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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IGF-I receptor (IGFR) content and its prognostic significance were evaluated in human breast cancer specimens using a sensitive and specific radioimmunoassay (V. Pezzino et al., Metabolism, 40: 861, 1991). The prognostic significance of IGFR expression was investigated by two different approaches: (a) detectable IGFR content was measured in 82% of specimens in a consecutive series of 184 human breast cancers and in 32% of 19 normal breast tissues. The average IGFR content in breast cancer was nearly 10-fold higher than the value observed in normal breast tissue (7.6 +/- 0.8 versus 0.8 +/- 0.1 ng/0.1 mg protein, mean +/- SEM; P < 0.001). IGFR content was positively correlated with estrogen (ER) and insulin receptor content (r = 0.269 and 0.515, respectively, Pearson correlation) but not with progesterone receptors (PR). No significant correlation was observed between IGFR content and a variety of tumor parameters (tumor size, lymph node involvement, grade) and host characteristics (age, body mass index, menopausal status); (b) IGFR content was measured in a noncontinuous series of 265 primary breast cancer specimens subdivided into 136 high-risk and 129 low-risk specimens on the basis of being either negative (ER-/PR-/aneuploid/high S-phase) or positive (ER+/PR+/diploid/low S-phase) for four well-established prognostic factors. IGFR levels were significantly higher in the low-risk group (6.4 +/- 0.4 ng/0.1 mg protein, mean +/- SEM) than in the high-risk group (3.6 +/- 0.5; P < 0.0001, Wilcoxon sum rank test). In summary, our data indicate that there is an elevated IGFR content in most human breast cancers compared with normal breast tissue and that an elevated IGFR content is a favorable prognostic indicator.
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PMID:Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. 833 84

Administration of exogenous insulin during an intravenous glucose tolerance test allows the use of the minimal model technique to determine the insulin sensitivity index in subjects with reduced endogenous insulin responses. To study the effect of different insulin administration protocols, we performed three intravenous glucose tolerance tests in each of seven obese subjects (age, 20-41 yr; body mass index, 30-43 kg/m2). Three different insulin administration protocols were used: a low-dose (0.025 U/kg) infusion given over 10 min, a low-dose (0.025 U/kg) bolus injection, and a high-dose (0.050 U/kg) bolus injection, resulting in peak insulin concentrations of 1,167 +/- 156, 3,014 +/- 483, and 6,596 +/- 547 pM, respectively. The mean insulin sensitivity index was 4.80 +/- 0.95 x 10(-5), 3.56 +/- 0.53 x 10(-5), and 2.42 +/- 0.40 x 10(-5) min-1/pM respectively (chi +/- SEM; P = 0.01). The association of higher peak insulin concentrations with lower measured insulin sensitivity values suggested the presence of a saturable process. Because results were not consistent with the known saturation characteristics of insulin action on tissue, a second saturable site involving the transport of insulin from plasma to interstitium was introduced, leading to a calculated Km of 807 +/- 165 pM for this site, a value near the 1/Kd of the insulin receptor. Thus, the kinetics of insulin action in humans in these studies is consistent with two saturable sites, and supports the hypothesis for transport of insulin to the interstitial space. Saturation may have an impact on minimal model results when high doses of exogenous insulin are given as a bolus, but can be minimized by infusing insulin at a low dose.
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PMID:The effect of insulin dose on the measurement of insulin sensitivity by the minimal model technique. Evidence for saturable insulin transport in humans. 856 73

To measure possible changes in basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from insulin-resistant individuals, soluble and particulate muscle fractions were prepared from biopsies taken before and after a 3-h hyperinsulinaemic euglycaemic clamp in eight non-insulin-dependent diabetic (NIDDM) patients and nine control subjects. We used a sensitive sandwich-immunofluorescence assay and the human insulin receptor as the substrate. PTPase activity was expressed as percentage of dephosphorylation of phosphotyrosyl-residues in immobilized insulin receptors per 2 h incubation time per 83 micrograms and 19 micrograms muscle fraction protein (soluble and particulate fraction, respectively). In the diabetic soluble muscle fractions, the basal PTPase activity was decreased compared with that of control subjects (11.5 +/- 5.5 vs 27.5 +/- 3.3, p < 0.04, mean +/- SEM). In the particulate muscle fractions from the control subjects, PTPase activity was increased after 3 h hyperinsulinaemia (20.0 +/- 3.2 vs 30.2 +/- 3.6, p < 0.03) and in the corresponding soluble fractions PTPase activity seemed decreased (27.5 +/- 3.3 vs 19.9 +/- 5.9, NS). No effect of insulin on PTPase activity was found in NIDDM patients (25.1 +/- 4.1 vs 27.2 +/- 5.2, 11.5 +/- 5.5 vs 15.1 +/- 4.5 [particulate and soluble fractions], NS). In conclusion, we found that the basal PTPase activity in soluble muscle fractions was decreased in NIDDM patients; furthermore, insulin stimulation was unable to increase PTPase activities in the particulate fractions, as opposed to the effect of insulin in control subjects.
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PMID:Altered basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from NIDDM patients compared with control subjects. 889 9

In cells, insulin stimulates autophosphorylation of the insulin receptor on tyrosine and its phosphorylation on serine and threonine by poorly characterized kinases. Here we describe methods for the purification of an insulin-stimulated insulin receptor serine kinase from human placenta and rat liver by sequential chromatography of solubilized membranes on wheat germ agglutinin-agarose, Mono Q, phenyl-Superose, and Superose 12. On silver-stained SDS-polyacrylamide gels, the resulting kinase was homogeneous (human) or near-homogeneous (rat) and had an apparent M(r) of 40000. The apparent M(r) determined by gel filtration was also 40000, suggesting that the kinase exists as a monomer. The kinase could be reconstituted back to the insulin receptor stripped of the kinase to yield a high stoichiometry of serine phosphorylation of the insulin receptor in the presence of insulin (0.75 +/- 0.15 mol/mol of beta-subunit, mean +/- SEM, n = 3). The activity of the reconstituted kinase toward the insulin receptor was insulin-regulated, being stimulated > 5-fold by insulin. Insulin increased the catalytic activity of the reconstituted kinase. The purified kinase specifically phosphorylated serine 1078 of the insulin receptor, a major site of insulin-stimulated serine phosphorylation in vivo, showing that the purified kinase phosphorylated a physiologically relevant site on the insulin receptor. Phosphorylation of serine 1078 of the insulin receptor to high stoichiometry by the kinase did not affect insulin-stimulated exogenous protein tyrosine kinase activity of the insulin receptor. Similarly, insulin receptor phosphorylated with or without the purified kinase exhibited the same levels of tyrosine autophosphorylation and of the tyrosine kinase-activating tris-phosphorylated kinase domain species. Properties of the kinase distinguished it from kinases known to act on the insulin receptor and other kinases that are insulin-stimulated, indicating that the kinase is a novel entity. The serine kinase underwent autophosphorylation on serine and immunoprecipitated with the insulin receptor. The availability of the purified kinase should facilitate cloning of the kinase, determination of the mechanism of activation of the kinase, and study of the wider potential role of the kinase in insulin signalling, and the ability to be able to phosphorylate serine 1078 to high stoichiometry should facilitate further studies into the function of this serine phosphorylation site.
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PMID:Purification and characterization of an insulin-stimulated insulin receptor serine kinase. 891 21

This study examined whether the treatment of streptozotocin (STZ)-diabetic rats with gliclazide (5 mg/kg body weight twice daily orally) increases muscle glucose uptake. Rats were treated (group G, n = 10) or untreated (group D, n = 11) for 12 days. Normal rats served as controls (group C, n = 11). At the end of the treatment, both basal and insulin-stimulated glucose uptake by the perfused hindquarters were measured. In gastrocnemious muscles, the protein content of GLUT4 and the insulin binding and tyrosine kinase activity of partially purified solubilized insulin receptors were measured. Group G had a lower mean glycemic value during the treatment period than group D (mean +/- SEM, 17 +/- 0.6 v 19.7 +/- 0.5 mmol/L, P < .05), without differences in serum insulin levels. Basal glucose uptake by the hindquarters was significantly higher in group G versus group D (2.8 +/- 0.3 v 1.3 +/- 0.2 mumol/g/h, P < .05), and was not different versus group C (3.6 +/- 0.2 mumol/g/h). Insulin-stimulated glucose uptake was higher (P < .05) in group C compared with the two groups of diabetic rats. Glucose uptake at 10(-7) mol/L insulin was higher in group G than in group D (9.2 +/- 0.6 v 7.0 +/- 0.6 mumol/g/h, P < .05). Both insulin binding and tyrosine kinase activity were similar in muscle insulin receptors from both groups of diabetic rats. The GLUT4 protein content was higher in group G than in group D (95 +/- 10 v 57 +/- 7 arbitrary units [AU]/microgram protein, P < .05) and similar to that of group C (113 +/- 13 AU/microgram protein). In conclusion, gliclazide has a glucose-lowering effect in STZ-diabetic rats that could be attributed to an increase in muscle glucose clearance by a post-insulin receptor mechanism, probably related to a normalization of GLUT4 content.
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PMID:Gliclazide treatment of streptozotocin diabetic rats restores GLUT4 protein content and basal glucose uptake in skeletal muscle. 943 52

Protein tyrosine phosphatases (PTPs) are required for the dephosphorylation of the insulin receptor (IR) and its initial cellular substrates, and it has recently been reported that PTP-1B may play a role in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus (DM). We therefore determined the amount and activity of PTP-1B in abdominal adipose tissue obtained from lean nondiabetic subjects (lean control (LC)), obese nondiabetic subjects (obese control (OC)), and subjects with both type 2 DM (DM2) and obesity (obese diabetic (OD)). PTP-1B protein levels were 3-fold higher in OC than in LC (1444 +/- 195 U vs 500 +/- 146 U (mean +/- SEM), P < .015), while OD exhibited a 5.5-fold increase (2728 +/- 286 U, P < .01). PTP activity was assayed by measuring the dephosphorylating activity toward a phosphorus 32-labeled synthetic dodecapeptide. In contrast to the increased PTP-1B protein levels, PTP-1B activity per unit of PTP-1B protein was markedly reduced, by 71% and 88% in OC and OD, respectively. Non-PTP-1B tyrosine phosphatase activity was comparable in all three groups. Similar results were obtained when PTP-1B activity was measured against intact human IR. A significant correlation was found between body mass index (BMI) and PTP-1B level (r = 0.672, P < .02), whereas BMI and PTP-1B activity per unit of PTP-1B showed a strong inverse correlation (r = -0.801, P < .002). These data suggest that the insulin resistance of obesity and DM2 is characterized by the increased expression of a catalytically impaired PTP-1B in adipose tissue and that impaired PTP-1B activity may be pathogenic for insulin resistance in these conditions.
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PMID:Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus. 1044 21

PC-1 is a membrane glycoprotein that impairs insulin receptor function. Its K121Q polymorphism is a genetic determinant of insulin resistance. We investigated whether the PC-1 gene modulates insulin sensitivity independently of weight status (i.e. both in nonobese and obese individuals). Nondiabetic subjects [164 males, 267 females; age, 37 +/- 0.6 yr, mean +/- SEM; body mass index (BMI), 32.7 +/- 0.5 kg/m(2)], who were subdivided into 220 nonobese (BMI < or = 29.9) and 211 obese, were studied. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P < 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. Insulin sensitivity, measured by euglycemic clamp in a representative subgroup of 131 of 431 randomly selected subjects, progressively decreased (P < 0.001) from nonobese K121K [n = 61; glucose disposal (M) = 34.9 +/- 1.1 micromol/kg/min] to nonobese Q (n = 21; M = 29.9 +/- 2.0), obese K121K (n = 31, M = 18.5 +/- 1.2), and obese Q (n = 18, M = 15.5 +/- 1.2) carriers. The K121Q polymorphism was correlated with insulin sensitivity independently (P < 0.05) of BMI, gender, age, and waist circumference. In conclusion, the Q121 PC-1 variant and obesity have independent and additive effects in causing insulin resistance.
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PMID:The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance. 1173 59

This study investigates the molecular mechanisms underlying the blood glucose-lowering effect of a 2-day very low-energy diet (VLED, 1883 kJ/d) in 12 obese (body mass index, 36.3 +/- 1.0 kg/m2 [mean +/- SEM]) type 2 diabetic (HbA(1C) 7.3% +/- 0.4%) patients simultaneously taken off all glucose-lowering therapy, including insulin. Endogenous glucose production (EGP) and glucose disposal ([6,6-2H2]-glucose) were measured before and after the VLED in basal and hyperinsulinemic (40 mU/m2 per minute) euglycemic conditions. Insulin signaling and expression of GLUT-4, FAT/CD36, and triglycerides were assessed in muscle biopsies, obtained before the clamp and after 30 minutes of hyperinsulinemia. Fasting plasma glucose decreased from 11.3 +/- 1.3 to 10.3 +/- 1.0 mmol/L because of a decreased basal EGP (14.2 +/- 1.0 to 11.9 +/- 0.7 micromol/kg per minute, P = .009). Insulin-stimulated glucose disposal did not change. No diet effect was found on the expression of the insulin receptor and insulin receptor substrate-1 or on phosphatidylinositol 3'-kinase activity, or on FAT/CD36 expression pattern, GLUT-4 translocation, or triglyceride distribution in either the basal or insulin-stimulated situation. Unexpectedly, basal PKB/Akt phosphorylation on T308 and S473 increased after the diet, at equal protein expression. In conclusion, a 2-day VLED lowers fasting plasma glucose via a decreased basal EGP without an effect on glucose disposal. Accordingly, no changes in activation of phosphatidylinositol 3'-kinase, triglyceride distribution, FAT/CD36 expression, and GLUT-4 translocation were found in skeletal muscle biopsies.
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PMID:Effect of a 2-day very low-energy diet on skeletal muscle insulin sensitivity in obese type 2 diabetic patients on insulin therapy. 1631 Nov 2

Previous genetic analysis has shown that dos/soc-1/Gab1 functions positively in receptor tyrosine kinase (RTK)-stimulated Ras/Map kinase signaling through the recruitment of csw/ptp-2/Shp2. Using sensitized assays in Caenorhabditis elegans for let-23/Egfr and daf-2/InsR (insulin receptor-like) signaling, it is shown that soc-1/Gab1 inhibits phospholipase C-gamma (PLCgamma) and phosphatidylinositol 3'-kinase (PI3K)-mediated signaling. Furthermore, as well as stimulating Ras/Map kinase signaling, soc-1/Gab1 stimulates a poorly defined signaling pathway that represses class 2 daf-2 phenotypes. In addition, it is shown that SOC-1 binds the C-terminal SH3 domain of SEM-5. This binding is likely to be functional as the sem-5(n2195)G201R mutation, which disrupts SOC-1 binding, behaves in a qualitatively similar manner to a soc-1 null allele in all assays for let-23/Egfr and daf-2/InsR signaling that were examined. Further genetic analysis suggests that ptp-2/Shp2 mediates the negative function of soc-1/Gab1 in PI3K-mediated signaling, as well as the positive function in Ras/Map kinase signaling. Other effectors of soc-1/Gab1 are likely to inhibit PLCgamma-mediated signaling and stimulate the poorly defined signaling pathway that represses class 2 daf-2 phenotypes. Thus, the recruitment of soc-1/Gab1, and its effectors, into the RTK-signaling complex modifies the cellular response by enhancing Ras/Map kinase signaling while inhibiting PI3K and PLCgamma-mediated signaling.
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PMID:The adaptor protein soc-1/Gab1 modifies growth factor receptor output in Caenorhabditis elegans. 1654

Limited research with rodents and humans suggests that oral ingestion of pinitol (3- O-methyl- D- CHIRO-inositol) might positively influence glucose tolerance. This double-blinded, placebo-controlled, and cross-over study assessed the effects of acute pinitol supplementation on plasma pinitol concentration, glucose tolerance, insulin sensitivity, and activation of the skeletal muscle insulin receptor. Fifteen older, nondiabetic subjects (62+/-1 years, mean+/-SEM) completed four, 1-day trials. Subjects consumed a non-nutritive beverage with nothing (placebo) or 1,000 mg pinitol. Sixty minutes later, the subjects consumed beverages that were either energy- and carbohydrate-free (Sham) or contained 75 g glucose (OGTT). Blood samples were collected frequently over the 240-min testing period. For the OGTT trials only, vastus lateralis samples were obtained before the placebo and pinitol supplementation and 60 min after consuming the 75 g glucose beverage. Plasma pinitol concentration increased and was maintained for 240 min. Pinitol did not influence the fasting state and 180-min area under the curves for plasma glucose and insulin during the Sham and OGTT trials or hepatic (placebo 0.83+/-0.08; pinitol 0.80+/-0.08) and whole-body (placebo 6.10+/-0.54; pinitol 6.22+/-0.52) insulin sensitivities. Activation of the muscle insulin receptor was increased by 140% with glucose ingestion (Pre 0.62+/-0.12; Post 1.49+/-0.35), but pinitol did not influence this response. These results show that the pinitol supplement was quickly absorbed, but did not acutely influence indices of whole-body glucose tolerance and insulin sensitivity, or the activation of the skeletal muscle insulin receptor in older, nondiabetic humans.
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PMID:Effects of acute pinitol supplementation on plasma pinitol concentration, whole body glucose tolerance, and activation of the skeletal muscle insulin receptor in older humans. 1922 77


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