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At least 1,135 records · Page 63Linked to original sources
PubMed2000

Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse.

AIMS/HYPOTHESIS: The Nagoya-Shibata-Yasuda (NSY) mouse closely mimics human Type II (non-insulin-dependent) diabetes mellitus in that the onset is age-dependent, the animals are not severely obese, and both insulin resistance and impaired insulin response to glucose contribute to disease development. The aim of this study was to clarify the influence of age on the pathogenesis of diabetes and to analyse a candidate gene for Type II diabetes in this strain. METHODS: Several phenotypic characteristics related to diabetes mellitus were monitored longitudinally in male NSY and control C3H/He mice. The nucleotide sequence of Glut4, a candidate gene for Nidd1nsy (a susceptibility gene for Type II diabetes) on Chromosome 11, encoding insulin-sensitive glucose transporter, was determined in NSY and C3H mice. RESULTS: Glucose intolerance worsened with age, and fasting blood glucose and fasting plasma insulin concentration increased with age in NSY mice. Pancreatic insulin content increased until 24 weeks of age but then decreased at 48 weeks of age in NSY mice. The hypoglycaemic response to insulin was statistically significantly smaller in NSY than in C3H/He mice. The nucleotide sequence of GLUT4 cDNA was identical in NSY and C3H/He mice, but both were different from the sequence reported previously. CONCLUSION/INTERPRETATION: Insulin secretion and insulin resistance, as well as ageing possibly play an important part in the disease development in NSY mice. A decline of pancreatic insulin content in older age might cause the relative insulin deficiency in this strain. Nucleotide sequencing suggests that Glut4 is unlikely to be a candidate gene for Nidd1nsy.

3T3 Cells↗
PubMed2001

Hyperosmotic shock induces both activation and translocation of glucose transporters in mammalian cells.

The effect of osmotic stress on sugar transport was investigated in Clone 9 epithelial cells, which express the glucose uniporter GLUT1, and in 3T3-L1 adipocytes, which express both GLUT1 and GLUT4. An acute hyperosmotic shock increased the uptake of sugars in both cell types. In Clone 9 cells, this was followed by a regulatory volume increase (RVI) response. Stimulation of transport was rapid and reversible, with half-lives (t 1/2) for stimulation of 2-deoxy-D-glucose uptake of 5.6 +/- 0.9 (n=6) and 22.7 +/- 1.5 (n=4) min for Clone 9 cells and adipocytes respectively. The effect was dose dependent, reaching a maximum at 1.1 osM of 2.9 +/- 0.1-fold (n=3) for Clone 9 cells and 8.2 +/- 0.8-fold (n=3) for adipocytes. In the latter, this stimulation correlated with translocation of the glucose transporter isoform GLUT4 to the cell surface and was not significantly different from that elicited by 160 nM insulin (7.6 +/- 1.2-fold, n=3). The effect of osmotic shock was not, however, influenced by inhibitors of either phosphoinositide 3-kinase (PI 3-kinase) (wortmannin, 250 nM) or of p38 mitogen-activated protein kinase (p38 MAP kinase) (SB203580, 20 microM), which reportedly prevent GLUT4 translocation and/or activation by insulin respectively. These inhibitors also had no effect on the stimulation of transport by osmotic shock in Clone 9 cells. However, in contrast to adipocytes, the effect of osmotic shock on glucose transport in Clone 9 cells reflected primarily a change in the intrinsic activity of cell surface transporters and there was only a minor change in their subcellular distribution as assessed by cell immunostaining or no change as assessed by surface biotinylation. These results indicate that the response of cells to osmotic shock can involve changes both in transporter activity and location. The signal transduction pathways involved include neither PI 3-kinase nor the classical, osmotically-activated component, p38 MAP kinase.

3T3 Cells↗
PubMed2007

Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters.

Cardiovascular disease is the primary cause of death in obesity and type-2 diabetes mellitus (T2DM). Alterations in substrate metabolism are believed to be involved in the development of both cardiac dysfunction and insulin resistance in these conditions. Under physiological circumstances the heart utilizes predominantly long-chain fatty acids (LCFAs) (60-70%), with the remainder covered by carbohydrates, i.e., glucose (20%) and lactate (10%). The cellular uptake of both LCFA and glucose is regulated by the sarcolemmal amount of specific transport proteins, i.e., fatty acid translocase (FAT)/CD36 and GLUT4, respectively. These transport proteins are not only present at the sarcolemma, but also in intracellular storage compartments. Both an increased workload and the hormone insulin induce translocation of FAT/CD36 and GLUT4 to the sarcolemma. In this review, recent findings on the insulin and contraction signalling pathways involved in substrate uptake and utilization by cardiac myocytes under physiological conditions are discussed. New insights in alterations in substrate uptake and utilization during insulin resistance and its progression towards T2DM suggest a pivotal role for substrate transporters. During the development of obesity towards T2DM alterations in cardiac lipid homeostasis were found to precede alterations in glucose homeostasis. In the early stages of T2DM, relocation of FAT/CD36 to the sarcolemma is associated with the myocardial accumulation of triacylglycerols (TAGs) eventually leading to an impaired insulin-stimulated GLUT4-translocation. These novel insights may result in new strategies for the prevention of development of cardiac dysfunction and insulin resistance in obesity and T2DM.

Animals↗
PubMed2006

Effect of sucrose and saturated-fat diets on mRNA levels of genes limiting muscle fatty acid and glucose supply in rats.

In this study, we examined whether the increased availability of lipids in blood resulting from two types of diet manipulation regulated metabolic gene expression in the skeletal muscle of rats. Feeding for 4 wk on an isocaloric-sucrose or a hypercaloric-fat diet increased plasma TAG in the fed condition by increments of 70 and 40%, respectively, and increased fasting insulinemia (approximately 3-fold) compared with a starch diet. The fat diet impaired glucose tolerance and caused obesity, whereas sucrose-fed rats maintained their normal weight. We analyzed the expression of genes that regulate the exogenous FA supply (LPL, FAT/CD36, FATP1), synthesis (ACC1), glucose (GLUT4, GLUT1, HK2, GFAT1, glycogen phosphorylase) or glycerol (glycerol kinase) provision, or substrate choice for oxidation (PDK4) in gastrocnemius and soleus muscles at the end of the glucose tolerance test. LPL, FAT/CD36, FATP1, PDK4, and GLUT4 mRNA as well as glycogen phosphorylase and glycerol kinase activity levels in both muscles were unchanged by the diets. Increased mRNA levels of GLUT1 (1.6- and 2.6-fold, respectively) and GFAT1 (about 1.7-fold) in gastrocnemius, and of ACC1 (about 1.5-fold) in soleus, were found in both the sucrose and fat groups. In the fat group, HK2 mRNA was also higher (1.8-fold) in the gastrocnemius. Both sucrose and saturated-fat diets prompted hyperinsulinemia and hyperlipemia in rats. These metabolic disturbances did not alter the expression of LPL, FAT/CD36, FATP1, PDK4, and GLUT4 genes or glycogen phosphorylase and glycerol kinase activity levels in either analyzed muscle. Instead, they were linked to the coordinated upregulation in gastrocnemius of genes that govern glucose uptake and the hexosamine pathway, namely, GLUT1 and GFAT1, which might contribute to insulin resistance.

Animals↗
PubMed1991

Liver and muscle-fat type glucose transporter gene expression in obese and diabetic rats.

In order to investigate the regulation of glucose transporter gene expression in the altered metabolic conditions of obesity and diabetes, we have measured mRNA levels encoding GLUT2 in the liver and GLUT4 in the gastrocnemius muscle from various insulin resistant animal models, including Zucker fatty, Wistar fatty, and streptozocin(STZ)-treated diabetic rats. Northern blot analysis revealed that GLUT2 mRNA levels were significantly (P less than 0.001) elevated in 14 wk Zucker fatty and Wistar fatty rats relative to lean littermates but were similar in these two groups at 5 wk of age. Furthermore, there was significant increase (P less than 0.01) in GLUT2 mRNA levels in STZ diabetic rats at 3 wk after treatment. GLUT4 mRNA levels were not significantly different between control and insulin resistant rats in all animal models. These results indicate that neither hyperinsulinemia nor hyperglycemia affects GLUT4 mRNA levels in the muscle. However, GLUT2 mRNA levels in the liver were elevated in obesity and diabetes, although this regulatory event occurred independently from circulating insulin or glucose concentrations.

Animals↗
PubMed1992

Cold exposure increases glucose utilization and glucose transporter expression in brown adipose tissue.

When rats were exposed to a cold environment (4 degrees C) for 10 days, tissue glucose utilization was increased in brown adipose tissue (BAT), a tissue specified for non-shivering thermogenesis, but not in skeletal muscle. Cold exposure also caused an increase in the amount of GLUT4, an isoform of glucose transporters expressed in insulin-sensitive tissues, in parallel with an increased cellular level of GLUT4 mRNA. In contrast to BAT, no significant effect of cold exposure was found in skeletal muscle. The results suggest the cold-induced increase in glucose utilization by BAT is attributable, at least in part, to the increased expression of GLUT4.

Acclimatization↗
PubMed1990

Restricted localization of the adipocyte/muscle glucose transporter species to a cell surface-derived vesicle fraction of 3T3-L1 adipocytes. Inhibited lateral mobility of integral plasma membrane proteins in newly inserted membrane areas of differentiated 3T3-L1 cells.

The recent demonstration of a large cell surface-derived pool of insulin-sensitive glucose transporters, presumably concentrated in the microvilli of 3T3-L1 adipocytes, induced the assumption that in differentiated adipocytes, newly inserted plasma membrane areas may display restricted lateral mobility, thereby preventing diffusion of integral membrane proteins out of these areas into the adjoining plasma membrane. In order to test this assumption, the cell surface distributions of the two glucose transporter species expressed by 3T3-L1 cells were determined using specific antisera against the HepG2/erythrocyte transporter, GluT1, which is synthesized in both fibroblasts and adipocytes, and the adipocyte/muscle-specific transporter, GluT4, expressed for the first time 3-4 days after induction of adipose conversion. GluT1 was shown to be localized in the plasma membrane of both 3T3-L1 preadipocytes and adipocytes, whereas GluT4 was almost entirely restricted to the low density surface-derived vesicle (LDSV) fraction of 3T3-L1 adipocytes most likely consisting of microvilli-derived vesicles. In contrast to the minor portion of GluT4 found in the adipocyte plasma membrane fraction, equal amounts of the GluT1 protein were detected in both the plasma membrane and the LDSV fractions of adipocytes. Both transporter species were present in the microsomal and the LDSV fractions of adipocytes. The observed distribution of the two transporter species is in accordance with the postulated restriction of the lateral mobility in plasma membrane areas formed by newly inserted transgolgi vesicles of differentiated adipocytes.

Adipose Tissue↗
PubMed1992

Acute and long-term effects of insulin-like growth factor I on glucose transporters in muscle cells. Translocation and biosynthesis.

Insulin-like growth factor I (IGF-I) rapidly (less than 10 min) stimulated glucose uptake into myotubes of the L6 muscle cell line, at concentrations that act specifically on IGF-I receptors. Uptake remained stimulated at a steady level for 1-2 h, after which a second stimulation occurred. The first phase was insensitive to inhibition of protein synthesis. Subcellular fractionation demonstrated that it was accompanied by translocation of glucose transporters (both GLUT1 and GLUT4) to the plasma membrane from intracellular membranes. Translocation sufficed to explain the first phase increase in glucose transport, and there was no change in the total cellular content of GLUT1 or GLUT4 glucose transporters. The second phase of stimulation was inhibitable by cycloheximide, and involved a net increase in either GLUT1 or GLUT4 transporter content, which was reflected in an increase in transporter number in plasma membranes. These results define a cellular mechanism of metabolic action of IGF-I in muscle cells; furthermore, they suggest that IGF-I has acute metabolic effects that mimic those of insulin, bypassing action on the insulin receptor.

Animals↗
PubMed1995

Insulin-dependent translocation of the small GTP-binding protein rab3C in cardiac muscle: studies on insulin-resistant Zucker rats.

The failure of insulin-regulated recruitment of the GLUT4 glucose transporter in cardiac muscle of obese Zucker rats is associated with alterations of the subcellular distribution of the small-molecular-mass GTP-binding protein rab4A. Here, we show by subcellular fractionation and Western blotting a translocation of the small-molecular-mass GTP-binding protein rab3C from microsomal membranes to plasma membranes in lean control rats following in vivo insulin stimulation. However, in cardiac muscle of obese animals no significant effect of the hormone on the subcellular distribution of rab3C was observed. In GLUT4-enriched membrane vesicles, obtained from cardiac microsomes of the obese group as well as of lean controls, rab3C was not detectable. It is suggested that the altered behaviour of rab3C may contribute to an impaired trafficking of GLUT4 in the insulin-resistant state.

Animals↗
PubMed2004

Functions of pancreatic beta cells and adipocytes in bombesin receptor subtype-3-deficient mice.

We previously reported that mice lacking bombesin receptor subtype-3 (BRS-3) exhibit mild late-onset obesity and glucose intolerance [Nature 390 (1997) 160]. To examine the mechanism by which glucose intolerance is developed in these mice, we studied insulin release and proinsulin biosynthesis in isolated pancreatic islets and glucose uptake and facilitative glucose transporter (GLUT)-4 translocation in adipose tissues. Although islet insulin contents and the size and number of islets of Langerhans in BRS-3-deficient mice decreased, there was no difference in glucose-stimulated insulin release and proinsulin biosynthesis between BRS-3-deficient and wild-type control mice. In contrast, adipose tissues exhibited a marked difference: the uptake of [(14)C]2-deoxy-D-glucose by adipocytes isolated from BRS-3-deficient mice was not stimulated by 10(-7)M insulin addition, and membrane fractionation analysis showed that GLUT4 was barely detected in the fraction of plasma membrane in BRS-3-deficient mice in the presence of 10(-7)M insulin. Quantitative reverse transcription-PCR (RT-PCR) showed that mRNA levels of GLUT4, insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2, syntaxin 4, SNAP23, and VAMP-2 in adipose tissues of BRS-3-deficient mice were unchanged compared with those in wild-type control mice. We concluded that impaired glucose metabolism observed in BRS-3-deficient mice was mainly caused by impaired GLUT4 translocation in adipocytes.

Adipocytes↗
PubMed2004

Rottlerin inhibits multiple steps involved in insulin-induced glucose uptake in 3T3-L1 adipocytes.

Recently, it was shown that rottlerin inhibits insulin-stimulated glucose uptake and reduces intracellular adenosine triphosphate (ATP) levels in 3T3-L1 adipocytes, suggesting that these two events are causally linked. However, several other reports show that ATP-depletion induces glucose uptake in both muscle cells and adipocytes. In the present study, the mechanism of inhibition by rottlerin was studied in detail, in order to resolve this apparent discrepancy. It was found that rottlerin strongly reduces insulin-stimulated 2-deoxyglucose (2-DOG) uptake in 3T3-L1 adipocytes by a partial inhibition of the translocation of the insulin-responsive GLUT4 glucose transporter towards the plasma membrane (PM). Whereas the insulin-induced phosphatidyl-inositol-3' (PI-3') kinase signaling pathway is unaffected by rottlerin, Cbl tyrosine phosphorylation, which provides an essential, PI-3' kinase-independent signal towards GLUT4 translocation, is markedly attenuated. Furthermore, we also observed a direct inhibitory effect of rottlerin on insulin-induced glucose uptake in 3T3-L1 adipocytes. The direct inhibition of insulin-stimulated 2-DOG uptake by rottlerin displayed characteristics of uncompetitive inhibition: with the K(m(app)) of glucose uptake reduced from 1.6 to 0.9 mM and the V(max(app)) reduced from 5.2 to 1.0 nmol/minmg in the presence of rottlerin. In conclusion, rottlerin inhibits multiple steps involved in insulin-stimulated 2-DOG uptake in 3T3-L1 adipocytes. The observed reduction in GLUT4 translocation towards the PM and the uncompetitive inhibition of the glucose transport process provide alternative explanations for the inhibitory effects of rottlerin aside from the effects of rottlerin on intracellular levels of ATP.

3T3 Cells↗
PubMed2006

Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart.

OBJECTIVE: Many patients with heart failure have whole-body insulin resistance and reduced cardiac fluorodeoxyglucose uptake, but whether these metabolic changes have detrimental effects on the heart is unknown. Here, we tested whether there is a link between insulin resistance and ischemic damage in the chronically infarcted Wistar rat heart, postulating that the heart would have decreased insulin sensitivity, with lower GLUT4 glucose transporter protein levels due to high circulating free fatty acid (FFA) concentrations. A decreased capacity for glucose uptake would lower glycolytic adenosine triphosphate (ATP) production and thereby increase ischemic injury in the infarcted heart. METHODS AND RESULTS: In vivo left ventricular ejection fractions, measured using echocardiography, were 40% lower in rats 10 weeks after coronary artery ligation than in sham-operated control rats. Insulin-stimulated D[2-3H]glucose uptake was 42% lower in isolated, perfused, infarcted hearts. Myocardial GLUT4 glucose transporter protein levels were 28% lower in the infarcted hearts and correlated negatively with ejection fractions and with fasting plasma FFA concentrations. Compared with controls, chronically infarcted hearts had 46% lower total glucose uptake and three-fold faster ATP hydrolysis rates, measured using phosphorus-31 nuclear magnetic resonance spectroscopy, during 32-min ischemia at 0.4 ml/min/gww. During reperfusion, recovery of left ventricular developed pressure in infarcted hearts was 42% lower than in control hearts. CONCLUSIONS: Glucose uptake, in response to insulin or ischemia, was lower in the chronically infarcted rat heart and associated with increased circulating FFA concentrations and decreased GLUT4 levels. Thus, infarcted hearts had greater ATP depletion, and consequently incurred greater damage, during ischemia.

Adenosine Triphosphate↗
PubMed2006

A type IV P-type ATPase affects insulin-mediated glucose uptake in adipose tissue and skeletal muscle in mice.

Mice carrying two pink-eyed dilution (p) locus heterozygous deletions represent a novel polygenic mouse model of type 2 diabetes associated with obesity. Atp10c, a putative aminophospholipid transporter on mouse chromosome 7, is a candidate for the phenotype. The phenotype is diet-induced. As a next logical step in the validation and characterization of the model, experiments to analyze metabolic abnormalities associated with these mice were carried out. Results demonstrate that mutants (inheriting the p deletion maternally) heterozygous for Atp10c are hyperinsulinemic, insulin-resistant and have an altered insulin-stimulated response in peripheral tissues. Adipose tissue and the skeletal muscle are the targets, and GLUT4-mediated glucose uptake is the specific metabolic pathway associated with Atp10c deletion. Insulin resistance primarily affects the adipose tissue and the skeletal muscle, and the effect in the liver is secondary. Gene expression profiling using microarray and real-time PCR show significant changes in the expression of four genes--Vamp2, Dok1, Glut4 and Mapk14--involved in insulin signaling. The expression of Atp10c is also significantly altered in the adipose tissue and the soleus muscle. The most striking observation is the loss of Atp10c expression in the mutants, specifically in the soleus muscle, after eating the high-fat diet for 12 weeks. In conclusion, experiments suggest that the target genes and/or their cognate factors in conjunction with Atp10c presumably affect the normal translocation and sequestration of GLUT4 in both the target tissues.

Adenosine Triphosphatases↗
PubMed2005

Possible mode of action for insulinomimetic activity of vanadyl(IV) compounds in adipocytes.

Vanadyl(IV) ions (+4 oxidation state of vanadium) and their complexes have been shown to have in vitro insulinomimetic activity and to be effective in treating animals with diabetes mellitus. Although, researchers have proposed many vanadyl compounds for the treatment of diabetes patients, the mode of action of vanadyl compounds remains controversial. In order to evaluate the mode of action of these compounds, we examined the insulinomimetic activity of VOSO4, bis(picolinato)oxovanadyl(IV), and bis(maltolato)oxovanadyl(IV) in the presence of several inhibitors relevant to the glucose metabolism. After confirming that these vanadyl compounds were incorporated in the adipocytes as estimated by ESR method, we evaluated the mode of action by examining free fatty acids (FFA) release in the adipocytes. Inhibition of FFA release by these vanadyl compounds was found to be reversed by the addition of inhibitors, typically by cytochalasin B (glucose transporter 4 (GLUT4) inhibitor), cilostamide (phosphodiesterase inhibitor), HNMPA-(AM)3 (tyrosine kinase inhibitor), and wortmannin (PI3-k inhibitor), indicating that these compounds affect primarily GLUT4 and phosphodiesterase, as named "ensemble mechanism". Based on these results, we suggest that vanadyl compounds act on at least four sites relevant to the glucose metabolism, and on GLUT4 and phosphodiesterase in particular in rat adipocytes, which in turn normalizes the blood glucose levels of diabetic animals. The obtained results provide evidence for the role of vanadyl ion and its complexes in stimulation of the uptake and degeneration of glucose.

Adipocytes↗
PubMed2006

α2 isoform-specific activation of 5'adenosine monophosphate-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a physiological level activates glucose transport and increases glucose transporter 4 in mouse skeletal muscle.

5'Adenosine monophosphate-activated protein kinase (AMPK) has been implicated in exercise-induced stimulation of glucose metabolism in skeletal muscle. Although skeletal muscle expresses both the alpha1 and alpha2 isoforms of AMPK, the alpha2 isoform is activated predominantly in response to moderate-intensity endurance exercise in human and animal muscles. The purpose of this study was to determine whether activation of alpha2 AMPK plays a role in increasing the rate of glucose transport, promoting glucose transporter 4 (GLUT4) expression, and enhancing insulin sensitivity in skeletal muscle. To selectively activate the alpha2 isoform, we used 5-aminoimidazole-4-carboxamide-1-beta-d-ribonucleoside (AICAR), which is metabolized in muscle cells and preferentially stimulates the alpha2 isoform. Subcutaneous administration of 250 mg/kg AICAR activated the alpha2 isoform for 90 minutes, but not the alpha1 isoform in hind limb muscles of the C57/B6J mouse. The maximal activation of the alpha2 isoform was observed 30 to 60 minutes after administration of AICAR and was similar to the activation induced by a 30-minute swim in a current pool. The increase in alpha2 activity paralleled the phosphorylation of Thr(172), the essential residue for full kinase activation, and the activity of acetyl-coenzyme A carboxylase beta, a known substrate of AMPK in skeletal muscle. Subcutaneous injection of AICAR rapidly increased, by 30%, the rate of 2-deoxyglucose (2DG) transport into soleus muscle; 2DG transport increased within 30 minutes and remained elevated for 4 hours after administration of AICAR. Repeated intraperitoneal injection of AICAR, 3 times a day for 4 to 7 days, increased soleus GLUT4 protein by 30% concomitant with a significant 20% increase in insulin-stimulated 2DG transport. These data suggest that moderate endurance exercise promotes glucose transport, GLUT4 expression, and insulin sensitivity in skeletal muscle at least partially via activation of the alpha2 isoform of AMPK.

AMP-Activated Protein Kinases↗
PubMed2004

Insulin sensitivity and skeletal muscle glucose transport in horses with equine polysaccharide storage myopathy.

Equine polysaccharide storage myopathy (PSSM) is an inherited disorder characterized by the accumulation of glycogen and abnormal polysaccharide in muscle with normal glyco(geno)lytic enzyme activities. The purpose of this study was to evaluate in vivo insulin sensitivity and glucose excursion in PSSM using a euglycemic hyperinsulinemic clamp. In addition, the content of muscle glucose transporters (GLUT1 and GLUT4) and the insulin receptor was determined in muscle biopsies using Western blot analysis. The glycogen content was 1.8-fold higher, and isolated polysaccharide analyzed by iodine absorption spectra, was less branched in equine PSSM. Throughout the clamp, the affected horses required a higher rate of glucose infusion to maintain euglycemia. Although GLUT1 content was lower, the total content of GLUT4 and insulin receptor was not different in myopathic vs. control horses. PSSM therefore represents a novel disorder where enhanced insulin sensitivity and elevated glucose excursion leads to increased synthesis of muscle glycogen, which in our horses appears to be independent of augmented GLUT4 or IR quantity.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2000

Effect of YM-126414 on glucose uptake and redistribution of glucose transporter isotype 4 in muscle cells.

We discovered a novel compound, YM-126414 [1,3, 3-trimethyl-2-(2-phenylaminovinyl)-3H-indolium perchlorate], which stimulates glucose uptake in skeletal muscle cells in vitro. This compound increased the rate of consumption of glucose by C2C12 mouse myoblast cells in a dose-dependent manner (EC(50)=10 nM). To investigate the mechanism of this stimulation, we determined the redistribution of insulin-regulatable glucose transporter isotype 4 (Glut4). When fully differentiated C2C12 cells stably expressing myc-tagged Glut4 protein were treated with YM-126414, redistribution was dramatically increased in a dose-dependent manner (EC(50)=21 nM). These results indicate that YM-126414 is a novel glucose uptake stimulator for muscle cells by causing up-regulation of Glut4 redistribution in differentiated muscle cells. Our findings for the in vitro effects of YM-126414 suggest a direction for the development of new drugs for the treatment of type 2 diabetes.

Animals↗
PubMed1997

Antihyperglycemic mechanism of M16209, an antidiabetic agent, in 3T3-L1 adipocytes.

We investigated the effect of M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) on glucose transport and the insulin signaling system in mouse-derived 3T3-L1 adipocytes. When M16209 (30 and 100 microM) was added to 3T3-L1 adipocytes and preincubated for 24 hours, the uptake of 2-deoxy-D-[3H]-glucose (2-DG) after insulin stimulation was enhanced. This effect was seen when preincubation with M16209 was performed in the presence of 6 and 20 ng/ml insulin, but M16209 did not increase the response to 600 ng/ml insulin. M16209 (100 microM) did not interfere with (125)I-insulin binding or with tyrosine phosphorylation of the insulin receptor beta-subunit and IRS-1. M16209 (100 microM) also had no effect on the level of glucose transporter (GLUT1 and GLUT4) protein, but it promoted the translocation of intracellular GLUT4 to the plasma membrane. In contrast, M16209 had no effect on the translocation of GLUT1. In summary, M16209 enhanced 2-DG uptake by 3T3-L1 adipocytes. Insulin binding to its receptor, autophosphorylation of the insulin receptor beta-subunit, and tyrosine phosphorylation of IRS-1 were unaffected by M16209. However, translocation of GLUT4 from the intracellular pool to the plasma membrane was facilitated.

3T3 Cells↗