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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of target cells to insulin results in the formation of ligand receptor complexes on the cell surface and their subsequent internalization into the endosomal apparatus. A current view is that endocytosis of the insulin receptor (IR) kinase results in its rapid deactivation and sorting of the IR back to the cell surface or to late endocytic compartments. We report herein that, in skeletal muscle, in vivo stimulation with insulin induced a rapid internalization of the IR to an insulin-sensitive GLUT4-enriched intracellular membrane fraction. After 30 min of stimulation, IR content and tyrosine phosphorylation were increased by three and nine times in that fraction, respectively, compared with unstimulated muscles. In vitro autophosphorylation assays revealed that the kinase activity of internalized IRs was markedly augmented (eight to nine times) by insulin. In marked contrast with hepatic endosomes or adipocyte low-density microsomes, no IR tyrosine dephosphorylation activity was observed in GLUT4-enriched vesicles isolated from skeletal muscle. The activated IR was recovered in immunopurified GLUT4 vesicles after insulin stimulation. Insulin also increased tyrosine-phosphorylated insulin receptor substrate 1 and phosphatidylinositol 3-kinase adapter (p85) subunit contents in the intracellular membrane fraction, but these signaling molecules were not directly associated with GLUT4 vesicles. These results show that, in skeletal muscle, the activated IR reaches a GLUT4-enriched compartment where its activity is apparently sustained. We propose that compartmentalization of activated IRs to GLUT4 vesicles may play a role in sustaining insulin signaling at this locus in skeletal muscle.
Diabetes 2000 Nov
PMID:Sustained activation of insulin receptors internalized in GLUT4 vesicles of insulin-stimulated skeletal muscle. 1107 43

Resistance to the normal action of insulin contributes to the pathogenesis of a number of common human disorders, Type II (non-insulin-dependent) diabetes mellitus. This review is focused on current understanding of the molecular mechanisms regulating insulin action and the factors contributing to insulin resistance in skeletal muscle. Since skeletal muscle is considered the major organ responsible for glucose uptake under insulin-stimulated conditions, defects in this target tissue are likely to contribute to metabolic disregulation in Type II diabetes mellitus. Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway is associated with reduced insulin-stimulated glucose transport activity in skeletal muscle from Type II diabetic patients. Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) translocation and can be activated in skeletal muscle by two separate and distinct signaling pathways; one stimulated by insulin and the second by muscle contractions. Level of physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity. Understanding the molecular mechanism for the activation of signal transduction pathways by which insulin and muscle contraction increase glucose transport will provide a link to defining new strategies to enhance glucose metabolism in the diabetic patient.
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PMID:Skeletal muscle and insulin sensitivity: pathophysiological alterations. 1117 54

Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1. After phosphorylation by activated receptors, these intracellular signaling molecules recruit various downstream effector pathways including phosphatidylinositol 3-kinase and Grb2. Ablation of the IRS-2 gene produces a diabetic phenotype; mice lacking IRS-2 display peripheral insulin resistance and beta-cell dysfunction characterized by a 50% reduction in beta-cell mass. In contrast, deletion of IRS-1 retards somatic growth and enhances beta-cell mass. IRS1-/- mice are 50% smaller than controls but have a twofold increase in pancreatic beta-cell mass. Thus, observations from these recently developed animal models implicate the IRS signaling systems in the response of classical insulin target tissues, and they suggest a critical role for these proteins in the regulation of beta-cell function. In humans, type 2 diabetes generally occurs when insulin-secretory reserves fail to compensate for peripheral insulin resistance. Study and identification of the signals downstream of IRS proteins in beta-cells may provide unique insights into the compensatory mechanisms by which these cells respond to insulin resistance. Therefore, the intent of this review is to summarize recent observations regarding the regulation of beta-cell function by members of the IRS protein family.
Diabetes 2001 Feb
PMID:IRS proteins and beta-cell function. 1127 76

Insulin resistance, an important feature of type 2 diabetes, is manifested as attenuated insulin receptor (IR) signaling in response to insulin binding. A drug that promotes the initiation of IR signaling by enhancing IR autophosphorylation should, therefore, be useful for treating type 2 diabetes. This report describes the effect of a small molecule IR sensitizer, TLK16998, on IR signaling. This compound activated the tyrosine kinase domain of the IR beta-subunit at concentrations of 1 micromol/l or less but had no effect on insulin binding to the IR alpha-subunit even at much higher concentrations. TLK16998 alone had no effect on IR signaling in mouse 3T3-L1 adipocytes but, at concentrations as low as 3.2 micromol/l, enhanced the effects of insulin on the phosphorylation of the IR beta-subunit and IR substrate 1, and on the amount of phosphatidylinositol 3-kinase that coimmunoprecipitated with IRS-1. Phosphopeptide mapping revealed that the effect of TLK16998 on the IR was associated with increased tyrosine phosphorylation of the activation loop of the beta-subunit tyrosine kinase domain. TLK16998 also increased the potency of insulin in stimulating 2-deoxy-D-glucose uptake in 3T3-L1 adipocytes, with a detectable effect at 8 micromol/l and a 10-fold increase at 40 micromol/l. In contrast, only small effects were observed on IGF-1-stimulated 2-deoxy-D-glucose uptake. In diabetic mice, TLK16998, at a dose of 10 mg/kg, lowered blood glucose levels for up to 6 h. These results suggest, therefore, that small nonpeptide molecules that directly sensitize the IR may be useful for treating type 2 diabetes.
Diabetes 2001 Apr
PMID:A novel small molecule that directly sensitizes the insulin receptor in vitro and in vivo. 1128 48

When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. To better understand the effects of the Q allele on IR function and downstream signaling, we transfected cultured cells with cDNAs for either the Q or the K alleles. In human MCF-7 cells, the Q allele was severalfold more effective (P < 0.05-0.01) than the K allele in reducing insulin stimulation of IR autophosphorylation, insulin receptor substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis, and cell proliferation. Similar data on IR autophosphorylation inhibition were also obtained in mouse R-/hIR and human HEK 293 cell lines. In transfected MCF-7 cells, 125I-labeled insulin binding and IR content were unchanged, and PC-1 overexpression did not influence IGF-1 stimulation of IGF-1 receptor autophosphorylation. Both the Q and K alleles directly interacted with the IR, as documented by coimmunoprecipitation assays. This interaction was greater for the Q allele than for the K allele (P < 0.01), suggesting that direct PC-1-IR interactions are important for the PC-1 inhibitory effect on insulin signaling. In conclusion, the Q allele has stronger inhibitory activity on IR function and insulin action than the more common K allele, and this is likely a consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the IR.
Diabetes 2001 Apr
PMID:The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121). 1128 49

Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r = -0.63, P = 0.02). Insulin (+/-1,000 pmol/l) induced a two- to threefold increase (P < 0.05) in hexokinase II, p85alphaPI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provides evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patients.
Diabetes 2001 May
PMID:Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. 1133 18

In many patients with human immunodeficiency virus (HIV) treated with HIV protease inhibitors, a complication develops that resembles abdominal obesity syndrome, with insulin resistance and glucose intolerance that, in some cases, progresses to diabetes. In this study, we tested the hypothesis that indinavir, an HIV-protease inhibitor, directly induces insulin resistance of glucose transport in skeletal muscle. Rat epitrochlearis muscles were incubated with a maximally effective insulin concentration (12 nmol/l) and 0, 1, 5, 20, or 40 micromol/l indinavir for 4 h. In control muscles, insulin increased 3-O-[(3)H]methyl-D-glucose (3MG) transport from 0.15 +/- 0.03 to 1.10 +/- 0.05 micromol. ml(-)(1). 10 min(-)(1). Incubation of muscles with 5 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 40%, whereas 20 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 58%. Indinavir induced a similar reduction in maximally insulin-stimulated 3MG transport in the soleus muscle. The increase in glucose transport activity induced by stimulating epitrochlearis muscles to contract was also markedly reduced by indinavir. The insulin-stimulated increase in cell-surface GLUT4, assessed using the 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-[2-(3)H] (D-mannose-4-yloxy)-2-propylamine exofacial photolabeling technique, was reduced by approximately 70% in the presence of 20 micromol/l indinavir. Insulin stimulation of phosphatidylinositol 3-kinase activity and phosphorylation of protein kinase B were not decreased by indinavir. These results provide evidence that indinavir inhibits the translocation or intrinsic activity of GLUT4 rather than insulin signaling.
Diabetes 2001 Jun
PMID:The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle. 1137 41

The present work analyzes the expression of insulin receptors and theirs related intracellular signaling molecules in partially hepatectomized-diabetic rats. Insulin binding through Scatchard analysis was studied using isolated hepatocytes of Control (Sham-operated), Hepatectomized, Diabetic and Diabetic-Hepatectomized male Wistar rats. In a set of in vivo experiments, the levels of alpha subunit of the insulin receptor, the insulin receptor substrate 1 (IRS-1) and the phosphatidylinositol 3-kinase (PI3K) were determined. [3H]-thymidine incorporation into DNA 24 or 48 h after surgery was assessed in all the experimental groups. Scatchard analysis showed that insulin receptor number was increased in diabetic and in hepatectomized rats in the same extent (64%, with respect to Controls). Diabetic-hepatectomized rats showed a dramatic increase of the receptor concentration (400%) and on the affinity constant (532%). Besides, the insulin receptor expression was increased in the treated groups, being the higher values those of the diabetic-hepatectomized rats. IRS-1 and PI3K showed similar increases. DNA synthesis was not impaired by the diabetes state. In conclusion, increased expression of IR and IRS-1 leads to increased association of PI3K in vivo in diabetic regenerating rats. The enhancement of this pathway may reveal an insulin hyperresponsiveness in these animals.
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PMID:Insulin hyperresponsiveness in partially hepatectomized diabetic rats. 1138 93

This review will provide insight on potential intracellular signalling mechanisms by which insulin and exercise/contraction increases glucose metabolism and gene expression. Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) and can be activated in skeletal muscle by two separate and distinct signalling pathways; one stimulated by insulin and the second by muscle contractions. Impaired insulin action on whole body glucose uptake is a hallmark feature of type II (non-insulin-dependent) diabetes mellitus. Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway are associated with reduced insulin-stimulated glucose transporter 4 translocation and glucose transport activity in skeletal muscle from type II diabetic patients. Studies performed using glucose transporter 4-null mice show that this glucose transporter isoform plays a major role in mediating exercise-stimulated glucose uptake in skeletal muscle. Level of physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity. Exercise training leads to alterations in expression and activity of key proteins involved in insulin signal transduction. These changes may be related to increased signal transduction through the mitogen-activated protein kinase (MAPK) signalling cascades. Because MAPK is associated with increased transcriptional activity, these signalling cascades are candidates for these exercise-induced changes in protein expression. Understanding the molecular mechanism for the activation of signal transduction pathways will provide a link for defining new strategies to enhance glucose metabolism and improve health in the general population.
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PMID:Intracellular mechanisms underlying increases in glucose uptake in response to insulin or exercise in skeletal muscle. 1141 37

1. Adenosine transport was measured in human cultured umbilical artery smooth muscle cells, isolated from non-diabetic or gestational diabetic pregnancies, under basal conditions and after pretreatment in vitro with insulin. 2. Adenosine transport in non-diabetic smooth muscle cells was significantly increased by insulin (half-maximal stimulation at 0.33 +/- 0.02 nM, 8 h) and characterized by a higher maximal rate (V(max)) for nitrobenzylthioinosine (NBMPR)-sensitive (es) saturable nucleoside transport (17 +/- 5 vs. 52 +/- 12 pmol (microg protein)(-1) min(-1), control vs. insulin, respectively) and maximal binding sites (B(max)) for [(3)H]NBMPR (0.66 +/- 0.07 vs. 1.1 +/- 0.1 fmol (microg protein)(-1), control vs. insulin, respectively), with no significant changes in Michaelis-Menten (K(m)) and dissociation (K(d)) constants. 3. In contrast, in smooth muscle cells from diabetic pregnancies, where the values of V(max) for adenosine transport (59 +/- 4 pmol (microg protein)(-1) min(-1)) and B(max) for [(3)H]NBMPR binding (1.62 +/- 0.16 fmol (microg protein)(-1)) were significantly elevated by comparison with non-diabetic cells, insulin treatment (1 nM, 8 h) reduced the V(max) for adenosine transport and B(max) for [(3)H]NBMPR binding to levels detected in non-diabetic cells. 4. In non-diabetic cells, the stimulatory effect of insulin on adenosine transport was mimicked by dibutyryl cGMP (100 nM) and reduced by inhibitors of phosphatidylinositol 3-kinase (10 nM wortmannin), nitric oxide synthase (100 microM N (G)-nitro-L-arginine methyl ester, L-NAME) or protein synthesis (1 microM cycloheximide), whereas inhibition of adenylyl cyclase (100 microM SQ-22536) had no effect. 5. Wortmannin or SQ-22536, but not L-NAME or cycloheximide, attenuated the inhibitory action of insulin on the diabetes-induced stimulation of adenosine transport. 6. Protein levels of inducible NO synthase (iNOS) were similar in non-diabetic and diabetic cells, but were increased by insulin (1 nM, 8 h) only in non-diabetic smooth muscle cells. 7. Our results suggest that adenosine transport via the es nucleoside transporter is modulated differentially by insulin in either cell type. Insulin increased adenosine transport in non-diabetic cells via NO and cGMP, but inhibited the diabetes-elevated adenosine transport via activation of adenylyl cyclase, suggesting that the biological actions of adenosine may be altered under conditions of sustained hyperglycaemia in uncontrolled diabetes.
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PMID:Modulation of adenosine transport by insulin in human umbilical artery smooth muscle cells from normal or gestational diabetic pregnancies. 1143 5


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