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PubMed2005

The prevalence of peanut sensitization and the association to pollen sensitization in a cohort of unselected adolescents--The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS).

In the last decade an increased occurrence of peanut hypersensitivity and severe anaphylactic reactions to peanut have been reported. However, few prevalence studies have been performed in unselected populations. This study evaluated the point prevalence of peanut hypersensitivity in Danish adolescents. The point prevalence of peanut allergy confirmed by oral challenge was estimated to 0.5%. The number of adolescents sensitized to peanut by specific immunoglobulin E (IgE) (CAP FEIA) and skin prick test (SPT) were higher (5.8% resp. 3.4%). In adolescents without clinically relevant peanut sensitization most cases were sensitized to grass pollen and the IgE class for grass was higher than for peanut. A correlation between peanut and pollen (grass) sensitization is therefore plausible. Before a positive SPT or specific IgE measurement to peanut is considered clinically relevant in a patient, the case history should be evaluated together with examination for pollen sensitization.

Adolescent↗
PubMed1989

Sensitivity to the anticonvulsant effects of ethanol and pentobarbital in mouse lines genetically selected for ethanol sensitivity.

Mouse lines genetically selected for susceptibility [long sleep (LS)] or resistance [short sleep (SS)] to the acute hypnotic effects of ethanol were tested for sensitivity to maximal electroshock seizures. LS mice were slightly more sensitive than SS mice. Ethanol or pentobarbital pretreatment elevated seizure thresholds in both lines. LS and SS mice were approximately equally protected by ethanol, but LS mice were somewhat more protected than SS mice by pentobarbital. These studies do not provide evidence that sensitivity to the anticonvulsant effect of ethanol is mediated by substantially the same genes as those mediating sensitivity to EtOH's hypnotic effects. However, sensitivity to pentobarbital's anticonvulsant effects may be genetically correlated.

Animals↗
PubMed1994

Spectral sensitivities of short- and long-wavelength sensitive cone mechanisms in the frog retina.

ERG mass photoreceptor responses were recorded across the isolated, aspartate-perfused retina of the frog, Rana temporaria, in order to determine spectral sensitivities of cones. Cone responses were distinguished from rod responses by their faster kinetics, and responses from different cone types were isolated by selective background adaptation. Our main finding is that of a novel short-wavelength sensitive cone population peaking at about 431 nm. Further, we find that the sensitivity spectrum of the dominant long-wavelength sensitive cone population fully accounts for the most common type of photopic ganglion cell spectrum. Both can be described by a nomogram with lambda max = 562 nm. This resolves a long-standing apparent conflict between cone absorbance spectra and ganglion cell sensitivities. Including the 502 nm cones previously described by microspectrophotometry, the frog possesses a collection of cones that could support trichromatic photopic vision.

Animals↗
PubMed2005

Pharmacological telomerase inhibition can sensitize drug-resistant and drug-sensitive cells to chemotherapeutic treatment.

Effective strategies to reverse or prevent chemotherapeutic resistance are required before cancer therapies can be curative. Telomerase is the ribonucleoprotein responsible for de novo synthesis and maintenance of telomeres, and its activity is predominantly observed in cancer cells. The telomerase enzyme has been successfully inhibited or inactivated to sensitize cells to cellular stresses; however, no studies have determined yet the effect of combining a pharmacological inhibitor of telomerase catalysis and traditional chemotherapeutics for the treatment of drug-sensitive or drug-resistant cancers. Here, we describe the effect of 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small-molecule inhibitor of telomerase catalytic activity, on drug-resistant leukemia and breast cancer cells and their parental counterparts when treated in combination with chemotherapeutics. We observed that BIBR1532-treated cells show progressive telomere shortening, decreased proliferative capacity, and sensitization to chemotherapeutic treatment. These effects are telomere length-dependent, because cells insensitive to BIBR1532 or cells released from telomerase inhibition did not demonstrate changes in growth ability or drug sensitivity. Our novel observations suggest that pharmacological telomerase inhibition in combination therapy may be a valid strategy for the treatment of both drug-sensitive and drug-resistant cancers.

Aminobenzoates↗
PubMed2005

Genotypic characterization of the DNA polymerase and sensitivity to antiviral compounds of foscarnet-resistant herpes simplex virus type 1 (HSV-1) derived from a foscarnet-sensitive HSV-1 strain.

Foscarnet is widely used for the treatment of acyclovir-resistant herpesvirus infections, and foscarnet-resistant herpesvirus infections are a serious concern in immunocompromised patients. Twenty-seven single-plaque isolates of herpes simplex virus type 1 (HSV-1) resistant to foscarnet were selected from foscarnet- and acyclovir-sensitive HSV-1 strain TAS by exposure to foscarnet, and the DNA polymerase genes were analyzed. The sensitivities of these mutants to foscarnet, cidofovir, S2242, acyclovir, ganciclovir, and penciclovir were determined. A single amino acid substitution, double amino acid substitutions, and a combination of a single amino acid substitution with a deletion or insertion of amino acid residues in the viral DNA polymerase were demonstrated in 21, 4, and 2 isolates, respectively. Of the 27 isolates, an amino acid substitution of serine for asparagine at amino acid position 724 in the DNA polymerase (724 S-N) was detected in 8 isolates. An amino acid substitution in conserved region II was demonstrated in these eight isolates as well as four other isolates. The mutation in the DNA polymerase responsible for resistance to foscarnet was located between the pre-IV region and conserved region V, especially within conserved region II. All the isolates were sensitive or hypersensitive to cidofovir and ganciclovir. Seven, 5, and 15 of the 27 isolates were also sensitive to S2242, acyclovir, and penciclovir, respectively. Thus, most of the foscarnet-resistant HSV-1 isolates were sensitive or hypersensitive to cidofovir and ganciclovir.

Animals↗
PubMed1980

Temperature-sensitive mutants of influenza A virus: transfer of the two temperature-sensitive lesions in the Udorn/72-ts-1A2 virus to the A2Hong Kong/123/77 (H1N1) wild-type virus.

The influenza A/Udorn/72-ts-1A2 virus possesses temperature-sensitive mutations in the genes coding for the P1 and P3 polymerase proteins. It is being evaluated as a donor of its attenuating temperature-sensitive genes to produce recombinant live vaccine strains of epidemic variants of influenza A virus. Transfer of the P1 and P3 genes to two viruses within the H3N2 subtype of influenza A virus (i.e., the A/Victoria/3/75 and A/Alaska/6/77 viruses) conferred on each variant the following properties: (i) 37 degrees C shutoff temperature for plaque formation, (ii) almost complete restriction of viral replication in the lungs, (iii) a 100-fold restriction of viral replication in the nasal turbinates, and (iv) genetic stability after replication in hamsters. This study was undertaken to determine whether the transfer of the two ts-1A2 temperature-sensitive genes into a virus belonging to the H1N1 subtype (i.e., the A/Hong Kong/123/77 virus) would result in a restriction of replication in vitro and in vivo comparable to that observed with the previously studied H3N2 recombinant viruses in hamsters. This was found to be the case. In addition, infection of hamsters with the A/Hong Kong/77-ts-1A2 virus induced significant resistance to infection with wild-type A/Hong Kong/77 virus. Thus, the two ts-1A2 temperature-sensitive genes attenuated influenza A viruses belonging to two distinct subtypes to a specific and predictable level. An unexpected genetic interaction was observed between several A/Hong Kong/77-ts-1A2 segregants bearing the group 5 (P1) temperature-sensitive lesion. One interpretation of these results is that intracistronic complementation occurred between these segregants.

Animals↗
PubMed1998

Species-dependent phenotypes of replication-temperature-sensitive trfA mutants of plasmid RK2: a codon-neutral base substitution stimulates temperature sensitivity by leading to reduced levels of trfA expression.

TrfA is the only plasmid-encoded protein required for initiation of replication of the broad-host-range plasmid RK2. Here we describe the isolation of four trfA mutants temperature sensitive for replication in Pseudomonas aeruginosa. One of the mutations led to substitution of arginine 247 with cysteine. This mutant has been previously described to be temperature sensitive for replication, but poorly functional, in Escherichia coli. The remaining three mutants were identical, and each of them carried two mutations, one leading to substitution of arginine 163 with cysteine (mutation 163C) and the other a codon-neutral mutation changing the codon for glycine 235 from GGC to GGU (mutation 235). Neither of the two mutations caused a temperature-sensitive phenotype alone in P. aeruginosa, and the effect of the neutral mutation was caused by its ability to strongly reduce the trfA expression level. The double mutant and mutant 163C could not be stably maintained in E. coli, but mutant 235 could be established and, surprisingly, displayed a temperature-sensitive phenotype in this host. Mutation 235 strongly reduced the trfA expression level also in E. coli. The glycine 85 codon in trfA mRNA is GGU, and a change of this to GGC did not significantly affect expression. In addition, we found that wild-type trfA was expressed at much lower levels in E. coli than in P. aeruginosa, indicating that this level is a key parameter in the determination of the temperature-sensitive phenotypes in different species. The E. coli lacZ gene was translationally fused at the 3' end and internally in trfA, in both cases leading to elimination of the effect of mutation 235 on expression. We therefore propose that this mutation acts through an effect on mRNA structure or stability.

Amino Acid Substitution↗
PubMed2006

A novel approach to assess insulin sensitivity reveals no increased insulin sensitivity in mice with a dominant-negative mutant hepatocyte nuclear factor-1alpha.

In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index (SI) by this technique showed good correlation to SI from a regular intravenous glucose tolerance test (r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter (beta-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1alpha [RIP-DN HNF-1alpha (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that SI was the same in the two groups (0.78 +/- 0.21 x 10(-4) min.pmol(-1).l(-1) in WT vs. 0.60 +/- 0.11 in Tg; P = 0.45) as was the glucose elimination rate (P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-1alpha mice is not compensated with increased insulin sensitivity.

Animals↗
PubMed2006

Colonic irritation in the rat sensitizes urinary bladder afferents to mechanical and chemical stimuli: an afferent origin of pelvic organ cross-sensitization.

Chronic pelvic pain (CPP) disorders frequently overlap. We have demonstrated that acute and chronic colonic irritation can lead to neurogenic cystitis. We hypothesize that acute colonic irritation can sensitize urinary bladder afferents to mechanical and chemical stimuli. Single-unit afferent activity was recorded from fine filaments of the pelvic nerve in urethane-anesthetized Sprague-Dawley female rats before and 1 h after intracolonic administration of trinitrobenzenesulfonic acid (TNBS). Only spontaneously active afferents with receptive fields in the bladder and conduction velocities <2.5 m/s (unmyelinated C-fibers) were studied. Mechanical sensitivity was tested by bladder distension (BD) during saline infusion, whereas chemical sensitivity was tested with intravesical capsaicin, bradykinin, or substance P. Colonic irritation increased the resting firing rate of bladder afferents twofold (1.0 +/- 0.2 vs. 0.49 +/- 0.2 impulses/s, P < 0.05). Moreover, at low-pressure BDs (10-20 mmHg), a greater percentage of afferents exhibited increased activity following TNBS (73 vs. 27%, P < 0.05). Although the magnitude of the afferent response to BD was unchanged at low pressures, the response was greatly enhanced at pressures 30 mmHg and above (2.36 +/- 0.56 vs. 8.55 +/- 0.73 impulses/s, P < 0.05). Responses to capsaicin, bradykinin, and substance P were also significantly enhanced following TNBS, and all responses were blocked by bladder denervation. In rats, colonic irritation sensitizes urinary bladder afferents to noxious mechanical and chemical stimuli. Interruption of the neural input to the bladder minimized this effect, suggesting a local afferent pathway from the colon. Thus, the overlap of CPP disorders may be a consequence of pelvic afferent cross-sensitization.

Action Potentials↗
PubMed2006

gamma-Radiation-induced chromosomal mutagen sensitivity is associated with breast cancer risk in African-American women: caffeine modulates the outcome of mutagen sensitivity assay.

Several different cancer studies have indicated that lymphocyte mutagen sensitivity is a marker of DNA repair deficiency and increased cancer risk. We have used a mutagen sensitivity assay (MSA) measuring gamma-radiation-induced chromosomal aberrations in freshly cultured lymphocytes and assessed breast cancer risk in African-American women. Concurrently, we conducted duplicate cultures in the presence of caffeine, which overrides G(2) arrest in cultured cells, decreases time to DNA repair, and hence increases the aberration rate. In comparison with the non-caffeine-treated cells, we are conceptually segregating the contribution of DNA repair and time for DNA repair as individual susceptibility phenotypes. Blood samples were obtained from 61 cases and 86 controls at Howard University Hospital. Two sets of whole-blood cultures were established and gamma-irradiated (1 Gy) at 67 hours, one of which was treated with caffeine (1 mg/mL). Thereafter, cultures were processed for obtaining metaphase spreads. Fifty metaphases were screened for chromatid breaks. The mean breaks per cell (MBPC) for cases (0.34 +/- 0.15) was significantly greater than for controls (0.24 +/- 0.12; P < 0.0001). Using the 75th percentile value of controls as a cutoff to define mutagen sensitivity, the sensitive individuals had an odds ratio of 4.5 (95% confidence intervals, 2.2-9.1) for breast cancer compared with individuals that were not sensitive. The adjusted odds ratio was 3.3 (95% confidence intervals, 0.147-73.917), which was statistically significant but was limited by the small number of subjects. The results for caffeine co-culture were not predictive of breast cancer (MBPC: cases, 1.6 +/- 0.9 versus controls, 1.5 +/- 0.8; P = 0.8663). Comparing the MBPC for caffeine and non-caffeine cultures, there was a correlation in controls (n = 79; Spearman r = 0.4286; P < 0.0001), but not in cases (n = 58; Spearman r = 0.06609; P = 0.6221). This study indicates that the MSA phenotype is a risk factor for breast cancer in African-American women, with a significant effect observable even in small studies. The use of caffeine did not enhance the predictivity of MSA, but the correlation with non-caffeine cultures in controls indicates that the MSA phenotype is due to both DNA repair and G(2) arrest capacity.

Adult↗
PubMed2006

The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity.

We examined the expression levels of the multidrug resistance protein 5 (ABCC5) gene in non-small cell lung cancer (NSCLC) cell lines to clarify the relationship with the sensitivity to gemcitabine. The expression levels of ABCC5 were inversely correlated with gemcitabine sensitivity significantly (r = 0.628; P < 0.01) in 17 NSCLC cells, whereas the expression of ABCC5 in the gemcitabine-resistant NSCLC cell line H23/GEM-R was the same as that in parental NCI-H23 cells. Treatment with the ABCC5 inhibitor zaprinast altered the sensitivity to gemcitabine in ABCC5-expressing NSCLC cells. In addition, decreasing the expression of ABCC5 by small interfering RNA altered the cytotoxicity to gemcitabine. These results indicate that modulation of ABCC5 activity could be used to increase the gemcitabine sensitivity in NSCLC. Previously, we found a decreased expression of deoxycytidine kinase in H23/GEM-R cells, and further investigation in this study showed an increased expression of ribonucleotide reductase subunit 1 in H23/GEM-R cells. We therefore also examined the effect of modifying the expression of both genes on gemcitabine resistance. We found that using small interfering RNA to decrease the expression of ribonucleotide reductase subunit 1 resulted in a decreased resistance to gemcitabine in H23/GEM-R cells. Furthermore, pretreatment with pemetrexed resulted in an increased deoxycytidine kinase expression concomitant with the alteration of the resistance to gemcitabine in H23/GEM-R cells. The determinants for sensitivity and the acquired resistance in gemcitabine are quite different; nonetheless, modification of these factors may increase the efficacy of gemcitabine in the treatment of NSCLC.

Antimetabolites, Antineoplastic↗
PubMed1989

Enhancement of potassium-sensitive current in heart cells by pinacidil. Evidence for modulation of the ATP-sensitive potassium channel.

Pinacidil belongs to a novel group of compounds that enhance the potassium permeability of vascular smooth muscle. Evidence also exists that this drug enhances the potassium permeability of cardiac tissue. The purpose of the present investigation was to determine if pinacidil alters potassium-channel activity in heart and, if so, which potassium channel is the target. We used the whole-cell arrangement of the patch voltage clamp to record membrane currents from isolated guinea pig ventricular cells. In solutions designed to isolate potassium currents, pinacidil enhances a time-independent current positive to the potassium equilibrium potential. Current measured at voltages negative to the potassium equilibrium potential are essentially unaltered by the drug. The potassium sensitivity of outward current indicates that the target for the drug is a potassium channel. Experiments designed to test for voltage-dependent channel gating strongly suggest that the pinacidil-sensitive current is not voltage gated. Pinacidil-sensitive current is blocked by externally applied Ba2+, Cs+, and tetraethylammonium ion. In addition, it is potently blocked after external application of 100 nM glibenclamide. Taken along with the time- and voltage-independent properties of pinacidil-sensitive current, this pharmacology strongly suggests that the target for pinacidil in heart is the ATP-sensitive potassium channel.

Adenosine Triphosphate↗
PubMed1980

Gluten-sensitive enteropathy. Influence of histocompatibility type on gluten sensitivity in vitro.

We previously developed an in vitro organ culture system in which gluten exerts a toxic effect on intestinal mucosa of patients with active gluten-sensitive enteropathy. Gluten generally inhibits the epithelial cell maturation of intestinal biopsy specimens that otherwise occurs if the tissue is cultured for 24-48 h in a gluten-free medium. However, small intestinal mucosa from 15-20% of patients with proven gluten-sensitive enteropathy fails to manifest the expected gluten-induced damage in vitro. In the present study, we explored the relation between in vitro gluten-induced intestinal damage and the presence of HLA-B8. We determined whether the patients' histocompatibility type (HLA-B8 positive or negative) influenced the ability of gluten protein to inhibit epithelial cell maturation of cultured intestinal biopsy specimens from patients with gluten-sensitive enteropathy. Intestinal biopsies from 21 of 24 patients with gluten-sensitive enteropathy and HLA-B8 showed gluten-induced damage in vitro. On the other hand, intestinal biopsies from only 4 of 16 patients with gluten-sensitive enteropathy but without HLA-B8 showed gluten-induced damage in vitro. The difference in the effect of gluten in vitro between these two groups was statistically significant (P < 0.01). The data show a dichotomy between gluten-induced tissue damage in vivo and in vitro in HLA-B8 negative patients, suggesting that HLA-B8 is important for gluten to manifest a cytotoxic influence in organ culture.

Alkaline Phosphatase↗
PubMed1981

Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.

The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the "minimal modeling technique" in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (phi 1) and second-phase (phi 2) responsivity of the beta-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameters, SI. Lean and obese subjects were subdivided into good (KG greater than 1.5) and lower (KG less than 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (phi 2 77% lower than in good tolerance controls [P less than 0.03]), but insulin sensitivity was normal (P greater than 0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (SI diminished 60% [P less than 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (phi 1: P greater than 0.06; phi 2: P greater than 0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity (phi 2 . SI). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of phi 1 was to modulate the KG value within those groups whose overall tolerance was determined by phi 2 . SI. This phi 1 modulating influence was more pronounced among insulin sensitive (phi 1 vs. KG, r = 0.79) than insulin resistant (obese, low tolerance; phi 1 vs. KG, r = 0.91) subjects. This study demonstrates the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.

Body Weight↗
PubMed2003

Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice.

Hormone-sensitive lipase (HSL) is a major enzyme for triglyceride (TG) lipolysis in adipose tissue. In HSL-knockout mice, plasma free fatty acid and TG levels are low, associated with low liver TG content. Because a decreased hepatic insulin sensitivity has been reported to be associated with high liver TG levels, our aim was to determine whether a hepatic TG content lower than normal, as observed in HSL-knockout mice, leads to increased hepatic insulin sensitivity. Therefore, hyperinsulinemic clamp experiments in combination with D-(3)H-glucose were used. Furthermore, hepatic insulin receptor and phosphorylated protein kinase B (PKB-P)/akt were analyzed by Western blotting. No significant differences where observed in insulin-mediated whole-body glucose uptake between HSL-knockout and control mice. Interestingly, hepatic insulin sensitivity of HSL-knockout mice was increased, because insulin caused a greater reduction in endogenous glucose production ( approximately 71% compared with approximately 31% in control mice; P < 0.05), despite decreased plasma adiponectin levels. PKB/akt phosphorylation and phosphatidylinositol-3-kinase activity was significantly higher in livers of HSL-knockout mice after insulin stimulation. In HSL-knockout mice, reduced hepatic TG stores result in an increased suppressive effect of insulin on hepatic glucose production, in line with an increased hepatic PKB-P/akt and phosphatidylinositol-3 kinase activity. Thus, hepatic insulin sensitivity is indeed increased after reducing hepatic TG stores below normal.

Adiponectin↗
PubMed2003

Homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, and oral glucose insulin sensitivity index in nonobese, nondiabetic subjects with high-normal blood pressure.

To investigate the relationships between high-normal blood pressure (BP) and insulin resistance, we examined insulin sensitivity in 306 nonobese and nondiabetic Japanese subjects with various BP categories (optimal BP, normal BP, high-normal BP, and hypertension). Insulin sensitivity was measured from fasting plasma glucose and insulin values and those during a 75-g oral glucose tolerance test by five formulas: the homeostasis model assessment of insulin resistance (HOMA-R), the quantitative insulin sensitivity check index (QUICKI), the oral glucose insulin sensitivity (OGIS) index, and two insulin sensitivity indexes (ISI-composite and ISI-stumvoll). The HOMA-R was significantly higher, and the QUICKI was significantly lower in subjects with hypertension than in subjects with optimal BP. Both HOMA-R and QUICKI values showed that high-normal BP patients had a higher (but not significant) degree of insulin resistance than optimal BP patients. The OGIS index was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP. The ISI-composite was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP, and it was also significantly lower in subjects with hypertension than in subjects with normal BP. The ISI-stumvoll was significantly lower in subjects with high-normal BP or hypertension than in subjects with optimal BP. The OGIS index, ISI-composite, and ISI-stumvoll significantly decreased with increasing severity of BP status among the normotensive groups (optimal BP, normal BP, and high-normal BP). These findings indicate that insulin resistance is present even in the high-normal BP categories of nonobese and nondiabetic Japanese individuals.

Aged↗
PubMed2001

Comparison of measured and estimated indices of insulin sensitivity and beta cell function: impact of ethnicity on insulin sensitivity and beta cell function in glucose-tolerant and normotensive subjects.

Type 2 diabetes mellitus is the result of an imbalance between insulin sensitivity and beta cell function. Although the assessment of these 2 parameters is critical for various studies, the current methods are time consuming and labor intensive. Recently, new estimated indices have been proposed. We examined the impact of ethnicity on the indices of insulin sensitivity and beta cell function measured from the hyperglycemic clamp and compared the results to the estimated indices, proposed by Matsuda and DeFronzo and Stumvoll et al., from a standard oral glucose tolerance test in 105 healthy, glucose-tolerant, and normotensive subjects from 4 ethnic groups. Among the ethnic groups, differences were noted in the measured insulin sensitivity (P = 0.0006) and beta cell function (P = 0.006 for the first phase insulin response, P = 0.0002 for the second phase insulin response). Although the estimated indices correlated with the measured indices (r(2) = 0.5184--0.3014), the estimated indices barely detected the differences among the ethnic groups. Multivariate analysis confirmed that ethnicity had an independent impact for the measured indices, but had only a modest impact on the estimated insulin sensitivity indices and had no impact on the estimated indices of beta cell function. We conclude that although the estimated indices of insulin sensitivity and beta cell function from the oral glucose tolerance test correlated with the measured ones in a wide spectrum of healthy, glucose-tolerant, and normotensive subjects, they were much less likely to detect the differences than measured ones among the ethnic groups.

Adolescent↗
PubMed1995

Possible involvement of a small G-protein sensitive to exoenzyme C3 of Clostridium botulinum in the regulation of myofilament Ca2+ sensitivity in beta-escin skinned smooth muscle of guinea pig ileum.

The effects of exoenzyme C3 of Clostridium botulinum on Ca(2+)- and drug-induced tension developments were investigated in beta-escin skinned smooth muscle of guinea pig ileum to test the involvement of a small G-protein in the regulation of myofilament Ca2+ sensitivity. C3 is known to ADP-ribosylate the rho p21 family of small G-proteins. Treatment with C3 (0.35 microgram/ml, for 30 min) shifted the pCa-tension curve rightward along the Ca2+ concentration axis, indicating a decrease in Ca2+ sensitivity of the contractile elements. The inhibitory effect of C3 was not preserved after treatment with GDP beta S (1 mM), an antagonist of GTP for the binding to G-proteins. Stimulation of muscarinic receptors with carbachol (CCh, 100 microM) shifted the pCa-tension curve leftward, indicating Ca2+ sensitization of tension development. The Ca(2+)-sensitizing effect of CCh was not observed after C3 treatment. When GTP gamma S (10 microM), an activator of G-proteins, was applied at a plateau of tension development produced by a moderate concentration of Ca2+, further increase in tension was elicited and the effect of GTP gamma S was inhibited by C3 treatment. The results suggest the possible involvement of a rho p21-like small G-protein in the regulation of Ca2+ sensitivity of smooth muscle myofilaments.

Animals↗