disposal, the major muscle glucose transporter GLUT4 is induced by thyroid hormone. To test the hypothesis that thyroid hormone alters muscle glucose transport, we examined the effect of L-triiodothyronine (T3) on glucose transport and GLUT4 protein content in isolated rat skeletal muscles. Euthyroid rats were treated with or without T3 for 3 days, and [3H]2-deoxy-D-glucose (2-DG) uptake in soleus and extensor digitorum longus (EDL) muscles was measured under conditions in which transport was rate limiting for uptake in the absence or presence of 10 nmol/l insulin. In control animals, insulin stimulated 2-DG uptake sevenfold in soleus and fivefold in EDL. T3 treatment increased basal 2-DG uptake in soleus and EDL by 115 +/- 29% and 136 +/- 23%, respectively, and increased insulin-stimulated 2-DG uptake in soleus and EDL by 55 +/- 9 and 42 +/- 12%, respectively. Immunoblot analysis revealed that T3 treatment increased GLUT4 protein content in soleus by 43 +/- 6% and in EDL by 56 +/- 13%. These data demonstrate that thyroid hormone increases basal and insulin-stimulated glucose transport in skeletal muscle. The percentage increase in insulin-stimulated transport in T3-treated muscles is similar to the increase in GLUT4 protein content, whereas the percentage change in basal transport greatly exceeds the change in GLUT4. Thus, increased insulin-stimulated glucose transport in T3-treated muscle can be accounted for by the induction of GLUT4 protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of GLUT2 glucose transporter expression in liver by thyroid hormone: evidence for hormonal regulation of the hepatic glucose transport system.

The extent to which the glucose transport system in hepatocytes is regulated in states of altered hepatic glucose metabolism is unclear. Because thyroid hormone is known to increase hepatic glucose output, we hypothesized that thyroid hormone might up-regulate expression of the principal hepatic glucose transporter, GLUT2, facilitating increased glucose efflux across the hepatocyte plasma membrane. GLUT2 protein concentration in crude liver membranes was twice as high in chronically hyperthyroid vs. hypothyroid animals, with intermediate levels in euthyroid controls. Similar results were obtained for total GLUT2 protein, measured in detergent extracts of liver. Northern analysis of total liver RNA demonstrated parallel changes in GLUT2 messenger RNA (mRNA) concentration per g tissue (hypothyroid, 76 +/- 6%; euthyroid, 100 +/- 11%; hyperthyroid, 158 +/- 12%; data expressed as percentage of mean euthyroid values). The daily administration of a large dose of T3 (100 micrograms/100 g BW) to hypothyroid rats caused a prompt increase in hepatic GLUT2 mRNA concentration (2.5-fold at 1 day), but only a modest and gradual change in hepatic GLUT2 protein concentration (+40% at 4 days), suggesting that the GLUT2 protein in liver may have a long half-life. We conclude that thyroid hormone regulates hepatic GLUT2 mRNA and protein expression. Up-regulation of GLUT2 protein expression by thyroid hormone may serve to facilitate increased hepatic glucose output. These results suggest that the hepatic GLUT2 glucose transporter, like the enzymes of gluconeogenesis and glycolysis, is indeed a regulatory target for hormones that control hepatic glucose metabolism.

Effects of thiazolidinediones on glucocorticoid-induced insulin resistance and GLUT4 glucose transporter expression in rat skeletal muscle.

Thiazolidine-2,4-diones, a new class of oral antihyperglycemic agents, have been shown to be effective in improving insulin sensitivity in a number of animal models of insulin resistance, and recent investigation has suggested that the mechanism of action of these agents may include upregulation of the GLUT4 (insulin-regulatable) glucose transporter. We studied the efficacy of two of these agents, pioglitazone and englitazone, in preventing glucocorticoid-induced insulin resistance in rats, and examined the potential role of changes in GLUT4 expression in their action in skeletal muscle. Rats were treated with 0.1 mg/d dexamethasone for 6 to 7 days with or without either pioglitazone (10 mg/kg/d) or englitazone (50 mg/kg/d). Both thiazolidinediones decreased the elevated fasting serum glucose and insulin levels in dexamethasone-treated animals. Dexamethasone treatment alone decreased insulin-stimulated 2-deoxyglucose uptake into isolated soleus muscles to 35% of control values. The addition of pioglitazone or englitazone increased insulin-stimulated 2-deoxyglucose uptake by 74% and 57%, respectively. Whereas dexamethasone treatment alone increased GLUT4 protein content in rat soleus muscle by 25%, additional treatment with pioglitazone or englitazone did not further significantly alter GLUT4 levels. We conclude that thiazolidinediones enhance insulin responsiveness in skeletal muscle during glucocorticoid treatment, but their mode of action in this setting is not via upregulation of GLUT4 expression.

Tissue distribution of the human GLUT3 glucose transporter.

The tissue distribution of the GLUT3 glucose transporter protein was examined in human tissues using a rabbit antiserum directed against the C-terminal peptide sequence of human GLUT3. This anti-serum was shown to recognize the human GLUT3 protein in Chinese hamster ovary cells transfected with GLUT3 cDNA and to immunoprecipitate an authentic glucose transport protein in brain and testis membranes, as assessed by glucose-inhibitable photolabeling with [3H] cytochalasin-B. The GLUT3 protein, migrating with an apparent mol wt of approximately 48 kilodaltons, was strongly expressed in brain and testis membranes as well as in spermatozoa. It was not detectable in membranes from erythrocytes, adipocytes, heart, skeletal muscle, liver, kidney, spleen, thyroid, and prostate. Very low levels may be present in placenta. In brain, GLUT3 protein was strongly expressed in grey matter regions and was only weakly expressed in white matter, suggesting that it may be important in providing glucose to regions of high metabolic activity, i.e. to areas associated with synaptic transmission. None was found in peripheral (femoral) nerve. It appeared to be stable for up to 47 h in autopsy brain tissue kept at 4 C. The tissue distribution of human GLUT3 protein thus appears to be highly restricted (brain and testis/spermatozoa), in contrast with a previous report. Its function may be to provide a high affinity glucose transport system in cells that are highly dependent on glucose as a fuel source.