Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the fatty acid inhibitor 4-bromocrotonic acid (4-BCA) on glucose utilization was studied in isolated rat myocytes. In contrast to its potent inhibition of [1-14C]palmitate oxidation, 4-BCA strongly stimulated the oxidation of [1-14C]glucose and [2-14C]-pyruvate in a concentration-dependent manner. At a concentration of 300 microM, 4-BCA increased glucose oxidation threefold and that of pyruvate oxidation twofold. The rate of transport of [U-14C]-2-deoxyglucose was significantly stimulated by 4-BCA. The transport of 2-deoxyglucose was increased sevenfold with 200 microM 4-BCA, whereas insulin (10 microU)/ml enhanced 2-deoxyglucose transport twofold. The addition of insulin to myocytes preincubated with 4-BCA did not further increase glucose transport. Cytochalasin B and anti-GLUT 4 antibody decreased the 4-BCA-induced stimulation of glucose transport. These results suggest that the stimulation of 2-deoxy-glucose transport by 4-BCA occurs through an increase in the activity of insulin-responsive glucose transporters, GLUT 4, in the sarcolemmal membrane.
Diabetes Res 1993
PMID:Stimulation of myocyte insulin-responsive glucose transporters by the inhibition of fatty acid oxidation. 820 Jan 80

Mechanisms causing cellular insulin resistance in gestational diabetes mellitus are not known. We, therefore, studied isolated omental adipocytes obtained during elective cesarean sections in nondiabetic (control) and GDM gravidas. Cellular insulin resistance was attributed to impaired stimulation of glucose transport; compared with control subjects, basal and maximally insulin-stimulated transport rates (per surface area) were reduced 38 and 60% in GDM patients, respectively. To determine underlying mechanisms, we assessed the number, subcellular distribution, and translocation of GLUT4, the predominant insulin-responsive glucose transporter isoform. The cellular content of GLUT4 was decreased by 44% in GDM patients as assessed by immunoblot analysis of total postnuclear membranes. However, GDM patients segregated into two subgroups; half expected profound (76%) cellular depletion of GLUT4 and half had GLUT4 levels in the normal range. Cellular GLUT4 was negatively correlated with adipocyte size in the control subjects and GDM patients with normal GLUT4 (r = 0.60), but fell way below this continuum in GDM patients with low GLUT4, indicating that heterogeneity was not caused by differences in obesity. All GDM. distribution. In basal cells, increased amounts of GLUT4 were detected in membranes fractionating with (such that the plasma membrane GLUT4 level in GDM (such that the plasma membrane GLUT4 level in GDM patients was equal to that observed in insulin-stimulated cells from control subjects). Furthermore, insulin stimulation induced translocation of GLUT4 from low-density microsomes to plasma membranes in control subjects but did not alter subcellular distribution in GDM patients. In other experiments, cellular content of GLUT1 was normal in GDM patients, and GLUT1 did not undergo insulin-mediated recruitment to plasma membranes in either control subjects or GDM patients. A faint signal was detected for GLUT3 only in low-density microsomes and only with one of two different antibodies. In GDM, we conclude that insulin resistance in adipocytes involves impaired stimulation of glucose transport and arises from a heterogeneity of defects intrinsic to the glucose transport effector system. GLUT4 content in adipocytes is profoundly depleted in approximately 50% of GDM patients, whereas all patients are found to exhibit a novel abnormality in GLUT4 subcellular distribution. This latter defect is characterized by accumulation of GLUT4 in membranes cofractionating with plasma membranes and high-density microsomes in basal cells and absence of translocation in response to insulin. The data suggest that abnormalities in cellular traffic or targeting relegate GLUT4 to a membrane compartment from which insulin cannot recruit transporters to the cell surface and have important implications regarding skeletal muscle insulin resistance in GDM and NIDDM.
Diabetes 1993 Dec
PMID:Multiple defects in the adipocyte glucose transport system cause cellular insulin resistance in gestational diabetes. Heterogeneity in the number and a novel abnormality in subcellular localization of GLUT4 glucose transporters. 824 23

Sulfonylurea drugs are widely used in the therapy of NIDDM. The improvement of glucose tolerance after long-term treatment of NIDDM patients with the drug can be explained by stimulation of glucose utilization in peripheral tissues that are characterized by insulin resistance in these patients. We studied whether the novel sulfonylurea drug, glimepiride, stimulates glucose transport into isolated insulin-resistant rat adipocytes. After long-term incubation of the cells in primary culture with high concentrations of glucose, glutamine, and insulin, stimulation of glucose transport by insulin was significantly reduced both with respect to maximal responsiveness (65% decrease of Vmax) and sensitivity (2.6-fold increase of ED50) compared with adipocytes cultured in medium containing a low concentration of glucose and no insulin. This reflects insulin resistance of glucose transport. In contrast, both responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only marginally reduced in insulin-resistant adipocytes (15% decrease of Vmax; 1.2-fold increase of ED50) versus control cells. Glimepiride, in combination with glucose and glutamine during the primary culture, caused desensitization of the glucose transport system toward stimulation by insulin, but to a lesser degree than insulin itself (50% reduction of Vmax; ninefold increase of ED50). Again, the maximal responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only slightly diminished. The presence of glimepiride during primary culture did not antagonize the induction of insulin resistance of glucose transport. The stimulation of glucose transport in insulin-resistant adipocytes by glimepiride is caused by translocation of glucose transporters from low-density microsomes to plasma membranes as demonstrated by subcellular fractionation and immunoblotting with anti-GLUT1 and anti-GLUT4 antibodies. Immunoprecipitation of GLUT4 from 32Pi- and [35S]methionine-labeled adipocytes revealed that the insulin resistance of GLUT4 translocation is accompanied by increased (three- to fourfold) phosphorylation of GLUT4 in both low-density microsomes and plasma membranes. Short-term treatment of desensitized adipocytes with glimepiride or insulin reduced GLUT4 phosphorylation by approximately 70 and 25%, respectively, in both fractions. We conclude that glimepiride activates glucose transport by stimulation of GLUT1 and GLUT4 translocation in rat adipocytes via interference at a site downstream of the putative molecular defect in the signaling cascade between the insulin receptor and the glucose transport system induced by high concentrations of glucose and insulin. The molecular site of glimepiride action is related to GLUT4 phosphorylation/dephosphorylation, which may regulate glucose transporter activity and translocation.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes 1993 Dec
PMID:The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro. 824 32

The effects of streptozotocin-induced diabetes (13 weeks) on the in-vivo glucose uptake and on the protein levels of glucose transporters in rat brain were studied and compared with those in cardiac muscle. Diabetes reduced the uptake of 2-[3H]deoxyglucose into lobus frontalis by 70%. However, uptake rates corrected for the 4-fold increase in serum glucose (glucose metabolic index, GMI) were essentially unaltered. The levels of glucose transporter proteins GLUT1 and GLUT3 in crude membranes from brain as assessed by immunoblotting were unaffected by diabetes, whereas GMI and levels of glucose transporters GLUT1 and GLUT4 in heart were reduced by 80 and 65%, respectively. Thus, glucose uptake and levels of glucose transporters in brain, unlike that in insulin sensitive tissues, are normal in long-term hypo-insulinaemia.
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PMID:In-vivo glucose uptake and glucose transporter proteins GLUT1 and GLUT3 in brain tissue from streptozotocin-diabetic rats. 826 11

Chronic exposure of fully differentiated 3T3-L1 adipocytes to 50 microM arachidonic acid (AA) resulted in an inhibition (approximately 91%) in cellular GLUT4 mRNA content after a 48-h exposure, without similarly affecting the mRNA content of the ubiquitous glucose transporter, GLUT1. Subsequent investigations revealed that transcription of the GLUT4 gene was reduced by approximately 50% in response to AA treatment and the half-life of GLUT4 mRNA decreased from 8.0 to 4.6 h. By contrast, AA increased the accumulation of GLUT1 mRNA by 65%, by a mechanism that also involved regulation at both transcriptional and mRNA stability levels. Western blot analysis revealed that AA was specifically reducing the insulin-responsive glucose transporter (GLUT4) in both plasma and intracellular membranes. Subsequently, AA was observed to alter the ability of the GLUT4 transporter to respond to insulin and mediate a significant enhancement of glucose uptake. The results presented in this study indicate that AA can partially mimic the effects of both tumor necrosis factor-alpha and insulin which, when chronically supplied to 3T3-L1 adipocytes, also down-regulate GLUT4 gene expression. Therefore, these data may have relevance to the insulin-resistance associated with non-insulin-dependent diabetes mellitus.
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PMID:Arachidonic acid down-regulates the insulin-dependent glucose transporter gene (GLUT4) in 3T3-L1 adipocytes by inhibiting transcription and enhancing mRNA turnover. 827 64

We assessed the effects of 4 weeks of streptozocin-induced diabetes on regional myocardial glycolytic metabolism during ischemia in anesthetized open-chest domestic swine. Diabetic animals were hyperglycemic (12.0 +/- 2.1 v 6.6 +/- .5 mmol/L), and had lower fasting insulin levels (27 +/- 8 v 79 +/- 19 pmol/L). Myocardial glycolytic metabolism was studied with coronary flow controlled by an extracorporeal perfusion circuit. Left anterior descending coronary artery (LAD) flow was decreased by 50% for 45 minutes and left circumflex (CFX) flow was constant. Myocardial glucose uptake and extraction were measured with D-[6-3H]-2-deoxyglucose (DG) and myocardial blood flow was measured with microspheres. The rate of glucose conversion to lactate and lactate uptake and output were assessed with a continuous infusion of [6-14C]glucose and [U-13C]lactate into the coronary perfusion circuit. Both diabetic and nondiabetic animals had sharp decreases in subendocardial blood flow during ischemia (from 1.21 +/- .10 to 0.43 +/- .08 mL.g-1.min-1 in the nondiabetic group, and from 1.30 +/- .15 to 0.55 +/- .11 in the diabetic group). Diabetes had no significant effect on myocardial glucose uptake or glucose conversion to lactate under either well-perfused or ischemic conditions. Forty-five minutes of ischemia resulted in significant glycogen depletion in the subendocardium in both nondiabetic and diabetic animals, with no differences between the two groups. Glycolytic metabolism is not impaired in hyperglycemic diabetic swine after 1 month of the disease when compared with that in normoglycemic nondiabetic animals. The myocardial content of the insulin-regulatable glucose transporter (GLUT 4) was measured in left ventricular biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial glucose transporters and glycolytic metabolism during ischemia in hyperglycemic diabetic swine. 828 77

The in vivo glucose uptake and the levels of two glucose transporter proteins (GLUT1 and GLUT4) were measured in heart and in various types of skeletal muscle from streptozotocin-diabetic rats. Diabetes (12-16 weeks) reduced the in vivo glucose uptake (glucose metabolic index, GMI), and the levels of GLUT1 and GLUT4 in heart by 75%, 60% and 70%, respectively. In diaphragm consisting of approximately equal amounts of type I (slow-contracting oxidative), IIa (fast-contracting oxidative) and IIb (fast-contracting glycolytic) fibers, GMI and GLUT4 levels were reduced by 60% and 40%, respectively, with no change in GLUT1 levels. In muscle consisting mainly of type I fibers (e.g., m. soleus), GMI and GLUT4 levels were reduced by 60% and 30%, respectively, whereas GLUT1 levels were unaltered. In mixed-type muscle consisting of type IIa and IIb fibers (e.g., m. plantaris and red part of m. gastrocnemius), GMI and GLUT1 levels were unchanged, whereas GLUT4 levels were decreased by 45%. In contrast, GMI was increased by 100% in type IIb fibers (e.g., the white part of m. gastrocnemius), probably reflecting the 4-fold increase in blood glucose levels, whereas GLUT4 levels were lowered by 55% with no change in GLUT1 levels. These data demonstrate a marked difference in the response of in vivo glucose uptake to long-term hypoinsulinemia between oxidative (type I) and glycolytic (type IIb) fibers. Furthermore, in contrast to the GLUT4, GLUT1 levels are regulated differentially in heart and skeletal muscle in response to streptozotocin-induced diabetes.
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PMID:In vivo glucose uptake and glucose transporter proteins GLUT1 and GLUT4 in heart and various types of skeletal muscle from streptozotocin-diabetic rats. 831 74

Whereas adipocytes normally play an important role as a major site for systemic energy homeostasis, adipocyte function is markedly altered in disorders such as diabetes. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on expression of glucose transporters GLUT1 and GLUT4 in 3T3-F442A cells. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (1 microM) and insulin (1 microgram/ml) resulted in nearly 100% differentiation of cells to lipid-accumulating adipocytes, and such adipocytes showed a markedly increased capacity for glucose uptake. Analysis of messenger RNA transcripts encoding GLUT1 and GLUT4 glucose transporters over the 7-day differentiation period indicated time-dependent increases in abundance of each type that were maximal at more than 5-fold with the combined presence of insulin and pioglitazone. In accord, GLUT1 and GLUT4 protein levels also increased to maximal levels of 10-fold and 7-fold, respectively, over those in undifferentiated preadipocytes. Increased messenger RNA half-lives from 2.2 to greater than 24 h for GLUT1 and from 1.2 to greater than 24 h for GLUT4 correlated with this induced adipocyte differentiation. Taken together, these findings indicated that pioglitazone markedly enhanced expression of cellular glucose transporters, and the mechanism for this action was mainly stabilization of transporter messenger RNA transcripts. Such increased expression of glucose transporters in adipocytes establishes the cells in a state active for glucose uptake, thus ultimately facilitating storage and metabolism as well.
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PMID:The antidiabetic agent pioglitazone increases expression of glucose transporters in 3T3-F442A cells by increasing messenger ribonucleic acid transcript stability. 831 81

Large decreases in insulin-responsive glucose transport occur in rat adipocytes maintained in culture for 24 h in the continuous presence of insulin. After 24 h in culture, an acute treatment with insulin increased 3-O-methyl-D-glucose transport by only approximately fivefold. In chronically insulin-treated cells, the transport activity was more severely reduced. The transport activity was only approximately twofold higher than in basal cells. To attribute changes in transport to alterations in cell surface transporters, we labeled the cell surface GLUT4 and GLUT1 transporters with the impermeant photoaffinity label 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis(D-mannos -4-yloxy)-2- propylamine. Cell surface labeling was compared with the labeling obtained in digitonin-permeabilized cells where the normally impermeant reagent had access to the total cellular pool of transporters. Labeling showed that in basal cells the proportions of GLUT4 and GLUT1 at the cell surface were 20 and 22% of the total. After an acute treatment with insulin, the proportions of GLUT4 and GLUT1 at the cell surface were increased to 49 and 37% of the total, respectively. The chronic insulin treatment was associated with a very low proportion of GLUT4 (25% of the total) at the cell surface. The downregulation of GLUT4 observed after chronic insulin treatment was alleviated by metformin, and the proportion of GLUT4 at the cell surface was maintained at 60% of the total.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Aug
PMID:Metformin blocks downregulation of cell surface GLUT4 caused by chronic insulin treatment of rat adipocytes. 832 47

The obese diabetic SHR/N-cp rat is a newly developed strain that inherits obesity as an autosomal recessive trait. These rats display early-onset hyperinsulinemia and hyperglycemia, which are hallmarks of type II diabetes. This study was undertaken to determine the expression and the subcellular distribution of the GLUT1 and GLUT4 glucose transporters in skeletal muscle of obese diabetic SHR rats. D-glucose-protectable cytochalasin-B binding to subcellular membrane fractions of hindlimb muscles was used to determine glucose transporter number. GLUT1 and GLUT4 glucose transporter isotypes were detected using antibodies to the COOH-terminal region of the GLUT1 and GLUT4 proteins. Glucose transporter number was significantly lower (-40%) in crude unfractionated membranes of obese diabetic SHR than of lean SHR muscles. When crude membranes were fractionated to separate plasma membranes and the intracellular membranes containing glucose transporters, the number of cytochalasin-B binding sites was found to be markedly lower (-50%) in intracellular membranes and slightly but not significantly reduced (-20%) in plasma membranes of muscle from obese diabetic SHR compared with lean SHR rats. Western blot analysis revealed that a lower GLUT4 protein abundance (-40%) accounts for the reduced glucose transporter number in intracellular membranes of obese diabetic SHR compared with lean SHR muscles. GLUT4 protein content was also reduced by 50% in plasma membranes from obese SHR muscles relative to lean rat muscles.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Aug
PMID:Differential regulation of GLUT1 and GLUT4 glucose transporters in skeletal muscle of a new model of type II diabetes. The obese SHR/N-cp rat. 832 52


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