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PubMed2004

Characterization of glucose uptake by cultured rat podocytes.

The nonmetabolizable glucose analogue [(3)H]-2-deoxy-D-glucose ((3)H-2DG) was used to study glucose transport in cultured rat podocytes. Intracellular accumulation of (3)H-2DG was linear up to 20 min and was inhibited by cytochalasin B (80% inhibition) and by phlorizin (20% inhibition). Pretreatment with insulin stimulated the (3)H-2DG uptake 1.5-fold. A Hill analysis of the rate of glucose transport yielded a V(max) value of approximately 10 mM and S(0.5)of 7.8 mM. The value h = 1.0 for a Hill coefficient confirmed that glucose uptake exhibited a Michaelis-Menten kinetics. Transporters GLUT2 and GLUT4 were expressed in over 90% podocytes. Of the GLUT2- and GLUT4-expressing cells, approximately one-fourth expressed the membrane-bound fraction. We conclude that cultured rat podocytes possess a differentiated glucose transport system consisting chiefly of facilitative GLUT2 and GLUT4 transporters. It seems likely that a sodium-dependent glucose cotransporter may also be present in these cells.

Animals↗
PubMed1997

Placental glucose transporters in fetal intrauterine growth retardation and macrosomia.

To investigate the role of placental glucose delivery in fetal growth, two glucose transporters (Glut3 and Glut4) were determined from term placentae. This was accomplished by immunoblotting from crude placental membrane samples from cases of fetal intrauterine growth retardation (IUGR, n = 6), macrosomia (n = 6), maternal diabetes mellitus (n = 4) and normal term (n = 8). Glut3 and Glut4 were detected in only very low numbers in all patient groups and there were no changes in their placental density, which suggests that the expression of these transporters is not involved in disorders of fetal growth. However, birth weight corresponded to placental weight, indicating that the total amount of Glut3 and Glut4 is reduced in IUGR and increased in macrosomia.

Adult↗
PubMed2003

Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells.

OBJECTIVE: In cultured human vascular smooth muscle cells, insulin increases cyclic GMP production by inducing nitric oxide (NO) synthesis. The aim of the present study was to determine whether in these cells the insulin-stimulated NO/cyclic GMP pathway plays a role in the regulation of glucose uptake. METHODS AND RESULTS: Glucose transport in human vascular smooth muscle cells was measured as uptake of 2-deoxy-d-[3H]glucose, cyclic GMP synthesis was checked by radioimmunoassay, and GLUT4 recruitment into the plasma membrane was determined by immunofluorescence. Insulin-stimulated glucose transport and GLUT4 recruitment were blocked by an inhibitor of NO synthesis and mimicked by NO-releasing drugs. Insulin- and NO-elicited glucose uptake were blocked by inhibitors of soluble guanylate cyclase and cyclic GMP-dependent protein kinase; furthermore, glucose transport was stimulated by an analog of cyclic GMP. CONCLUSIONS: Our results suggest that insulin-elicited glucose transport (and the corresponding GLUT4 recruitment into the plasma membrane) in human vascular smooth muscle cells is mediated by an increased synthesis of NO, which stimulates the production of cyclic GMP and the subsequent activation of a cyclic GMP-dependent protein kinase.

Biological Transport↗
PubMed2002

ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO.

Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[3H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation.

The genetically obese Zucker rat (fa/fa) is characterized by a severe resistance to the action of insulin to stimulate skeletal muscle glucose transport. The goal of the present study was to identify whether the defect associated with this insulin resistance involves an alteration of transporter translocation and/or transporter activity. Various components of the muscle glucose transport system were investigated in plasma membranes isolated from basal or maximally insulin-treated skeletal muscle of lean and obese Zucker rats. Measurements of D- and L-glucose uptake by membrane vesicles under equilibrium exchange conditions indicated that insulin treatment resulted in a four-fold increase in the Vmax for carrier-mediated transport for lean animals [from 4.5 to 17.5 nmol/(mg.s)] but only a 2.5-fold increase for obese rats [from 3.6 to 9.1 nmol/(mg.s)]. In the lean animals, this increase in glucose transport function was associated with a 1.8-fold increase in the transporter number as indicated by cytochalasin B binding, a 1.4-fold increase in plasma membrane GLUT4 protein, and a doubling of the average carrier turnover number (intrinsic activity). In the obese animals, there was no change in plasma membrane transporter number measured by cytochalasin B binding, or in GLUT4 or GLUT1 protein. However, there was an increase in carrier turnover number similar to that seen in the lean litter mates. Measurements of GLUT4 mRNA in red gastrocnemius muscle showed no difference between lean and obese rats. We conclude that the insulin resistance of the obese rats involves the failure of translocation of transporters, while the action of insulin to increase the average carrier turnover number is normal.

Animals↗
PubMed2005

MUNC-ing around with insulin action.

Defective uptake of glucose into muscle and fat cells, or insulin resistance, is a central feature of obesity and type 2 diabetes. As we brace ourselves for the diabetes epidemic, it is reassuring to know that real progress is being made in defining the molecular biology of how insulin stimulates glucose uptake and what goes awry in obesity and type 2 diabetes. An understanding of the molecular determinants of insulin-stimulated glucose transport has been one of the holy grails of hormone action research. A major breakthrough was the discovery that insulin stimulates the translocation of a specific glucose transport protein, GLUT4, from intracellular vesicles to the cell surface. Elucidating how this process is regulated has remained a challenge because it represents a convergence of 2 disparate and complex fields of research--namely, vesicle transport and signal transduction. A study reported in this issue of the JCI using mice lacking Munc18c, one of the vesicle-trafficking proteins involved in GLUT4 translocation, has provided new insights into the signaling/trafficking intersection that controls insulin-stimulated GLUT4 movement.

Animals↗
PubMedDate not supplied

The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function.

Glucose enters eucaryotic cells via 2 different types of membrane associated carrier proteins, the Na+-coupled glucose transporters (SGLT) and glucose transporter facilitators (GLUT). Three members of the SGLT family function as sugar transporters (SGLT1 and SGLT2) or sensors (SGLT3). The human GLUT family consists of 14 members, of which 11 have been shown to catalyze sugar transport. The individual isotypes exhibit different substrate specificity, kinetic characteristics, and expression profiles, thereby allowing a tissue-specific adaptation of glucose uptake through regulation of their gene expression. Furthermore, some transporters (eg, GLUT4 and GLUT8) are regulated by their subcellular distribution. In addition to catalyzing glucose entry into cells, some isotypes (eg, GLUT2) seem to be involved in the mechanisms of glucosensing of pancreatic beta-cells, neuronal, or other cells, thereby playing a major role in the hormonal and neural control. Targeted disruption in mice has helped to elucidate the physiologic function of some isotypes (GLUT1, GLUT2, GLUT4). Furthermore, several congenital defects of sugar metabolism are caused by aberrant transporter genes (eg, the glucose-galactose malabsorption syndrome, SGLT1; the glucose transporter 1 deficiency syndrome; and the Fanconi-Bickel syndrome, GLUT2). In addition, a malfunction of glucose transporter expression or regulation (GLUT4) appears to contribute to the insulin resistance syndrome.

Animals↗
PubMed2005

Palmitate induces tumor necrosis factor-alpha expression in C2C12 skeletal muscle cells by a mechanism involving protein kinase C and nuclear factor-kappaB activation.

The mechanisms responsible for increased expression of TNF-alpha in skeletal muscle cells in diabetic states are not well understood. We examined the effects of the saturated acid palmitate on TNF-alpha expression. Exposure of C2C12 skeletal muscle cells to 0.75 mm palmitate enhanced mRNA (25-fold induction, P < 0.001) and protein (2.5-fold induction) expression of the proinflammatory cytokine TNF-alpha. This induction was inversely correlated with a fall in GLUT4 mRNA levels (57% reduction, P < 0.001) and glucose uptake (34% reduction, P < 0.001). PD98059 and U0126, inhibitors of the ERK-MAPK cascade, partially prevented the palmitate-induced TNF-alpha expression. Palmitate increased nuclear factor (NF)-kappaB activation and incubation of the cells with the NF-kappaB inhibitors pyrrolidine dithiocarbamate and parthenolide partially prevented TNF-alpha expression. Incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C (PKC), abolished palmitate-induced TNF-alpha expression, and restored GLUT4 mRNA levels. Palmitate treatment enhanced the expression of phospho-PKCtheta, suggesting that this PKC isoform was involved in the changes reported, and coincubation of palmitate-treated cells with the PKC inhibitor chelerythrine prevented the palmitate-induced reduction in the expression of IkappaBalpha and insulin-stimulated Akt activation. These findings suggest that enhanced TNF-alpha expression and GLUT4 down-regulation caused by palmitate are mediated through the PKC activation, confirming that this enzyme may be a target for either the prevention or the treatment of fatty acid-induced insulin resistance.

Alkaloids↗
PubMed2006

Role of insulin receptor in the regulation of glucose uptake in neonatal hepatocytes.

The liver plays a major role in the regulation of glucose homoeostasis. Evidence from liver-specific insulin receptor knockout mice (LIRKO) suggested that insulin's direct and indirect effects on glucose utilization by the liver both require the presence of hepatic insulin receptors (IR). To address this issue, we have generated immortalized neonatal hepatocytes bearing (HIR LoxP) or not (HIR KO) IR. The lack of IR significantly decreased basal glucose uptake in neonatal hepatocytes from 3- to 14-d-old mice, and the expression of glucose transporter 1 (GLUT1), GLUT2, and glucokinase (GK) remained unchanged throughout development. HIR KO reconstituted hepatocytes with IRA but not with IRB isoform and restored basal glucose uptake up to the levels observed in HIR LoxP cells. However, both IR isoforms associated with GLUT1 or GLUT2. Overexpression of IGF-I receptor (IGF-IR) increased basal glucose uptake in neonatal hepatocytes lacking or not IR. This effect was also accompanied by its association with GLUT1 or GLUT2. Exogenous expression of GLUT4 had no effect on basal glucose uptake in neonatal hepatocytes. However, HIR LoxP hepatocytes expressing exogenous GLUT4 increased glucose uptake in the presence of insulin without showing association between GLUT4 and IR. Our data clearly indicate that IR plays a direct role in the regulation of basal glucose uptake/transport by the hepatocytes, and either type A IR or IGF-IR works on glucose uptake as a GLUT1- or GLUT2-associated cotransporter. Thus, IR mediates glucose uptake through its specific association with endogenous, but not with exogenous, glucose transporters in neonatal hepatocytes.

Animals↗
PubMed1992

Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells.

The effects of the oral hypoglycemic drug metformin on glucose and amino acid transporter activity and subcellular localization of GLUT1 and GLUT4 glucose transporters were tested in cultured L6 myotubes. In muscle cells preexposed to maximal doses of metformin (2 mM, for 16 h), 2-deoxyglucose uptake was stimulated by over 2-fold from 5.9 +/- 0.3 to 13.3 +/- 0.5 pmol/min.mg protein. Uptake of the nonmetabolizable amino acid analog methylaminoisobutyrate was unaffected by treatment with the drug under identical conditions. Extracellular calcium was required to preserve the full response to the biguanide. Exposure of muscle cells to insulin in the presence of metformin resulted in further activation of 2-deoxyglucose transport. The latter effect was additive to the maximum effect of metformin, suggesting that the biguanide stimulates hexose uptake into muscle cells by an insulin-independent mechanism. Glucose transporter number quantified by performing studies of D-glucose-protectable binding of cytochalasin-B in plasma membranes (PM) and internal membranes (IM) prepared from L6 myotubes revealed that a 16-h treatment with 800 microM metformin significantly elevated glucose transporter number in the PM (by 47%), with an equivalent decrement in glucose transporter number (47%) in the IM. Western blot analysis using antisera reactive with the GLUT1 and GLUT4 isoforms of glucose transporters showed that metformin caused a reduction in GLUT1 content in the IM fraction and a concomitant increase in the PM. Unlike insulin, metformin treatment had no effect on the subcellular distribution of GLUT4. We propose that the molecular basis of metformin action in skeletal muscle involves the subcellular redistribution of GLUT1 proteins from an intracellular compartment to the plasma membrane. Such a recruitment process may form an integral part of the mechanism by which the drug stimulates glucose uptake (and utilization) in skeletal muscle and facilitates lowering of blood glucose in the management of type II diabetes.

Aminoisobutyric Acids↗
PubMed1994

High and polarized expression of GLUT1 glucose transporters in epithelial cells from mammary gland: acute down-regulation of GLUT1 carriers by weaning.

During lactation, the mammary gland shows high metabolic activity, which is dependent at least in part on the availability of glucose. We have studied the regulation of glucose transporter expression in different types of cell in rat mammary gland during the reproductive cycle. Glucose transporter expression varied markedly in the mammary gland during ontogeny. Thus, GLUT1 protein expression increased progressively during pregnancy, reaching the highest levels during lactation. A peak of lactation, GLUT1 protein content, expressed per g issue, was greater in mammary gland than in GLUT1-enriched tissues such as rat brain. In contrast, GLUT4 showed a marked decrease during pregnancy and practically disappeared during lactation. Regardless of the developmental stage, GLUT4 was expressed in adipocytes but not in epithelial cells from mammary gland. On the other hand, GLUT1 was expressed in both cell types. The overall pattern of GLUT1 and GLUT4 expression during the reproductive cycle reflects differences in the cell composition of the mammary gland. Thus, whereas adipocytes predominate before pregnancy, epithelial cells are the main cell type in the mammary gland during late pregnancy and lactation. Immunofluorescence and immunoelectron microscopy indicated that GLUT1 was essentially localized to the basolateral domain of epithelial cells in the mammary gland at peak of lactation, and hardly any labeling was found in the luminal membrane of epithelial cells. GLUT1 expression was acutely regulated in epithelial cells from mammary gland. Thus, GLUT1 protein markedly decreased in lactating rats 24 h after abrupt weaning in the presence of a moderate decrease in GLUT1 mRNA levels. The effect of weaning on GLUT1 protein content was not due to the fall in the plasma concentration of PRL. Thus, bromocriptine treatment for 24 h decreased GLUT1 mRNA levels in the mammary gland, but did not alter the content of GLUT1 protein. Our results demonstrate 1) the existence of a high and polarized expression of GLUT1 glucose transporters in epithelial cells from mammary gland, and 2) that GLUT1 expression is acutely regulated at a posttranslational level by weaning; this is not mimicked by bromocriptine treatment, which rules out PRL as the regulatory factor involved in the effect.

Animals↗
PubMed1997

Fatty acid-induced insulin resistance in adipocytes.

Elevated serum-free fatty acid (FFA) levels induce insulin resistance in whole animals and humans. To understand the direct mechanism by which FFAs impact insulin-responsive tissue, we have used our previously developed in vitro model of long-chain saturated fatty acids (LCSFA)-induced insulin resistance in adipocytes. In addition to explanted rat adipocytes, we now demonstrate that overnight exposure of 3T3-L1 adipocytes to 1 mM individually of the LCSFA palmitate, myristate, and stearate, leads to an approximately 50% inhibition of insulin-induced glucose transport. Insulin resistance can be accomplished at 0.3 mM palmitate, which is within the range ofpalmitate found in diabetic and obese individuals. This inhibition was noted within 4 h of exposure to FFA, which is comparable to in vivo lipid infusion studies. Initial LCSFA-induced resistance is specific to glucose transport and does not affect insulin stimulation of glucose incorporation into glycogen. In 3T3-L1 adipocytes overexpressing the EGF receptor, LCSFA exposure also specifically inhibited EGF-induced GLUT4-mediated glucose transport, but not EGF-induced glycogen synthesis. We find that LCSFA treatment did not impair insulin stimulation of GLUT4 translocation or exofacial presentation on the cell surface as determined by trypsin accessibility. Our results suggest that the initial direct effect of elevated LCSFA is to impair activation of GLUT4 transporter activity and that this effect is specific for glucose transport.

Adipocytes↗
PubMed1997

Changes in facilitative glucose transporter messenger ribonucleic acid levels in the diabetic rat kidney.

Facilitative glucose transporter (GLUTs 1, 2, 4, and 5) messenger RNAs (mRNAs) are differentially distributed in the rat nephron: GLUT1 is widely expressed, GLUT4 is selectively concentrated in thick ascending limbs, and GLUT2 and 5 are exclusively localized in proximal tubules, consistent with differential roles for these transporters in renal glucose handling. In the present study, quantitative in situ hybridization was used to evaluate changes in these mRNA levels during acute (2 and 7 days) and chronic (30, 90, and 180 days) streptozotocin-induced diabetes mellitus (STZ-DM). Medullary GLUT1 and GLUT4 mRNA levels were significantly increased during the acute phase but returned to normal after 1 week. Cortical GLUT1 mRNA levels, however, were decreased significantly from 7 days through 6 months of STZ-DM. Cortical GLUT2 mRNA was slightly increased acutely and increased 5-fold in chronic STZ-DM, with the largest increase focally concentrated in the convoluted portion of the proximal tubule. Proximal tubule GLUT5 mRNA levels also were increased significantly during chronic STZ-DM. In summary, medullary GLUT1 and GLUT4 mRNA levels are acutely increased in STZ-DM, paralleling the increased renal epithelial metabolic activity accompanying early diabetes. Proximal tubular GLUT2 and 5 mRNA levels were increased in chronic STZ-DM, possibly adapting to the increased need for glucose transport out of these epithelial cells, whereas the concomitant decrease in cortical GLUT1 expression may reflect the decreased requirement for basolateral import of glucose into these same cells. Thus, renal GLUTs demonstrate complex, nephron segment-specific and duration-dependent responses to the effects of STZ-DM.

Acute Disease↗
PubMed1998

Effects of general receptor for phosphoinositides 1 on insulin and insulin-like growth factor I-induced cytoskeletal rearrangement, glucose transporter-4 translocation, and deoxyribonucleic acid synthesis.

We investigated the effects of general receptor for phosphoinositides-1 (GRP1), a recently cloned protein that binds 3,4,5-phosphatidylinositol [PtdIns(3,4,5)P3] with high affinity, but not PtdIns(3,4)P2 nor PtdIns(3)P, on insulin and insulin-like growth factor I (IGF-I)-induced cytoskeletal rearrangement, glucose transporter-4 (GLUT4) translocation, and DNA synthesis. GRP1 consists of an NH2-terminally located coiled coil domain followed by a Sec7 domain and a COOH-terminal pleckstrin homology (PH) domain that is required for PtdIns binding. We used microinjection of glutathione-S-transferase fusion proteins containing residues 239-399 (PH domain), residues 52-260 (Sec7 domain), residues 5-71 (N-terminal domain), full-length GRP1, and an antibody (AB) raised against full-length GRP1 coupled with immunofluorescent detection of actin filament rearrangement, GLUT4 translocation, and 3'-bromo-5'-deoxyuridine incorporation. Microinjection of these constructs and the AB had no effect on insulin-induced GLUT4 translocation or DNA synthesis. However, microinjection of the GRP1-PH and the GRP1-Sec7 domain as well as the alpha-GRP1-AB significantly inhibited insulin- and IGF-I-stimulated actin rearrangement in an insulin receptor-overexpressing cell line (HIRcB) compared with that in control experiments. Coinjection of GRP1-Sec7 along with constitutively active Rac (Q67L) did not inhibit Rac-induced actin rearrangement. Furthermore, GRP1 is not able to bind and act as a nucleotide exchange factor for the small GTP-binding proteins of the Rho family. As GRP1 acts as a guanine nucleotide exchange factor for ARF6 proteins, we propose a signaling pathway distinct from the small GTP-binding protein Rac, connecting PtdIns(3,4,5)P3 via GRP1 to ARF6, leading to insulin- and IGF-I-induced actin rearrangement.

3T3 Cells↗
PubMed2000

Effects of adenoviral gene transfer of wild-type, constitutively active, and kinase-defective protein kinase C-lambda on insulin-stimulated glucose transport in L6 myotubes.

We used adenoviral gene transfer methods to evaluate the role of atypical protein kinase Cs (PKCs) during insulin stimulation of glucose transport in L6 myotubes. Expression of wild-type PKC-lambda potentiated maximal and half-maximal effects of insulin on 2-deoxyglucose uptake, but did not alter basal uptake. Expression of constitutively active PKC-lambda enhanced basal 2-deoxyglucose uptake to virtually the same extent as that observed during insulin treatment. In contrast, expression of kinase-defective PKC-lambda completely blocked insulin-stimulated, but not basal, 2-deoxyglucose uptake. Similar to alterations in glucose transport, constitutively active PKC-lambda mimicked, and kinase-defective PKC-lambda completely inhibited, insulin effects on GLUT4 glucose transporter translocation to the plasma membrane. Expression of kinase-defective PKC-lambda, in addition to inhibition of atypical PKC enzyme activity, was attended by paradoxical increases in GLUT4 and GLUT1 glucose transporter levels and insulin-stimulated protein kinase B enzyme activity. Our findings suggest that in L6 myotubes, 1) atypical PKCs are required and sufficient for insulin-stimulated GLUT4 translocation and glucose transport; and 2) activation of protein kinase B in the absence of activation of atypical PKCs is insufficient for insulin-induced activation of glucose transport.

Adenoviridae↗
PubMed2001

High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells.

Obesity is a major risk factor for the development of insulin resistance, characterized by impaired stimulation of glucose disposal into muscle. The mechanisms underlying insulin resistance are unknown. Here we examine the direct effect of leptin, the product of the obesity gene, on insulin-stimulated glucose uptake in cultured rat skeletal muscle cells. Preincubation of L6 myotubes with leptin (2 or 100 nM, 30 min) had no effect on basal glucose uptake but reduced insulin-stimulated glucose uptake. However, leptin had no effect on the insulin-induced gain in myc-tagged glucose transporter 4 (GLUT4) appearance at the cell surface of L6 myotubes. Preincubation of cells with leptin also had no effect on insulin-stimulated tyrosine phosphorylation of insulin receptor, IRS-1 and IRS-2, phosphatidylinositol 3-kinase activity, or Akt phosphorylation. We have previously shown that insulin regulates glucose uptake via a signaling pathway sensitive to inhibitors of p38 MAP kinase. Here, leptin pretreatment reduced the extent of insulin-stimulated p38 MAP kinase phosphorylation and phosphorylation of cAMP response element binder, a downstream effector of p38 MAP kinase. These results show that high leptin levels can directly reduce insulin-stimulated glucose uptake in L6 muscle cells despite normal GLUT4 translocation. The mechanism of this effect could involve inhibition of insulin-stimulated p38 MAP kinase and GLUT4 activation.

Animals↗
PubMed2001

The MEF2A and MEF2D isoforms are differentially regulated in muscle and adipose tissue during states of insulin deficiency.

Previously we have demonstrated that striated muscle GLUT4 gene expression decreased following streptozotocin-induced diabetes due to a loss of MEF2A transcription factor expression without any significant effect on the MEF2D isoform (Mora, S. and J. E. Pessin (2000) J Biol Chem, 275:16323-16328). In contrast to both cardiac and skeletal muscle, adipose tissue displays a selective decrease in MEF2D expression in diabetes without any significant alteration in MEF2A protein content. Adipose tissue also expresses very low levels of the MEF2 transcription factors and nuclear extracts from white adipose tissue exhibit poor in vitro binding to the MEF2 element. However, addition of in vitro synthesized MEF2A to adipose nuclear extracts results in the formation of the expected MEF2/DNA complex. More importantly, binding to the MEF2 element was also compromised in the diabetic condition. Furthermore, in vivo overexpression of MEF2A selectively in adipose tissue did not affect GLUT4 or MEF2D expression and was not sufficient to prevent GLUT4 down-regulation that occurred in insulin-deficient states.

Adipose Tissue↗
PubMed2004

Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes.

Since the discovery of insulin roughly 80 yr ago, much has been learned about how target cells receive, interpret, and respond to this peptide hormone. For example, we now know that insulin activates the tyrosine kinase activity of its cell surface receptor, thereby triggering intracellular signaling cascades that regulate many cellular processes. With respect to glucose homeostasis, these include the function of insulin to suppress hepatic glucose production and to increase glucose uptake in muscle and adipose tissues, the latter resulting from the translocation of the glucose transporter 4 (GLUT4) to the cell surface membrane. Although simple in broad outline, elucidating the molecular intricacies of these receptor-signaling pathways and membrane-trafficking processes continues to challenge the creative ingenuity of scientists, and many questions remain unresolved, or even perhaps unasked. The identification and functional characterization of specific molecules required for both insulin signaling and GLUT4 vesicle trafficking remain key issues in our pursuit of developing specific therapeutic agents to treat and/or prevent this debilitating disease process. To this end, the combined efforts of numerous research groups employing a range of experimental approaches has led to a clearer molecular picture of how insulin regulates the membrane trafficking of GLUT4.

Adipocytes↗